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Sample records for gemcitabine etoposide cisplatin

  1. Economic value of gemcitabine compared to cisplatin and etoposide in non-small cell lung cancer.

    PubMed

    Copley-Merriman, C; Corral, J; King, K; Whiteside, R; Voi, M; Dorr, F A; McDonald, R C

    1996-02-01

    Although chemotherapy costs have not been highlighted traditionally, there is increasing pressure to demonstrate the value of new treatments within the health care budget. Pharmaceutical companies are assessing the economic value of their products before launch. Gemcitabine is a nucleoside analogue developed for use in solid tumours. The purpose of this model was to investigate the clinical outcomes and potential cost savings for gemcitabine used as monotherapy compared to cisplatin and etoposide combination therapy in late stage non-small cell lung cancer (NSCLC), in a palliative (as opposed to aggressive) chemotherapy setting. Gemcitabine treatment data were taken from a large NSCLC study and data from retrospective chart reviews identified through the National Oncology Data Base. The model population and effectiveness of the two regimens were judged to be similar, except for baseline performance status. If drug costs were not included, the probability distribution resulting from the simulation showed median cost savings per cycle ranging from $US 1504 to $US 7425, with a medium value of $US 2154. The model suggested that gemcitabine would result in cost savings per cycle more than 90% of the time. Outpatient versus inpatient drug administrations accounted for the majority of potential cost savings. Most of the remaining cost savings were attributable to the difference in febrile neutropenia and antiemetic use. This economic model showed susbstantial savings if gemcitabine was used instead of cisplatin and etoposide combination therapy in the United States' community care setting. Some savings would be realized even if the location of treatment for both regimens was mostly outpatient. Assessment of the product's economic value before launch has assisted in our understanding of the potential areas of cost savings for gemcitabine and has guided us in the design of prospective randomized studies which included pharmacoeconomic endpoints. PMID:8696720

  2. Phase II study of induction chemotherapy with gemcitabine and vinorelbine followed by concurrent chemoradiotherapy with oral etoposide and cisplatin in patients with inoperable stage III non-small-cell lung cancer

    SciTech Connect

    Lee, Dae Ho; Han, Ji-Youn; Cho, Kwan Ho; Pyo, Hong Ryull; Kim, Hyae Young; Yoon, Sung Jin B.S.; Lee, Jin Soo . E-mail: jslee@ncc.re.kr

    2005-11-15

    Purpose: For locoregionally advanced inoperable non-small-cell lung cancer (NSCLC), concurrent chemoradiotherapy has become a standard therapy. We conducted a Phase II trial to examine the efficacy and toxicity of adding gemcitabine and vinorelbine induction chemotherapy to concurrent chemoradiotherapy with oral etoposide and cisplatin. Methods and Materials: Eligibility included inoperable clinical Stage III NSCLC without pleural effusion, ECOG performance status 0-1, and weight loss {<=}5%. Induction chemotherapy consisted of three cycles of gemcitabine 1,000 mg/m{sup 2} and vinorelbine 30 mg/m{sup 2}, each given i.v. on Days 1 and 8, every 3 weeks. During once-daily thoracic radiotherapy (1.8 Gy/day, total 63 Gy), two cycles of oral etoposide (100 mg on Days 1-5 and 8-12) plus cisplatin (50 mg/m{sup 2} on Days 1 and 8) were given concurrently 4 weeks apart. Results: Between April 2002 and November 2003, 42 patients were enrolled and 40 were included in response and toxicity evaluation. The median age was 59 years and 13 patients had IIIA and 27 had IIIB; 24 had squamous ca, 12 had adenocarcinoma, and 4 had others. Objective tumor responses were obtained in 29 patients (72.5%), including 18 (45.0%) after induction chemotherapy. After a median follow-up of 23.8 months, the median survival time and progression-free survival was 23.2 months and 10.9 months, respectively, with 2-year survival rate of 43.9%. For the patients with supraclavicular nodal involvement, the median survival time was 11.8 months with 2-year survival rate of 16.7%, whereas the corresponding figures were 27.8 months and 52.0%, respectively, for those without supraclavicular nodal involvement. Toxicity of induction chemotherapy was mild and well tolerated. However, concurrent chemoradiotherapy was associated with G3/4 hematologic toxicity in 75.7%, G3 esophagitis in 24.2%, and two treatment-related deaths. There were nonlife-threatening late toxicities in additional 6 patients. Conclusions

  3. Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin

    PubMed Central

    Mitry, E; Baudin, E; Ducreux, M; Sabourin, J-C; Rufié, P; Aparicio, T; Lasser, P; Elias, D; Duvillard, P; Schlumberger, M; Rougier, P

    1999-01-01

    The purpose of this study was to evaluate by a retrospective analysis of 53 patients the efficacy of chemotherapy combining etoposide and cisplatin in the treatment of neuroendocrine tumours. The regimen was a combination of etoposide 100 mg m–2 day–1 for 3 days and cisplatin 100 mg m–2 on day 1, given by 2-h intravenous infusion, administered every 21 days. Twelve patients had a well-differentiated and 41 a poorly differentiated neuroendocrine tumour. Toxicity of treatment was assessed in 50 patients and efficacy in 52 patients. Among the 11 patients with a well-differentiated tumour evaluable for tumoural response, only one (9.4%) had a partial response for 8.5 months. Forty-one patients with a poorly differentiated tumour showed an objective response rate of 41.5% (four complete and 13 partial responses); the median duration of response was 9.2 months, the median overall survival 15 months and the median progression-free survival 8.9 months. Haematological grade 3–4 toxicity was observed in 60% of the cases with one treatment-related death, digestive grade 3–4 toxicity in 40% and grade 3 alopecia was constant. No severe renal, hearing and neurological toxicities were observed (grade 1 in 6%, 14%, 72% respectively and no grade >1). We confirm that poorly differentiated neuroendocrine tumours are chemosensitive to the etoposide plus cisplatin combination. However, the prognosis remains poor with a 2-year survival lower than 20% confirming that new therapeutic strategies have to be developed. © 1999 Cancer Research Campaign PMID:10604732

  4. Schedule-dependent response of neuroblastoma cell lines to combinations of etoposide and cisplatin

    PubMed Central

    Meczes, E L; Pearson, A D J; Austin, C A; Tilby, M J

    2002-01-01

    The growth inhibitory effects of cisplatin and etoposide on neuroblastoma cell lines were investigated in several scheduled combinations. Results were analyzed using median effect and combination index analyses. In all schedules in which cisplatin was administered prior to etoposide a synergistic effect was observed. Conversely, an antagonistic effect was seen in all schedules where etoposide was administered before cisplatin. British Journal of Cancer (2002) 86, 485–489. DOI: 10.1038/sj/bjc/6600060 www.bjcancer.com © 2002 The Cancer Research Campaign PMID:11875719

  5. Pharmacoeconomic benefit of cisplatin and etoposide chemoregimen for metastatic non small cell lung cancer: An Indian study

    PubMed Central

    Kamath, Mangesh P; Lakshmaiah, KC; Babu, K Govind; Loknatha, D; Jacob, Linu A; Babu, Suresh MC

    2016-01-01

    Background: The incidence of lung cancer is rising in developing countries like India. Due to unaffordability among the low socioeconomic status (SES) patients, there is a significant delay in seeking appropriate medical treatment due to which a high proportion of patients present in an advanced/metastatic stage and the outcomes are poor. Objective: In this study, we studied the progression-free survival (PFS) and the pharmacoeconomic benefits with the cisplatin plus etoposide (EtoP) chemo regimen and compared it with the current generation chemo regimen. Materials and Methods: We performed a retrospective analysis of metastatic nonsmall cell lung cancer patients who received one or more cycles of platinum-based chemotherapy between 2011 and 2014. Results: Of the 304 patients, 56.6% of the patients were of the low SES. Of the low socioeconomic group patients, 67.45% and 31.4% received etoposide and paclitaxel platinum doublet combination regimen as first line, respectively. The mean PFS with the etoposide, paclitaxel, pemetrexed, and gemcitabine platinum-based doublet regimens were 9.35, 10, 10.76, and 9.83 months, respectively. Kaplan–Meier survival curve analysis showed a statistically significant initial survival with the first line EtoP cisplatin regimen for the initial 6 months of starting chemotherapy in comparison with the other regimens. Conclusions: This study showed a substantial pharmacoeconomic benefit with the cisplatin and etoposide chemo regimen in the lower socioeconomic group of patients. We believe that this is the first pharmacoeconomic study on metastatic non small cell lung treatment of great relevance to countries with limited resources. PMID:27051102

  6. Cisplatin/gemcitabine or oxaliplatin/gemcitabine in the treatment of advanced biliary tract cancer: a systematic review

    PubMed Central

    Fiteni, Frédéric; Nguyen, Thierry; Vernerey, Dewi; Paillard, Marie-Justine; Kim, Stefano; Demarchi, Martin; Fein, Francine; Borg, Christophe; Bonnetain, Franck; Pivot, Xavier

    2014-01-01

    Cisplatin/gemcitabine association has been a standard of care for first-line regimen in advanced biliary tract cancer nevertheless oxaliplatin/gemcitabine regimen is frequently preferred. Because comparative effectiveness in clinical outcomes of cisplatin- versus oxaliplatin-containing chemotherapy is not available, a systematic review of studies assessing cisplatin/gemcitabine or oxaliplatin/gemcitabine chemotherapies in advanced biliary tract cancer was performed. Published studies evaluating cisplatin/gemcitabine or oxaliplatin/gemcitabine in advanced biliary tract cancer were included. Each study was weighted according to the number of patients included. The primary objective was to assess weighted median of medians overall survival (mOS) reported for both regimens. Secondary goals were to assess weighted median of medians progression-free survival (mPFS) and toxic effects were pooled and compared within each arm. Thirty-three studies involving 1470 patients were analyzed. In total, 771 and 699 patients were treated by cisplatin/gemcitabine and oxaliplatin/gemcitabine, respectively. Weighted median of mOS was 9.7 months in cisplatin group and 9.5 months in oxaliplatin group. Cisplatin-based chemotherapy was significantly associated with more grade 3 and 4 asthenia, diarrhea, liver toxicity, and hematological toxicity. Sensitivity analysis including only the studies with the standard regimen of cisplatin (25–35 mg/m2 administered on days 1 and 8) showed that the weighted median of mOS increased from 9.7 to 11.7 months but Gem/CDDP regimen remained more toxic than Gemox regimen. These results suggest that the Gem/CDDP regimen with cisplatin (25–35 mg/m2) administered on days 1 and 8 is associated with survival advantage than Gemox regimen but with addition of toxicity. PMID:25111859

  7. Wortmannin potentiates the combined effect of etoposide and cisplatin in human glioma cells.

    PubMed

    Pastwa, Elzbieta; Poplawski, Tomasz; Lewandowska, Urszula; Somiari, Stella B; Blasiak, Janusz; Somiari, Richard I

    2014-08-01

    The combination of etoposide and cisplatin represents a common modality for treating of glioma patients. These drugs directly and indirectly produce the most lethal DNA double-stand breaks (DSB), which are mainly repaired by non-homologous DNA end joining (NHEJ). Drugs that can specifically inhibit the kinase activity of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), the major component of NHEJ, are of special interest in cancer research. These small molecule inhibitors can effectively enhance the efficacy of current cancer treatments that generate DNA damage. In this study, we investigated the effect of DNA-PKcs inhibitor, wortmannin, on the cytotoxic mechanism of etoposide and cisplatin in MO59K and MO59J human glioblastoma cell lines. These cell lines are proficient and deficient in DNA-PKcs, respectively. Wortmannin synergistically increased the cytotoxicity of cisplatin and etoposide, when combined, in NHEJ-proficient MO59K cells. Surprisingly, wortmannin sensitizing effect was also observed in DNA-PKcs-deficient MO59J cells. These data suggest that wortmannin sensitization to etoposide and cisplatin in human glioma cells is mediated by inhibition of not only DNA-PKcs activity but other enzymes from PI3-K family, e.g. ATM and ATR. A concentration-dependent increase in etoposide and cisplatin-induced DSB levels was potentiated by inhibitor in both cell lines. Moreover, drug-induced accumulation in the G2/M checkpoint and S-phase was increased by wortmannin. Wortmannin significantly inhibited drug-induced DSB repair in MO59 cells and this effect was more pronounced in MO59J cells. We conclude that the mechanism of wortmannin potentiation of etoposide and cisplatin cytotoxicity involves DSBs induction, DSBs repair inhibition, G2/M checkpoint arrest and inhibition of not only DNA-PKcs activity. PMID:24953561

  8. Pooled Analysis of Clinical Outcomes with Neoadjuvant Cisplatin and Gemcitabine Chemotherapy for Muscle Invasive Bladder Cancer

    PubMed Central

    Yuh, Bertram E.; Ruel, Nora; Wilson, Timothy G.; Vogelzang, Nicholas; Pal§, Sumanta K.

    2014-01-01

    Purpose Neoadjuvant chemotherapy for muscle invasive bladder cancer has been shown to confer a survival advantage in phase III studies. Although cisplatin and gemcitabine are often used in this setting, a comprehensive evaluation of this regimen is lacking. In this review we summarize the efficacy of neoadjuvant cisplatin and gemcitabine chemotherapy for muscle invasive bladder cancer based on currently published studies. Materials and Methods A systematic literature review was conducted in April 2012 searching MEDLINE® databases. Articles were selected if they included patients with muscle invasive bladder cancer, evaluated the combination of cisplatin and gemcitabine as neoadjuvant treatment, and reported pathological data after cystectomy. Cisplatin and gemcitabine dosing regimens and clinical data were further summarized using weighted averages. Results Seven studies encompassing 164 patients were published between 2007 and 2012. The majority of patients (79%) received cisplatin and gemcitabine on a 21-day cycle. A weighted average of 19.2 lymph nodes was obtained at cystectomy, and 29.7% of patients were found to have pN1 disease. Pathological down staging to pT0 and less than pT2 occurred in 42 (25.6%) and 67 (46.5%) patients, respectively. Conclusions Neoadjuvant cisplatin and gemcitabine yield appreciable pathological response rates in patients with muscle invasive bladder cancer. Since pathological response has been implicated as a potential surrogate for survival in muscle invasive bladder cancer, these data suggest that neoadjuvant cisplatin and gemcitabine may warrant further prospective assessment. PMID:23123547

  9. Gemcitabine Plus Cisplatin for Advanced Biliary Tract Cancer: A Systematic Review

    PubMed Central

    Park, Joon Oh; Oh, Do-Youn; Hsu, Chiun; Chen, Jen-Shi; Chen, Li-Tzong; Orlando, Mauro; Kim, Jong Seok; Lim, Ho Yeong

    2015-01-01

    Evidence suggests that combined gemcitabine-cisplatin chemotherapy extends survival in patients with advanced biliary tract cancer (BTC). We conducted a systematic review in order to collate this evidence and assess whether gemcitabine-cisplatin efficacy is influenced by primary tumor site, disease stage, or geographic region, and whether associated toxicities are related to regimen. MEDLINE (1946-search date), EMBASE (1966-search date), ClinicalTrials. gov (2008-search date), and abstracts from major oncology conferences (2009- search date) were searched (5 Dec 2013) using terms for BTC, gemcitabine, and cisplatin. All study types reporting efficacy (survival, response rates) or safety (toxicities) outcomes of gemcitabine-cisplatin in BTC were eligible for inclusion; efficacy data were extracted from prospective studies only. Evidence retrieved from one meta-analysis (abstract), four randomized controlled trials, 12 nonrandomized prospective studies, and three retrospective studies supported the efficacy and safety of gemcitabine-cisplatin for BTC. Median overall survival ranged from 4.6 to 11.7 months, and response rate ranged from 17.1% to 36.6%. Toxicities were generally acceptable and manageable. Heterogeneity in study designs and data collected prevented formal meta-analysis, however exploratory assessments suggested that efficacy did not vary with primary tumor site (gallbladder vs. others), disease stage (metastatic vs. locally advanced), or geographic origin (Asia vs. other). Incidence of grade 3/4 toxicities was not related to gemcitabine dose or cisplatin frequency. Despite individual variation in study designs, the evidence presented suggests that gemcitabine-cisplatin is effective in patients from a diverse range of countries and with heterogeneous disease characteristics. No substantial differences in toxicity were observed among the different dosing schedules of gemcitabine and cisplatin. PMID:25989801

  10. Salvage chemotherapy for ovarian cancer recurrence: weekly cisplatin in combination with epirubicin or etoposide.

    PubMed

    Zanaboni, F; Scarfone, G; Presti, M; Maggi, R; Borello, C; Bolis, G

    1991-10-01

    From December 1986 to April 1990, 40 consecutive ovarian cancer patients who relapsed after response to cisplatin-based chemotherapy regimens were treated with seven courses of weekly cisplatin, in combination with epirubicin or etoposide. The overall response rate obtained with the intensive schedule was 60% and the complete response rate was 25%; median duration of response was 7 months and median survival time, 13.5 months. Responsive cases seem to have longer survival; a prognostic factor for response to salvage treatment and longer survival is the disease-free interval after the first-line chemotherapy. Weekly cisplatin as intensive treatment was very well tolerated and showed acceptable toxicity in both the combination protocols with epirubicin or etoposide. PMID:1959783

  11. Complete Resolution of Metastatic Gallbladder Cancer after Standard Gemcitabine-Cisplatin Combination Therapy

    PubMed Central

    Barrera, Ivan; Metrakos, Peter; Kavan, Petr

    2015-01-01

    Gallbladder carcinoma (GBC) is a rare and deadly disease. The only curative option is a total surgical resection. If the disease is inoperable, palliative combination chemotherapy with gemcitabine-cisplatin remains the standard of care. We present here a case of a 47-year-old gentleman diagnosed with metastatic GBC who saw a complete resolution of his disease with seven cycles of standard gemcitabine-cisplatin chemotherapy. This case illustrates the importance of multidisciplinary care to explore all available options to provide optimal and tailored patient care. PMID:26848408

  12. Induction gemcitabine in standard dose or prolonged low-dose with cisplatin followed by concurrent radiochemotherapy in locally advanced non-small cell lung cancer: a randomized phase II clinical trial

    PubMed Central

    Vrankar, Martina; Zwitter, Matjaz; Bavcar, Tanja; Milic, Ana; Kovac, Viljem

    2014-01-01

    Background The optimal combination of chemotherapy with radiation therapy for treatment locally advanced non-small cell lung cancer (NSCLC) remains an open issue. This randomized phase II study compared gemcitabine in two different schedules and cisplatin - as induction chemotherapy, followed by radiation therapy concurrent with cisplatin and etoposid. Patients and methods. Eligible patients had microscopically confirmed inoperable non-metastatic non-small cell lung cancer; fulfilled the standard criteria for platin-based chemotherapy; and signed informed consent. Patients were treated with 3 cycles of induction chemotherapy with gemcitabine and cisplatin. Two different aplications of gemcitabine were compared: patients in arm A received gemcitabine at 1250 mg/m2 in a standard half hour i.v. infusion on days 1 and 8; patients in arm B received gemcitabine at 250 mg/m2 in prolonged 6-hours i.v. infusion on days 1 and 8. In both arms, cisplatin 75 mg/m2 on day 2 was administered. All patients continued treatment with radiation therapy with 60–66 Gy concurrent with cisplatin 50 mg/m2 on days 1, 8, 29 and 36 and etoposid 50 mg/m2 on days 1–5 and 29–33. The primary endpoint was response rate (RR) after induction chemotherapy; secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). Results From September 2005 to November 2010, 106 patients were recruited to this study. No statistically signifficant differences were found in RR after induction chemotherapy between the two arms (48.1% and 57.4%, p = 0.34). Toxicity profile was comparable and mild with grade 3/4 neutropenia as primary toxicity in both arms. One patient in arm B suffered from acute peripheral ischemia grade 4 and an amputation of lower limb was needed. With a median follow-up of 69.3 months, progression-free survival and median survival in arm A were 15.7 and 24.8 months compared to 18.9 and 28.6 months in arm B. The figures for 1- and 3-year overall survival were

  13. Acute gastroduodenal mucosal injury after cisplatin plus etoposide chemotherapy. Clinical and endoscopic study.

    PubMed

    Sartori, S; Nielsen, I; Maestri, A; Beltrami, D; Trevisani, L; Pazzi, P

    1991-01-01

    The effects on gastric and duodenal mucosa induced by cisplatin plus etoposide (PE) chemotherapy were investigated in 32 patients with lung cancer. They were submitted to gastroduodenoscopy before receiving cisplatin 100 mg/m2 (day 1) plus etoposide at a mean dose of 107 mg/m2 (days 1, 3 and 5). Endoscopic examination was repeated on day 8. Before chemotherapy, 22 patients showed normal endoscopic appearance and 10 minimal lesions (3 or fewer erosions). After chemotherapy, 16 remained normal, 1 had minimal lesions and 15 developed major lesions: 11 gastric or duodenal multiple erosions, 1 diffuse erosive gastritis, 2 gastric and 1 duodenal ulcer (p less than 0.001). No difference was observed in the number of vomiting episodes nor in severity of upper gastrointestinal symptoms between the patients who remained normal and those who developed mucosal injury. We conclude that PE chemotherapy can have a properly called gastroduodenal toxicity, leaving nausea and vomiting out which are rather due to central than peripheral mechanisms. Some trials are necessary to investigate which kind of drugs (H2-receptor blockers, sucralfate, prostaglandin E analogues) may be useful in preventing acute gastroduodenal mucosal injury induced by PE chemotherapy. PMID:1745480

  14. E5501 - Phase II Study of Topotecan Sequenced with Etoposide/Cisplatin, and Irinotecan/Cisplatin Sequenced with Etoposide for Extensive Stage Small Cell Lung Cancer

    PubMed Central

    Owonikoko, Taofeek K.; Aisner, Joseph; Wang, Xin Victoria; Dahlberg, Suzanne E.; Rubin, Eric H.; Ramalingam, Suresh S.; Gounder, Murugesan; Rausch, Paul Gregory; Axelrod, Rita S.; Schiller, Joan H.

    2015-01-01

    Purpose Sequence dependent improved efficacy of topoisomerase I followed by topoisomerase 2 inhibitors was assessed in a randomized phase II study in extensive-stage small cell lung cancer (SCLC). Methods Patients with previously untreated extensive stage SCLC with measurable disease, ECOG performance status of 0 to 3 and stable brain metastases were eligible. Arm A consisted of topotecan (0.75 mg/m2) on days 1, 2 and 3, etoposide (70 mg/m2) and cisplatin (20 mg/m2) [PET] on days 8, 9 and 10 in a 3-week cycle. Arm B consisted of irinotecan (50 mg/m2) and cisplatin (20 mg/m2) on days 1 and 8 followed by etoposide (85 mg/m2 PO bid) on days 3 and 10 [PIE] in a 3-week cycle. Results We enrolled 140 patients and randomized 66 eligible patients to each arm. Only 54.5% of all patients completed the planned maximum 6 cycles. There were grade ≥3 treatment-related adverse events in approximately 70% of the patients on both arms including 6 treatment-related grade 5 events. The overall response rates (CR+PR) were 69.7% (90% CI: 59.1–78.9%, 95% CI: 57.1–80.4%) for arm A and 57.6% (90% CI: 46.7–67.9%, 95% CI:44.8–69.7%) for arm B. The median PFS and OS were 6.4 months (95% CI: 5.4–7.5 months) and 11.9 months (95% CI: 9.6–13.7 months) for arm A and 6.0 months (95% CI: 5.4–7.0 months) and 11.0 months (95% CI: 8.6–13.1 months) for arm B. Conclusion Sequential administration of topoisomerase inhibitors did not improve on the historical efficacy of standard platinum-doublet chemotherapy for extensive stage SCLC. PMID:24288121

  15. A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma

    PubMed Central

    Nowak, A K; Byrne, M J; Williamson, R; Ryan, G; Segal, A; Fielding, D; Mitchell, P; Musk, A W; Robinson, B W S

    2002-01-01

    Our previous phase II study of cisplatin and gemcitabine in malignant mesothelioma showed a 47.6% (95% CI 26.2–69.0%) response rate with symptom improvement in responding patients. Here we confirm these findings in a multicentre setting, and assess the effect of this treatment on quality of life and pulmonary function. Fifty-three patients with pleural malignant mesothelioma received cisplatin 100 mg m−2 i.v. day 1 and gemcitabine 1000 mg m−2 i.v. days 1, 8, and 15 of a 28 day cycle for a maximum of six cycles. Quality of life and pulmonary function were assessed at each cycle. The best response achieved in 52 assessable patients was: partial response, 17 (33%, 95% CI 20–46%); stable disease, 31 (60%); and progressive disease, four (8%). The median time to disease progression was 6.4 months, median survival from start of treatment 11.2 months, and median survival from diagnosis 17.3 months. Vital capacity and global quality of life remained stable in all patients and improved significantly in responding patients. Major toxicities were haematological, limiting the mean relative dose intensity of gemcitabine to 75%. This schedule of cisplatin and gemcitabine is active in malignant mesothelioma in a multicentre setting. Investigation of alternative scheduling is needed to decrease haematological toxicity and increase the relative dose intensity of gemcitabine whilst maintaining response rate and quality of life. British Journal of Cancer (2002) 87, 491–496. doi:10.1038/sj.bjc.6600505 www.bjcancer.com © 2002 Cancer Research UK PMID:12189542

  16. Phase Ib study of dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin in patients with advanced solid tumors

    PubMed Central

    Galsky, Matthew D.; Posner, Marshall; Holcombe, Randall F; Lee, Karen M.; Misiukiewicz, Krzysztof; Tsao, Che-Kai; Godbold, James; Soto, Rothschild; Gimpel-Tetra, Kiev; Lowe, Nancy; Oh, William K.

    2014-01-01

    Purpose Dovitinib is a small molecule kinase inhibitor with activity against the fibroblast growth factor and vascular endothelial growth factor receptor families. The purpose of this phase Ib study was to define the recommended phase 2 dose of the combinations of gemcitabine and cisplatin or gemcitabine and carboplatin plus dovitinib. Methods Patients with advanced solid tumors were enrolled in two parallel dose escalation arms (cisplatin- or carboplatin-based regimens). Treatment was administered with gemcitabine (1000 mg/m2 on days 1 and 8), cisplatin (70 mg/m2) or carboplatin (AUC 5) on day 1, and dovitinib (orally on days 1-5, 8-12 and 15-19), every 21 days. The starting dose of dovitinib was 300 mg and was dose escalated in successive cohorts using 3+3 dose escalation rules. Results Fourteen patients with advanced solid tumors were enrolled, 5 to the cisplatin arm and 9 to the carboplatin arm. Patients enrolled in the cisplatin arm received a median of 2 cycles of treatment (range, 1-5) and patients enrolled in the carboplatin arm received a median of 1 cycle of treatment (range, 1-4). There were no protocol-defined dose-limiting toxicities in the cisplatin arm. However, the cohort was closed due to the need for frequent dose delays and/or reductions and two patients experiencing severe thromboembolic events. There were two dose-limiting toxicities in the carboplatin arm at the starting dose level of dovitinib (both prolonged neutropenia) and the dose of dovitinib was de-escalated to 200 mg. Two additional dose-limiting toxicities (prolonged neutropenia and febrile neutropenia) occurred in the lower dose cohort and the study was closed. No patients achieved an objective response to treatment. Conclusions Dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin was poorly tolerated due to myelosuppression. PMID:25023489

  17. Advanced adult esthesioneuroblastoma successfully treated with cisplatin and etoposide alternated with doxorubicin, ifosfamide and vincristine.

    PubMed

    Turano, Salvatore; Mastroianni, Candida; Manfredi, Caterina; Biamonte, Rosalbino; Ceniti, Silvia; Liguori, Virginia; De Simone, Rosanna; Conforti, Serafino; Filice, Aldo; Rovito, Antonio; Viscomi, Caterina; Patitucci, Giuseppe; Palazzo, Salvatore

    2010-05-01

    The esthesioneuroblastoma is a rare neuroendocrine tumor that derives from the olfactory cells. In the last 20 years, around 1,000 cases have been described, with an overall survival rate of 60-70% at 5 years. The most common symptoms are nasal bleeding, nasal clogging and, in locally advanced cases, signs/symptoms of intracranic hypertension such as papilla edema, cefalea, and vomiting. The standard treatments are surgery and radiotherapy. Chemotherapy can be used in an adjuvant/neoadjuvant setting and in the metastatic phase, even if its role is still not established with certainty. Here, the case is reported of a young man (38 years old) with a locally advanced esthesioneuroblastoma. Two months before coming to our clinic, he had been treated elsewhere with debulking surgery through bilateral frontal craniotomy. After surgery, MRI showed residual disease in the nasal cavities and in the medial wall of the orbits responsible for blindness and bilateral exophthalmos within a month: a very short time. Octreoscan and whole body CT scan confirmed a locally advanced disease, in the absence of metastases. Chemotherapy was begun with cisplatin and etoposide alternated with doxorubicin, ifosfamide and vincristine with granulocyte colony-stimulating factor (G-CSF) support after every cycle. Soon after the first cycle, an important reduction of pain and decrease of the exophthalmos and vertigos was observed. No improvement in blindness was seen. The patient is still stable after 24 months of follow up. PMID:19924514

  18. Cisplatin, Gemcitabine, and Lapatinib as Neoadjuvant Therapy for Muscle-Invasive Bladder Cancer

    PubMed Central

    Narayan, Vivek; Mamtani, Ronac; Keefe, Stephen; Guzzo, Thomas; Malkowicz, S. Bruce; Vaughn, David J.

    2016-01-01

    Purpose We sought to investigate the safety and efficacy of gemcitabine, cisplatin, and lapatinib (GCL) as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC) planned for radical cystectomy. Materials and Methods Four cycles of GCL were administered as neoadjuvant therapy for patients with MIBC. Although initially designed as a phase II efficacy study with a primary endpoint of pathologic complete response at the time of radical cystectomy, the dose selected for investigation proved excessively toxic. A total of six patients were enrolled. Results The initial four patients received gemcitabine 1,000 mg/m2 intravenously on days 1 and 8 and cisplatin 70 mg/m2 intravenously on day 1 of each 21-day treatment cycle. Lapatinib was administered as 1,000 mg orally daily starting one week prior to the initiation of cycle 1 of gemcitabine and cisplatin (GC) and continuing until the completion of cycle 4 of GC. These initial doses were poorly tolerated, and the final two enrolled patients received a reduced lapatinib dose of 750 mg orally daily. However, reduction of the lapatinib dose did not result in improved tolerance or drug-delivery, and the trial was terminated early due to excessive toxicity. Grade 3/4 toxicities included diarrhea (33%), nausea/vomiting (33%), and thrombocytopenia (33%). Conclusion The addition of lapatinib to GC as neoadjuvant therapy for MIBC was limited by excessive treatment-related toxicity. These findings highlight the importance of thorough dose-escalation investigation of combination therapies prior to evaluation in the neoadjuvant setting, as well as the limitations of determination of maximum tolerated dose for novel targeted combination regimens. PMID:26639198

  19. Gemcitabine and cisplatin as neo-adjuvant chemotherapy for non-small cell lung cancer: a phase II study.

    PubMed

    Aydiner, Adnan; Kiyik, Murat; Cikrikcioglu, Saadettin; Kosar, Filiz; Gurses, Atilla; Turna, Akif; Yazar, Aziz; Dilege, Sukru; Goksel, Tuncay; Cakan, Alpaslan

    2007-11-01

    The combination of gemcitabine and cisplatin is one of the most active chemotherapy regimens against non-small cell lung cancer (NSCLC). This study was designed to evaluate the efficacy and safety of gemcitabine combined with cisplatin in a 3-week cycle regimen for patients with operable, early stage NSCLC. Gemcitabine at a dose of 1000 mg/m(2) on days 1 and 8 of each 21-day cycle for 3 cycles, followed by cisplatin at a dose of 75 mg/m(2) on day 1 was administered to patients with previously untreated, operable, early stage (IB-IIIA) NSCLC. A total of 47 patients (46 male, mean age 56.0+/-8.0 years) who met the eligibility criteria were enrolled. The pathological complete response rate was 5.3% of operated patients and 4.3% of total patients. At visit 4, 57.1% of the patients had partial response, 38.1%, stable disease and 4.8%, progressive disease. The main toxicities - leukopenia, neutropenia and thrombocytopenia - were usually clinically asymptomatic and did not require hospitalization. Non-hematological toxicities were minimal and manageable. Disease free and 12-month overall survival rates were over 70% and 80%, respectively. This study demonstrates that the administration of gemcitabine and cisplatin combination for 3 cycles is effective and tolerable for patients with operable, early stage NSCLC. Low toxicity profile and promising survival outcome suggest that this regimen has an encouraging activity in this subset of patients. PMID:17683827

  20. Gemcitabine and carboplatin for patients with advanced non-small cell lung cancer.

    PubMed

    Dómine, M; Casado, V; Estévez, L G; León, A; Martin, J I; Castillo, M; Rubio, G; Lobo, F

    2001-06-01

    The survival of patients with advanced non-small cell lung cancer remains poor. Cisplatin-based chemotherapy produces a modest benefit in survival compared with that observed with best supportive care. Gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN), a novel nucleoside antimetabolite, is active and well tolerated. The combination of gemcitabine/cisplatin has shown a significant improvement in response rate and survival over cisplatin alone. Phase III trials comparing gemcitabine/cisplatin with older combinations such as cisplatin/etoposide or mitomycin/ifosfamide/cisplatin have shown a higher activity for gemcitabine/cisplatin; however, the best way to combine these drugs remains unclear. In addition, the 3-week schedule has obtained a higher dose intensity with less toxicity and similar efficacy as the 4-week schedule. The role of carboplatin in combination with new drugs is still under evaluation. Gemcitabine/carboplatin seems to be a good alternative, with the advantage of ambulatory administration and lower nonhematologic toxicity. The 4-week schedule has produced frequent grade 3/4 neutropenia and thrombocytopenia in some studies. The 3-week schedule, using gemcitabine on days 1 and 8 and carboplatin on day 1, is a convenient and well-tolerated regimen. The toxicity profile is acceptable without serious symptoms. This schedule could be considered a good option as a standard regimen. Semin Oncol 28 (suppl 10):4-9. PMID:11510027

  1. The synergistic effects of DNA-damaging drugs cisplatin and etoposide with a histone deacetylase inhibitor valproate in high-risk neuroblastoma cells.

    PubMed

    Groh, Tomas; Hrabeta, Jan; Khalil, Mohammed Ashraf; Doktorova, Helena; Eckschlager, Tomas; Stiborova, Marie

    2015-07-01

    High-risk neuroblastoma remains one of the most important therapeutic challenges for pediatric oncologists. New agents or regimens are urgently needed to improve the treatment outcome of this fatal tumor. We examined the effect of histone deacetylase (HDAC) inhibitors in a combination with other chemotherapeutics on a high-risk neuroblastoma UKF-NB-4 cell line. Treatment of UKF-NB-4 cells with DNA-damaging chemotherapeutics cisplatin or etoposide combined with the HDAC inhibitor valproate (VPA) resulted in the synergistic antitumor effect. This was associated with caspase-3-dependent induction of apoptosis. Another HDAC inhibitor trichostatin A and a derivative of VPA that does not exhibit HDAC inhibitory activity, valpromide, lacked this effect. The synergism was only induced when VPA was combined with cytostatics targeted to cellular DNA; VPA does not potentiate the cytotoxicity of the anticancer drug vincristine that acts by a mechanism different from that of DNA damage. The VPA-mediated sensitization of UKF-NB-4 cells to cisplatin or etoposide was dependent on the sequence of drug administration; the potentiating effect was only produced either by simultaneous treatment with these drugs or when the cells were pretreated with cisplatin or etoposide before their exposure to VPA. The synergistic effects of VPA with cisplatin or etoposide were associated with changes in the acetylation status of histones H3 and H4. The results of this study provide a rationale for clinical evaluation of the combination of VPA and cisplatin or etoposide for treating children suffering from high-risk neuroblastoma. PMID:25963435

  2. Synergistic cytotoxicity of bcl-2 antisense oligodeoxynucleotides and etoposide, doxorubicin and cisplatin on small-cell lung cancer cell lines.

    PubMed Central

    Zangemeister-Wittke, U.; Schenker, T.; Luedke, G. H.; Stahel, R. A.

    1998-01-01

    Expression of Bcl-2 is life-sustaining for small-cell lung cancer cells and associated with drug resistance. In the present study, the interactions between the bcl-2 antisense oligodeoxynucleotide 2009 and the chemotherapeutic agents etoposide, doxorubicin and cisplatin were investigated on small-cell lung cancer cell lines to search for synergistic combinations. The cell lines NCI-H69, SW2 and NCI-H82 express high, intermediate-high and low basal levels of Bcl-2, respectively, which are inversely correlated with the sensitivities of the cell lines to treatment with oligodeoxynucleotide 2009 and the chemotherapeutic agents alone. Moreover, differences were found in the responsiveness of the cell lines to treatment with combinations of oligodeoxynucleotide 2009 and the chemotherapeutic agents. In the cell lines NCI-H69 and SW2, all combinations resulted in synergistic cytotoxicity. In NCI-H69 cells, maximum synergy with a combination index of 0.2 was achieved with the combination of oligodeoxynucleotide 2009 and etoposide. In SW2 cells, the combination of oligodeoxynucleotide 2009 and doxorubicin was the most effective (combination index = 0.5). In the cell line NCI-H82, which expresses a low basal level of Bcl-2, most of the combinations were slightly antagonistic. Our data suggest the use of oligodeoxynucleotide 2009 in combination with chemotherapy for the treatment of small-cell lung cancer that overexpresses Bcl-2. Images Figure 1 PMID:9792147

  3. [A Case of Advanced Seminoma in a 79-Year-Old Man Successfully Treated with Etoposide and Cisplatin].

    PubMed

    Shiga, Masanobu; Kawai, Koji; Kojyo, Kousuke; Kurobe, Masahiro; Ichioka, Daishi; Yoshino, Takayuki; Ikeda, Atsushi; Kojima, Takahiro; Joraku, Akira; Suetomi, Takahiro; Tsutsumi, Masakazu; Miyazaki, Jun; Nishiyama, Hiroyuki

    2015-12-01

    Testicular tumors are representative solid cancers that occur in young men, and the standard multi-drug combination chemotherapy has been established for metastatic tumors. However, they develop rarely in elderly men over 70 years old, and there are few reports about the information of combination chemotherapy for elderly testicular tumor patients. Here, we present a case in a 79-year-old who had right testicular tumors (seminoma, cT2N3M1a, IGCC classification : good prognosis) safely treated with multi-drug combination chemotherapy. To reduce the risk of side effects, we selected 4 courses of etoposide and cisplatin (EP) to the patient. The patient suffered from febrile neutropenia (FN) and oral mucositis during the first cycle of EP. However, no further episodes of oral mucositis and FN were observed after introduction of oral health care by a dentist. The patient received 4 courses of EP without dose reduction or treatment postponement. There was no evidence of recurrence 6 months after chemotherapy. To our knowledge, the present case is the oldest patient with metastatic testicular treated with combination chemotherapy including cisplatin. PMID:26790767

  4. Downregulation of Bim by brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from paclitaxel but not etoposide or cisplatin-induced cell death.

    PubMed

    Li, Z; Zhang, J; Liu, Z; Woo, C-W; Thiele, C J

    2007-02-01

    Chemoresistance and increased expression of TrkB and brain-derived neurotrophic factor (BDNF) are biomarkers of poor prognosis in tumors from patients with neuroblastoma (NB). Previously, we found BDNF activation of TrkB through PI3K/Akt protects NB from etoposide/cisplatin-induced cell death. In this study, the role of Bim, a proapoptotic protein, was investigated. Bim was involved in paclitaxel but not etoposide or cisplatin-induced cell death in NB cells. Pharmacological and genetic studies showed that BDNF-induced decreases in Bim were regulated by MAPK and not PI3K/Akt pathway. Both MAPK and PI3K pathways were involved in BDNF protection of NB cells from paclitaxel-induced cell death, while PI3K predominantly mediated BDNF protection of NB cells from etoposide or cisplatin-induced cell death. These data indicate that different chemotherapeutic drugs induce distinct death pathways and growth factors utilize different signal transduction pathways to modulate the effects of chemotherapy on cells. PMID:16778834

  5. Weekly Gemcitabine and Cisplatin in Combination With Radiotherapy in Patients With Locally Advanced Head-and-Neck Cancer: Phase I Study

    SciTech Connect

    Arruda Viani, Gustavo; Afonso, Sergio Luis; Cardoso Tavares, Vivian; Bernardes Godoi da Silva, Lucas; Stefano, Eduardo Jose

    2011-11-15

    Purpose: To define the maximum tolerated dose by describing the dose-limiting toxicity (DLT) of weekly gemcitabine and cisplatin in patients with locally advanced head-and-neck (LAHN) cancer concomitant to irradiation. Methods and Materials: Patients with LAHN cancer were enrolled in a prospective, dose-escalation Phase I study. Toxicity was graded according to the Common Toxicity Criteria score. Maximum tolerated dose was defined when DLT developed in 2 of 6 patients. The starting dose of cisplatin was 20 mg/m{sup 2} and that of gemcitabine was 10 mg/m{sup 2} in 3 patients, with a subsequent dose escalation of 10 mg/m{sup 2} of cisplatin only for 3 new patients. In the next levels, only a dose escalation of gemcitabine with 10 mg/m{sup 2} for each new cohort was used (Level 1, 10 mg/m{sup 2} of gemcitabine and 20 mg/m{sup 2} of cisplatin; Level 2, 10 mg/m{sup 2} of gemcitabine and 30 mg/m{sup 2} of cisplatin; and Level 3, 20 mg/m{sup 2} of gemcitabine and 30 mg/m{sup 2} of cisplatin). Radiation therapy was administered by use of a conformal technique over a period of 6 to 7 weeks in 2.0-Gy daily fractions for 5 consecutive days per week to a total dose of 70 Gy. Results: From 2008 to 2009, 12 patients completing 3 dose levels were included in the study. At Dose Level 3, 1 of 3 patients had DLT with Grade 3 mucositis. Of the next 3 required patients, 2 showed DLT with Grade 3 dermatitis. At a follow-up of 3 months, 10 of 12 evaluable patients (83.3%) obtained a complete response and 1 patient (8.3%) obtained a partial response. Among the complete responders, at a median follow-up of 10 months (range, 6-14 months), 9 patients are alive and disease free. Conclusion: Gemcitabine at low doses combined with cisplatin is a potent radiosensitizer effective in patients with LAHN cancer. The recommended Phase II dose is 10 mg/m{sup 2} of gemcitabine and 30 mg/m{sup 2} of cisplatin with an acceptable tolerability profile.

  6. Contrasting effects of cardiac glycosides on cisplatin- and etoposide-induced cell death.

    PubMed

    Kulikov, Andrey V; Slobodkina, Ekaterina A; Alekseev, Andrey V; Gogvadze, Vladimir; Zhivotovsky, Boris

    2016-07-01

    Cardiac glycosides (CGs) or cardiotonic steroids, which constitute a group of naturally occurring compounds with a steroid-like structure, can act on Na+/K+-ATPase as a receptor and activate intracellular signaling messengers leading to a variety of cellular responses. Epidemiological studies have revealed that CGs, used for the treatment of cardiac disorders, may also be beneficial as anti-cancer agents. CGs, acting in combination with other chemotherapeutic agents, may significantly alter their efficiency in relation to cancer cell elimination, causing both sensitization and an increase in cancer cell death, and in some cases resistance to chemotherapy. Here we show the ability of CGs to modulate apoptotic response to conventionally used anti-cancer drugs. In combination with etoposide, CGs digoxin may enhance cytotoxic potential, thereby allowing the chemotherapeutic dose to be decreased and minimizing toxicity and adverse reactions. Mechanisms behind this event are discussed. PMID:26854291

  7. The Effects of Chemotherapeutic Agents, Bleomycin, Etoposide, and Cisplatin, on Chromatin Remodeling in Male Rat Germ Cells.

    PubMed

    Bagheri-Sereshki, Negar; Hales, Barbara F; Robaire, Bernard

    2016-04-01

    The coadministration of bleomycin, etoposide, and cisplatin (BEP) has increased the survival rate of testicular cancer patients to over 90%. Previous studies have demonstrated that BEP induces germ cell damage during the final stages of spermatogenesis, when major chromatin remodeling occurs. Chromatin remodeling permits histone-protamine exchange, resulting in sperm head chromatin compaction. This process involves different epigenetic modifications of the core histones. The objective of these studies was to investigate the effects of BEP on epigenetic modifications to histones involved in chromatin remodeling. Brown Norway rats were treated with BEP, and their testes were removed to isolate pachytene spermatocytes and round spermatids by unit gravity sedimentation. Western blot analyses were conducted on extracted proteins to detect the expression of key modified histones. In a second cohort testes were prepared for immunohistochemical analysis. The stage-specific expression of each modified histone mark in rat spermatogenesis suggests the involvement of these modifications in chromatin remodeling. BEP treatment significantly increased expression of H3K9m and decreased that of tH2B (or Hist1h2ba) in pachytene spermatocytes, suggesting that nucleosomes were not destabilized to allow for transcription of genes involved in chromatin remodeling. Moreover, BEP treatment altered the expression of H4K8ac in round and elongating spermatids, suggesting that histone eviction was compromised, leading to a looser chromatin structure in mature spermatozoa. Less-compacted sperm chromatin, with alterations to the sperm epigenome, may have an adverse effect on male fertility. PMID:26911428

  8. Nuphar lutea thioalkaloids inhibit the nuclear factor kappaB pathway, potentiate apoptosis and are synergistic with cisplatin and etoposide.

    PubMed

    Ozer, Janet; Eisner, Nadav; Ostrozhenkova, Elena; Bacher, Adelbert; Eisenreich, Wolfgang; Benharroch, Daniel; Golan-Goldhirsh, Avi; Gopas, Jacob

    2009-10-01

    We screened thirty-four methanolic plant extracts for inhibition of the constitutive nuclear factor kappaB (NFkappaB) activity by a NFkappaB-luciferase reporter gene assay. Strong inhibition of NFkappaB activity was found in extracts of leaf and rhizome from Nuphar lutea L. SM. (Nuphar). The inhibitory action was narrowed down to a mixture of thionupharidines and/or thionuphlutidines that were identified in chromatography fractions by one- and two-dimensional NMR analysis. Dimeric sesquiterpene thioalkaloids were identified as the major components of the mixture. The Nuphar alkaloids mixture (NUP) showed a dose dependent inhibition of NFkappaB activity in a luciferase reporter gene assay as well as reduction of nuclear NFkappaB subunits expression as tested by western blots and immunohistochemistry. Decreased DNA binding was demonstrated in electro mobility shift assays. NUP inhibited both inducible and constitutive NFkappaB activation and affected the canonical and alternative pathways. Suppression of NFkappaB was not cell type specific. Induction of apoptosis by the alkaloid mixture was demonstrated by time-dependent and dose-dependent cleavage of procaspase-9 and PARP. Synergistic cytotoxicity of the active mixture with cisplatin and etoposide was demonstrated. Overall, our results show that NUP inhibits the NFkappaB pathway and acts as a sensitizer to conventional chemotherapy, enabling the search for its specific target and application against cancer and inflammation. PMID:19713755

  9. Retrospective study of irinotecan/cisplatin followed by etoposide/cisplatin or the reverse sequence in extensive-stage small cell lung cancer

    PubMed Central

    Xiao, Xiaoguang; Wang, Shujing; Xia, Shu; Zou, Man; Li, Yang; Wei, Yao; Mei, Qi; Chen, Yuan

    2015-01-01

    Background Much research has confirmed the favorable effect of irinotecan/cisplatin (IP) and etoposide/cisplatin (EP) on extensive-stage small cell lung cancer (E-SCLC). This study investigated two sequential orders of IP and EP in the treatment of E-SCLC. We also compared the efficacy and safety of IP and EP in first-line chemotherapy in E-SCLC. Methods Ninety-three untreated patients with E-SCLC were randomly allocated to two groups. Group A received IP as first-line therapy until progression and then changed to EP; group B received EP as first-line therapy until tumor progression followed by IP. The primary endpoints were overall survival and time to second tumor progression. The secondary endpoints were first progression-free survival (PFS), ie, time from randomization to first occurrence of tumor progression after first-line treatment with IP or EP, tumor response, and safety of the different sequential treatment orders of IP and EP. Results Median overall survival was 15.4 months in group A (IP followed by EP) versus 15.7 months in group B (EP followed by IP; P=0.483). The median time to second tumor progression was 9.5 months in group A versus 9.9 months in group B (P=0.361). As first-line and second-line therapy, IP achieved a 95.9% and 60% disease control rate, respectively, and EP achieved 95.6% and 59% disease control rate. The median first PFS was not significantly different between group A and group B (6.5 months and 6.3 months, respectively; P=0.256). Grade 3/4 diarrhea appeared to be significantly more frequent with IP than with EP. The probability of anemia and thrombocytopenia was not significantly different between the two groups. However, significantly more patients who received the IP regimen as second-line treatment developed grade 3/4 neutropenia than those who received the IP regimen as first-line therapy. Conclusion There were no statistically significant differences in between the two sequences of IP and EP in the treatment of E

  10. Biweekly administration of gemcitabine and cisplatin chemotherapy in patients with anthracycline and taxane-pretreated metastatic breast cancer.

    PubMed

    Tas, Faruk; Guney, Nese; Derin, Duygu; Camlica, Hakan; Aydiner, Adnan; Topuz, Erkan

    2008-08-01

    Gemcitabine and cisplatin are the active agents in metastatic breast cancer pretreated with anthracycline and/or taxane as a second line treatment. The present study was designed to assess the efficacy and safety of this regimen given biweekly schedule in these patients. Twenty-seven women, median age 57, with metastatic breast cancer previously treated with anthracycline and taxane were eligible for enrollment. Gemcitabine was administered intravenously on days 1 and 15 at a dose of 2,000 mg/m(2) and Cisplatin was given intravenously on day 1 and 15 at a dose of 50 mg/m(2). Treatment cycles were repeated on an outpatient basis every 28 days. Of all 27 evaluable patients, the overall response rate was 26% (7 of 27; 95% CI: 11-46%) with seven all partial responses. The stable diseases were found in 9 (33%) patients. At the time of last follow-up, 11 (41%) of the patients died of their disease progression. The median overall survival duration was 7.4 +/- 2.8 months. The 1-year overall survival rate was 46.9% +/- 12.3. Hematological toxicity was not found as the principal dose-limiting toxicity. Severe (grade III/IV) neutropenia was observed only one (4%) patients. No patient was complicated by febrile neutropenia and G-CSF usage was not performed. Grade III and IV anemia were seen in only 4 (15%) and thrombocytopenia was noted only one (4%) patients. Severe hepatic (n = 2) and renal toxicity (n = 1) were observed and these all recovered completely without complication. Several other severe non-hematological side effects were managed easily. Permanent dose reductions were necessary in 9 (33%) patients and chemotherapy administration was also delayed in 7 (26%) patients because of delayed both hematological and non-hematological toxicity recovery. Treatment was discontinued in one (4%) patient due to severe fatigue and deteriorating performance status. In conclusion, gemcitabine and cisplatin combination therapy with this biweekly schedule and dosage is moderately

  11. Randomized Phase III Study Comparing Paclitaxel/Cisplatin/ Gemcitabine and Gemcitabine/Cisplatin in Patients With Locally Advanced or Metastatic Urothelial Cancer Without Prior Systemic Therapy: EORTC Intergroup Study 30987

    PubMed Central

    Bellmunt, Joaquim; von der Maase, Hans; Mead, Graham M.; Skoneczna, Iwona; De Santis, Maria; Daugaard, Gedske; Boehle, Andreas; Chevreau, Christine; Paz-Ares, Luis; Laufman, Leslie R.; Winquist, Eric; Raghavan, Derek; Marreaud, Sandrine; Collette, Sandra; Sylvester, Richard; de Wit, Ronald

    2012-01-01

    Purpose The combination of gemcitabine plus cisplatin (GC) is a standard regimen in patients with locally advanced or metastatic urothelial cancer. A phase I/II study suggested that a three-drug regimen that included paclitaxel had greater antitumor activity and might improve survival. Patients and Methods We conducted a randomized phase III study to compare paclitaxel/cisplatin/gemcitabine (PCG) with GC in patients with locally advanced or metastatic urothelial carcinoma. Primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), overall response rate, and toxicity. Results From 2001 to 2004, 626 patients were randomly assigned; 312 patients were assigned to PCG, and 314 patients were assigned to GC. After a median follow-up of 4.6 years, the median OS was 15.8 months on PCG versus 12.7 months on GC (hazard ratio [HR], 0.85; P = .075). OS in the subgroup of all eligible patients was significantly longer on PCG (3.2 months; HR, 0.82; P = .03), as was the case in patients with bladder primary tumors. PFS was not significantly longer on PCG (HR, 0.87; P = .11). Overall response rate was 55.5% on PCG and 43.6% on GC (P = .0031). Both treatments were well tolerated, with more thrombocytopenia and bleeding on GC than PCG (11.4% v 6.8%, respectively; P = .05) and more febrile neutropenia on PCG than GC (13.2% v 4.3%, respectively; P < .001). Conclusion The addition of paclitaxel to GC provides a higher response rate and a 3.1-month survival benefit that did not reach statistical significance. Novel approaches will be required to obtain major improvements in survival of incurable urothelial cancer. PMID:22370319

  12. 1,25D3 enhances antitumor activity of gemcitabine and cisplatin in human bladder cancer models

    PubMed Central

    Ma, Yingyu; Yu, Wei-Dong; Trump, Donald L.; Johnson, Candace S.

    2010-01-01

    Background 1,25 dihydroxyvitamin D3 (1,25D3) potentiates the cytotoxic effects of several common chemotherapeutic agents. The combination of gemcitabine and cisplatin (GC) is a current standard chemotherapy regimen for bladder cancer. We investigated whether 1,25D3 could enhance the antitumor activity of GC in bladder cancer model systems. Methods Human bladder cancer T24 and UMUC3 cells were pretreated with 1,25D3 followed by GC. Apoptosis were assessed by annexin V staining. Caspase activation was examined by immunoblot analysis and substrate-based caspase activity assay. The cytotoxic effects were examined using MTT and in vitro clonogenic assay. p73 protein levels were assessed by immunoblot analysis. Knockdown of p73 was achieved by siRNA. The in vivo antitumor activity was assessed by in vivo excision clonogenic assay and tumor regrowth delay in the T24 xenograft model. Results 1,25D3 pretreatment enhanced GC-induced apoptosis and the activities of caspases- 8, 9 and 3 in T24 and UMUC3 cells. 1,25D3 synergistically reduced GC-suppressed surviving fraction in T24 cells. 1,25D3, gemcitabine, or cisplatin induced p73 accumulation, which was enhanced by GC or 1,25D3 and GC. p73 expression was lower in human primary bladder tumor tissue compared with adjacent normal tissue. Knockdown of p73 increased clonogenic capacity of T24 cells treated with 1,25D3, GC or 1,25D3 and GC. 1,25D3 and GC combination enhanced tumor regression compared with 1,25D3 or GC alone. Conclusions 1,25D3 potentiates GC-mediated growth inhibition in human bladder cancer models in vitro and in vivo, which involves p73 induction and apoptosis. PMID:20564622

  13. Bleomycin-induced pulmonary fibrosis after tumor lysis syndrome in a case of advanced yolk sac tumor treated with bleomycin, etoposide and cisplatin (BEP) chemotherapy.

    PubMed

    Doi, Mihoko; Okamoto, Yohei; Yamauchi, Masami; Naitou, Hiroyuki; Shinozaki, Katsunori

    2012-10-01

    Ovarian yolk sac tumor (YST) is a highly aggressive malignancy arising in young women. Chemotherapy has dramatically improved the prognosis, and bleomycin, etoposide, and cisplatin (BEP) combination chemotherapy appears to be the most effective combination regimen. A 23-year-old woman was admitted to our hospital with worsening abdominal distention and a lower abdominal mass. She was diagnosed with a stage IIIc pure YST of the right ovary, and right salpingo-oophorectomy was performed; there were numerous disseminated peritoneal tumors within the abdominal cavity. A few days postoperatively, massive ascites developed, and right hydronephrosis occurred. Chemotherapy with BEP was started, and after 24 h of administration, oliguria and tumor lysis syndrome (TLS) developed. Continuous hemodiafiltration was started, and hemodialysis was initiated following full-dose standard cisplatin and etoposide on days 2-5 of the 1st cycle. After the electrolyte abnormalities and the elevation of creatinine became normal, the patient received an additional three cycles of BEP and achieved complete remission. However, she also suffered from severe non-hematological toxicities, including grade 3 left ventricular dysfunction and grade 4 pulmonary fibrosis. In the case of rapidly progressing and high-volume YST treated with BEP chemotherapy, special attention should be paid to bleomycin-induced pulmonary toxicity following TLS. Further study is required to optimize drug exposure to ensure efficacy and reduce the risk of side effects in this population. PMID:22127348

  14. Recurrence 11 years after complete response to gemcitabine, 5-Fluorouracil, and Cisplatin chemotherapy followed by radiotherapy in a patient with advanced pancreatic cancer: a case report.

    PubMed

    Uchihara, Tomoyuki; Yamashita, Yo-Ichi; Hualin, Wang; Takeishi, Kazuki; Itoh, Shinji; Harimoto, Norihumi; Yoshizumi, Tomoharu; Aishima, Shinichi; Shirabe, Ken; Baba, Hideo; Maehara, Yoshihiko

    2015-05-01

    A 63-year-old man diagnosed with locally advanced pancreatic ductal adenocarcinoma (PDAC; stage IIa) was treated with chemotherapy (gemcitabine, 5-fluorouracil and cisplatin) followed by radiotherapy. He had complete response by imaging and relapse-free survival for 11 years. However, he subsequently presented with local tumor recurrence and underwent pancreaticoduodenectomy followed by chemotherapy; a partial response was achieved. As in liver metastasis of colonic cancer, complete response by imaging in PDAC may not mean pathological complete response. We would propose the importance of adjuvant surgery for a patient with PDAC with complete response by imaging after chemoradiotherapy. PMID:25964569

  15. Tetrandrine Combined with Gemcitabine and Cisplatin for Patients with Advanced Non-Small Cell Lung Cancer Improve Efficacy

    PubMed Central

    Liu, Wenchao; Zhang, Ju; Ying, Cheng; Wang, Qianrong; Yan, Chen; Jingyue, Yang; Zhaocai, Yu; Yan, Xue; Heng-jun, Shi; Lin, Jiang

    2012-01-01

    Lung cancer has the highest morbidity and mortality of any malignant tumor. To improve efficacy and reduce toxicity in patients with advanced non-small cell lung cancer (NSCLC), it is important to integrate traditional and conventional medicine. Two hundred and forty patients with advanced NSCLC were randomized to tetrandrine plus GP or GP only. We infused gemcitabine on days 1 and 8; cisplatin on day 1. The tetrandrine group received continuous i.v. infusion for 10 days, with treatment repeated every 21 days. After 2 consecutive treatment cycles, we used RECIST criteria to evaluate short-term efficacy. Quality of life (QOL) was assessed according to Karnofsky score (KPS) and body weight change. We used NCI CTC 3.0 to evaluate treatment toxicity. The short-term objective response rate was 36.1% in the tetrandrine group and 24.3% in the controls (P=0.057). The short-term disease control rate was 63.9% in the tetrandrine group and 52.3% in the controls (P=0.081). The 1-year survival rates were 45.7% and 31.3%, respectively (P=0.059). KPS scores improved by 49.1% and 32.4%, respectively (P=0.012). Body weight increased by 28.7% in the tetrandrine group and 16.2% in the controls (P=0.027). The incidence of grade 2-4 leukopenia, thrombocytopenia, nausea, and vomiting in the tetrandrine group was 38.0%, 19.4%, 46.3%, and 16.7%, respectively; the control group figures were 53.2%, 34.2%, 63.0% and 27.9% (P<0.05). Tetrandrine may improve short-term efficacy and survival in patients with advanced NSCLC. Tetrandrine may also mitigate adverse reactions to chemotherapy and improve QOL for patients with NSCLC. PMID:23675254

  16. Etoposide, cisplatin, bleomycin, and cyclophosphamide (ECBC) as first-line chemotherapy for poor-risk non-seminomatous germ cell tumors.

    PubMed

    Gerl, A; Clemm, C; Hentrich, M; Hartenstein, R; Wilmanns, W

    1993-01-01

    Sixty-one patients with advanced metastatic non-seminomatous germ cell tumors were treated with etoposide 120 mg/m2, cisplatin 30 mg/m2, bleomycin 12 mg/m2, and cyclophosphamide 300 mg/m2 daily for four days; and additional bleomycin bolus injection of 15 mg was given on day 1. Fifty patients (82%) were treated with four to six courses at 3-week intervals. Forty patients (66%) attained complete remission, and further 7 patients (11%) achieved a marker-negative partial remission accounting for a favorable response rate of 77%. Hematologic toxicity was considerable and there were two treatment-related deaths. After a median observation time of 47 months (range 12 to 108 months), 43 patients were alive, of which 38 had continuous complete remission, one a second complete remission, two marker-negative stable disease and two progressive disease. Our results are similar to those reported by other investigators for poor-risk metastatic non-seminomatous germ cell tumors treated with dose-intensified regimens. PMID:7692901

  17. Gemcitabine and cisplatin in a concomitant alternating chemoradiotherapy program for locally advanced head-and-neck cancer: A pharmacology-guided schedule

    SciTech Connect

    Numico, Gianmauro . E-mail: gianmauro.numico@fastwebnet.it; Russi, Elvio G.; Vitiello, Raffele; Sorrentino, Raffaele; Colantonio, Ida; Cipolat, Marco; Taglianti, Riccardo Vigna; Pelissero, Antonio; Fea, Elena; Granetto, Cristina; Di Costanzo, Gianna; Gasco, Milena; Garrone, Ornella; Occelli, Marcella; Merlano, Marco

    2006-11-01

    Purpose: Administration of gemcitabine together with cisplatin at cytotoxic doses in a chemoradiotherapy regimen is hampered by a high degree of local toxicity. Using the pharmacologic properties of the drug we designed a modified schedule aimed at reducing toxicity while preserving activity. Methods and Materials: Patients with squamous cell carcinomas of the oral cavity, pharynx and larynx, bulky T4, and/or N2 to N3 were eligible. Gemcitabine was administered at a dose of 800 mg/m{sup 2} on Days 1 and 12 and cisplatin at a dose of 20 mg/m{sup 2} on Days 2 to 5, every 21 days for 3 courses. Radiotherapy, delivered with standard fractionation, was given on Days 8 to 12 and 15 to 19 and was repeated 3 times up to a total dose of {>=}60 Gy. Results: A total of 28 patients were selected. Grade 3 to 4 stomatitis was recorded in 25 patients (89%). Thirteen patients (46%) experienced Grade 3 to 4 neutropenia. Febrile neutropenia occurred in 8 patients (29%) and in 2 was complicated by infection and death. The overall complete response rate was 79%. At a median follow up of 71 months, 11 patients had a locoregional relapse (3-year locoregional control, 64%); 6 patients had distant metastases, among whom only 2 were without locoregional recurrence. The 3-year progression-free survival is 39% and 3-year overall survival has been 43%. Conclusion: The schedule modification did not attenuate local toxicity. Moreover, infections and especially pneumonia, were a major problem. The high activity of gemcitabine when combined with radiotherapy would most likely be better exploited in the context of modified radiation schemes.

  18. Expression of DNA Translesion Synthesis Polymerase η in Head and Neck Squamous Cell Cancer Predicts Resistance to Gemcitabine and Cisplatin-Based Chemotherapy

    PubMed Central

    Zhou, Wendi; Chen, Yih-wen; Liu, Xiyong; Chu, Peiguo; Loria, Sofia; Wang, Yafan; Yen, Yun; Chou, Kai-Ming

    2013-01-01

    Purpose The development of resistance against anticancer drugs has been a persistent clinical problem for the treatment of locally advanced malignancies in the head and neck mucosal derived squamous cell carcinoma (HNSCC). Recent evidence indicates that the DNA translesion synthesis (TLS) polymerase η (Pol η; hRad30a gene) reduces the effectiveness of gemcitabine/cisplatin. The goal of this study is to examine the relationship between the expression level of Pol η and the observed resistance against these chemotherapeutic agents in HNSCC, which is currently unknown. Methods Sixty-four mucosal derived squamous cell carcinomas of head and neck (HNSCC) from 1989 and 2007 at the City of Hope National Medical Center (Duarte, CA) were retrospectively analyzed. Pretreatment samples were immunostained with anti-Pol η antibody and the correlation between the expression level of Pol η and clinical outcomes were evaluated. Forty-nine cases treated with platinum (n=40) or gemcitabine (n=9) based chemotherapy were further examined for Pol η expression level for comparison with patient response to chemotherapy. Results The expression of Pol η was elevated in 67% of the head and neck tumor samples. Pol η expression level was significantly higher in grade 1 to grade 2 tumors (well to moderately differentiated). The overall benefit rate (complete response+ partial response) in patients treated with platinum and gemcitabine based chemotherapy was 79.5%, where low Pol η level was significantly associated with high complete response rate (p=0.03), although not associated with overall survival. Furthermore, no significant correlation was observed between Pol η expression level with gender, age, tobacco/alcohol history, tumor stage and metastatic status. Conclusions Our data suggest that Pol η expression may be a useful prediction marker for the effectiveness of platinum or gemcitabine based therapy for HNSCC. PMID:24376779

  19. Cisplatin combined with irinotecan or etoposide for untreated extensive-stage small cell lung cancer: A multicenter randomized controlled clinical trial

    PubMed Central

    Shi, Yuankai; Hu, Yi; Hu, Xingsheng; Li, Xue; Lin, Lin; Han, Xiaohong

    2015-01-01

    Background This study evaluated the efficacy and safety of irinotecan/cisplatin (IP) and etoposide/cisplatin (EP) in extensive-stage small cell lung cancer (ES-SCLC) and the distribution of uridine diphosphate glucuronosyltransferase (UGT1A1). The relationship between UGT1A1 genotypes and patient outcomes was also assessed. Method Patients with untreated ES-SCLC were randomly assigned to receive either IP or EP, and blood specimens were collected to test the genotypes of UGT1A1*28 and UGT1A1*6. The association of efficacy and toxicity of an IP regimen with UGT1A1 genotype was analyzed. Results Of the 62 patients enrolled from three institutions, 30 patients were in the IP and 32 patients were in the EP arms, respectively. Disease control rates with IP and EP were 83.3% and 71.9%, respectively (P = 0.043). Median progression-free survival for IP and EP were both six months. Median overall survival for IP and EP were 18.1 and 15.8 months respectively, without significant difference. Grade 3-4 thrombocytopenia was more common with EP (18.8% vs. 6.7%; P = 0.035), while the incidence of diarrhea was higher with IP (70% vs. 15.6%; P = 0.008). The incidence of grade 1-4 late-onset diarrhea of wild-type, heterozygous, and homozygous UGT1A1*28 were 65.0%, 85.7%, and 66.7%, respectively (P = 0.037). UGT1A1*28 polymorphisms, Eastern Cooperative Oncology Group performance status, and chemotherapy cycles were essential factors affecting grade 1-4 late-onset diarrhea in logistic regression analysis. Conclusions The efficacy of the IP regimen was similar to the EP regimen for untreated ES-SCLC. UGT1A1 polymorphisms were associated with late-onset diarrhea; however, there was no influence on efficacy. PMID:26557919

  20. Avastin® in combination with gemcitabine and cisplatin significantly inhibits tumor angiogenesis and increases the survival rate of human A549 tumor-bearing mice

    PubMed Central

    LIU, YING; XIA, XIZHENG; ZHOU, MINGKAI; LIU, XIAOJUN

    2015-01-01

    The aim of this study was to investigate the effect of Avastin® in combination with gemcitabine and cisplatin (GP) on the tumor growth of A549 tumor-bearing mice and the potential anti-tumor mechanism. A total of 30 human A549 tumor-bearing nude mice were randomly divided into the Avastin, chemotherapy and combined treatment groups for treatment with an intraperitoneal injection of Avastin (5 mg/kg) (Avastin group); an intraperitoneal injection of gemcitabine (4 mg/kg) and cisplatin (4 mg/kg) (chemotherapy group); or intraperitoneal injections of Avastin and GP (combined treatment group). The mice were observed for 30 days and the tumor growth, survival and body weight of the mice in the three groups were analyzed. The protein level of vascular endothelial growth factor (VEGF) in the tumor tissues was analyzed by ELISA. The vascular density and structural changes of the tumor were analyzed using immunohistochemistry. Compared with the Avastin and chemotherapy groups, the tumor growth of mice in the combined treatment group was significantly inhibited, and the survival rate of the mice was increased significantly. No difference in body weight was observed among the three groups of mice (P>0.05). The levels of VEGF in the combined treatment group tumor tissues were significantly reduced compared with those in the chemotherapy group tumor tissues (P<0.05). Furthermore, the vessel density of the tumor tissue in the combined treatment group was significantly reduced compared with that in the chemotherapy group (P<0.05), and the number of normal vessels in the combined treatment group tumors was significantly higher than that in the chemotherapy group tumors after 7 days of treatment (P<0.05). In conclusion, Avastin can significantly decrease the level of VEGF in tumor tissue, inhibit tumor angiogenesis and promote the normalization of tumor vascular structure, which may explain the enhanced efficacy of Avastin in combination with chemotherapy. PMID:26136956

  1. ERCC1 and RRM1 as a predictive parameter for non-small cell lung, ovarian or pancreas cancer treated with cisplatin and/or gemcitabine

    PubMed Central

    Ulker, Mehmet; Sahin, Berksoy; Gumurdulu, Derya

    2015-01-01

    Background We aimed to investigate the impact of RRM1 and ERCC1 expression on response to cisplatin and/or gemcitabine chemotherapy in patients with lung, ovarian or pancreatic cancer. Material and methods Patients with lung, ovarian or pancreatic cancer, who used cisplatin and/or gemcitabine therapy were included; hospital files were examined and RRM1 and ERCC1 expression were evaluated with an immunohistochemical method on tissue cross sections from paraffin blocks of the tumour. Results Out of 89 patients, 51%, 30% and 19% had lung, ovarian and pancreatic cancer, respectively. The response rates to the therapy in patients with lung and ovarian cancer having low ERCC1 expression were 62% and 90%, respectively (p = 0.028 and p = 0.044, respectively). No significant association was found between ERCC1 expression and response to therapy in patients with pancreatic cancer (p = 0.354). Therapeutic response rates in patients with lung and pancreatic cancer with low RRM1 expression were 60% and 82%, respectively. Survival rates were higher in patients with lung cancer in which ERCC1 and RRM1 expressions were low. Median survival duration in patients with ovarian cancer showing low ERCC1 and RRM1 expressions was longer than that seen in patients with high expressions. Although no significant correlation was found between ERCC1 and the survival in ovarian cancer (p = 0.183), there was a significant correlation between RRM1 expression and survival in patients with pancreatic cancer (p = 0.005). Conclusions Our results suggest a predictive value of ERCC1 in lung and ovarian cancers, and also RRM1 in lung and pancreatic cancers. PMID:26557761

  2. Comparison of gemcitabine, oxaliplatin and L-asparaginase and etoposide, vincristine, doxorubicin, cyclophosphamide and prednisone as first-line chemotherapy in patients with stage IE to IIE extranodal natural killer/T-cell lymphoma: a multicenter retrospective study.

    PubMed

    Wang, Hua; Wuxiao, Zhi-Jun; Zhu, Jiayu; Wang, Zhihui; Wang, Ke-Feng; Li, Su; Chen, Xiaoqin; Lu, Yue; Xia, Zhong-Jun

    2015-04-01

    Optimal chemotherapy regimen for Extranodal natural killer/T-cell lymphoma (ENKTL) has not yet been defined. We retrospectively compared the outcome of 93 patients newly diagnosed with stage IE to IIE ENKTL who received gemcitabine, oxaliplatin and L-asparaginase (GELOX) (n = 40) or etoposide, vincristine, doxorubicin, cyclophosphamide and prednisone (EPOCH) (n = 53) as induction chemotherapy. After induction chemotherapy, the complete response (CR) rate and overall response rate (ORR) for the GELOX group were higher than those for the EPOCH group (70.0% vs. 41.5%, p = 0.007 for CR; 87.5% vs. 67.9%, p = 0.047 for ORR). The GELOX regimen resulted in significantly superior 5-year progression-free survival (PFS) (79.0% vs. 46.5%, p = 0.005) and overall survival (OS) rates (78.9% vs. 50.4%, p = 0.003). Toxicity of both regimens was acceptable. The GELOX regimen produces a better long outcome with less toxicity than the EPOCH regimen for patients with early stage ENKTL. PMID:24991715

  3. Nanoparticles with Precise Ratiometric Co-Loading and Co-Delivery of Gemcitabine Monophosphate and Cisplatin for Treatment of Bladder Cancer

    PubMed Central

    Miao, Lei; Guo, Shutao; Zhang, Jing; Kim, William Y.; Huang, Leaf

    2014-01-01

    Combination chemotherapy is a common practice in clinical management of malignancy. Synergistic therapeutic outcome is only achieved when tumor cells are exposed to cells in an optimal ratio. However, due to diverse physicochemical properties of drugs, no free drug cocktails or nanomaterials are capable of co-loading and co-delivering drugs at an optimal ratio. Herein, we develop a novel nano-platform with precise ratiometric co-loading and co-delivery of two hydrophilic drugs for synergistic anti-tumor effects. Based on previous work, we utilize a solvent displacement method to ratiometrically load dioleoyl phosphatidic acid (DOPA)-gemcitabine monophosphate and DOPA coated cisplatin-precipitate nanocores into the same PLGA NP. These cores are designed to have similar hydrophobic surface properties. GMP and cisplatin are engineered into PLGA NP at an optimal synergistic ratio (5:1, mol:mol) with over 70% encapsulation efficiency and were ratiometrically taken up by tumor cells in vitro and in vivo. These PLGA NP exhibit synergistic anti-cancer effects in a stroma-rich bladder tumor model. A single injection of dual drugs in PLGA NP can significantly inhibit tumor growth. This nanomaterial-system solves problems related to ratiometric co-loading and co-delivery of different hydrophilic moieties and provides possibilities for co-loading hydrophilic drugs with hydrophobic drugs for combination therapy. PMID:25395922

  4. SUCCINCT: An Open-label, Single-arm, Non-randomised, Phase 2 Trial of Gemcitabine and Cisplatin Chemotherapy in Combination with Sunitinib as First-line Treatment for Patients with Advanced Urothelial Carcinoma

    PubMed Central

    Geldart, Thomas; Chester, John; Casbard, Angela; Crabb, Simon; Elliott, Tony; Protheroe, Andrew; Huddart, Robert A.; Mead, Graham; Barber, Jim; Jones, Robert J.; Smith, Joanna; Cowles, Robert; Evans, Jessica; Griffiths, Gareth

    2015-01-01

    Gemcitabine and cisplatin chemotherapy (GC regimen) represents a standard treatment for advanced urothelial carcinoma. We performed an open-label, single-arm, non-randomised, phase 2 trial evaluating the addition of sunitinib to standard GC chemotherapy (SGC regimen). Overall, 63 treatment-naïve participants were recruited and received up to six 21-d cycles of cisplatin 70 mg/m2 (intravenously [IV], day 1) and gemcitabine 1000 mg/m2 (IV, days 1 and 8) combined with sunitinib 37.5 mg (orally, days 2–15). Following review of toxicity after the first six patients, the sunitinib dose was reduced to 25 mg for all patients. Overall response rate was 64%, with response noted in 37 of 58 patients. At 6 mo, 30 of 58 assessable patients (52%; 90% confidence interval [CI], 40–63%) were progression free. Median overall survival was 12 mo (95% CI, 9–15) and was heavily influenced by Bajorin prognostic group. Grade 3–4 toxicities were predominantly haematologic and limited the deliverability of the triple SGC regimen. The trial did not meet its prespecified primary end point of >60% patients progression free at 6 mo. Cumulative myelosuppression led to treatment delays of gemcitabine and cisplatin and dose reduction and/or withdrawal of sunitinib in the majority of cases. The triple-drug combination was not well tolerated. Phase 3 evaluation of the triple SGC regimen in advanced transitional cell carcinoma is not recommended. Patient summary The addition of sunitinib to standard cisplatin and gemcitabine chemotherapy was poorly tolerated and did not improve outcomes in advanced urothelial carcinoma. Treatment delivery was limited by myelotoxicity. PMID:25465968

  5. A Phase II Study of Fixed-Dose Rate Gemcitabine Plus Low-Dose Cisplatin Followed by Consolidative Chemoradiation for Locally Advanced Pancreatic Cancer

    SciTech Connect

    Ko, Andrew H.; Venook, Alan P.

    2007-07-01

    Purpose: The optimal strategy for treating locally advanced pancreatic cancer remains controversial, including the respective roles and timing of chemotherapy and radiation. We conducted a Phase II nonrandomized trial to evaluate sequential chemotherapy followed by chemoradiation in this patient population. Methods and Materials: Chemotherapy naive patients with locally advanced pancreatic adenocarcinoma were treated with fixed-dose rate gemcitabine (1,000 mg/m{sup 2} at 10 mg/m{sup 2}/min) plus cisplatin 20 mg/m{sup 2} on Days 1 and 15 of a 28-day cycle. Those without evidence of extrapancreatic metastases after six cycles of chemotherapy received radiation (5,040 cGy over 28 fractions) with concurrent capecitabine (800 mg/m{sup 2} orally twice daily on the day of radiation) as a radiosensitizer. Results: A total of 25 patients were enrolled with a median follow-up time of 656 days. Twelve patients (48%) successfully received all six cycles of chemotherapy plus chemoradiation. Eight patients (32%) progressed during chemotherapy, including 7 with extrapancreatic metastases. Grade 3/4 hematologic toxicities were uncommon. Two patients sustained myocardial infarctions during chemotherapy, and 4 were hospitalized for infectious complications, although none in the setting of neutropenia. Median time to progression was 10.5 months and median survival was 13.5 months, with an estimated 1-year survival rate of 62%. Patients receiving all components of therapy had a median survival of 17.0 months. Conclusions: A strategy of initial fixed-dose rate gemcitabine-based chemotherapy, followed by chemoradiation, shows promising efficacy for treatment of locally advanced disease. A substantial proportion of patients will be identified early on as having extrapancreatic disease and spared the potential toxicities associated with radiation.

  6. Final Results of Sequential Doxorubicin Plus Gemcitabine and Ifosfamide, Paclitaxel, and Cisplatin Chemotherapy in Patients With Metastatic or Locally Advanced Transitional Cell Carcinoma of the Urothelium

    PubMed Central

    Milowsky, Matthew I.; Nanus, David M.; Maluf, Fernando C.; Mironov, Svetlana; Shi, Weiji; Iasonos, Alexia; Riches, Jamie; Regazzi, Ashley; Bajorin, Dean F.

    2009-01-01

    Purpose Sequential chemotherapy with doxorubicin and gemcitabine (AG) followed by ifosfamide, paclitaxel, and cisplatin (ITP) was previously demonstrated to be well tolerated in patients with advanced transitional cell carcinoma (TCC). This study sought to evaluate the efficacy and to additionally define toxicity. Patients and Methods Sixty patients with advanced TCC received AG every 2 weeks for five or six cycles followed by ITP every 21 days for four cycles. Granulocyte colony-stimulating factor was given between cycles. Results Myelosuppression was seen with 68% of patients who experienced grades 3 to 4 neutropenia and with 25% who experienced febrile neutropenia. Grade 3 or greater nonhematologic toxicities were infrequent. Forty (73%) of 55 evaluable patients (95% CI, 59% to 84%) demonstrated a major response (complete, n = 19; partial, n = 21) and had a median response duration of 11.3 months (range, 1.7 to ≥ 105.6 months). Twenty-seven (79%) of 34 patients with locally advanced disease (ie, T4, N0, M0) or with regional lymph node involvement (ie, T3-4, N1, M0) and 10 (56%) of 18 patients with distant metastases achieved a major response. The median progression-free survival was 12.1 months (95% CI, 9.0 to 14.8 months), and the median overall survival was 16.4 months (95% CI, 14.0 to 22.5 months). At a median follow-up of 76.4 months, seven (11.7%) patients remain alive, and all were disease free. Conclusion AG plus ITP is an active regimen in previously untreated patients with advanced TCC; however, it is associated with toxicity and does not clearly offer a benefit compared with other nonsequential, cisplatin-based regimens. PMID:19636012

  7. Intermediate dose gemcitabine-cisplatin combination chemotherapy without treatment delay for cytopenia followed by autografting--a new standard of care in relapsed or refractory Hodgkin lymphoma?

    PubMed

    Todd, T; Raj, S; Camilleri, D; Stafford, G; Bulusu, R; Follows, G; Williams, M; Marcus, R

    2009-11-01

    Ten percent to 20% of patients with Hodgkin Lymphoma (HL) are refractory to first-line therapy or relapse. Existing salvage regimens have response rates of 60-85%, considerable toxicity and frequent treatment delay or dose reduction. We report a gemcitabine, cisplatin, and dexamethasone regimen (GemCis) with intensive growth factor and platelet support and no treatment delay. Seventeen patients with relapsed or refractory biopsy proven HL were treated. Toxicity, transfusion requirement, stem cell harvesting and engraftment data were collected. Response assessment was by computed tomography and positron emission tomography. Overall and complete response rates were high (94% and 65%, respectively). There were no episodes of febrile neutropenia, treatment delays or hospital admissions. All 15 patients intended for autograft were successfully harvested. All engrafted successfully with a median time for the entire group to neutrophil engraftment of 14 days. With a median follow-up of 22 months, the median survival has not yet been reached, and the estimated 2-year survival is 88%. GemCis is a well-tolerated outpatient regimen for relapsed/ refractory Hodgkin lymphoma which does not inhibit stem cell mobilisation, gives excellent response rates and compares favourably with previously published salvage regimens using these or other chemotherapy agents. PMID:19418054

  8. A phase II clinical trial of gemcitabine and split dose cisplatin in advanced non-small cell lung cancer in an outpatient setting.

    PubMed

    Hussain, S A; Palmer, D H; Swinson, D E; Riley, P; Wills, A; Brown, C; Draycott, C; El-Modir, A; Peake, D R; Rea, D W; Chetiyawardana, A D; Cullen, M H

    2008-07-01

    In response to increasing pressure on inpatient services and a meta-analysis indicating that cisplatin (C) is superior to carboplatin, we report a phase II trial of gemcitabine (G) and split-dose C in advanced non-small cell lung cancer (NSCLC) in an outpatient setting. Patients with stage IIIB/IV NSCLC received: G/C 1250/40 mg/m(2); G and C were given on day (d) 1 and d8 in a 21d cycle. Patients with performance status 0-2, adequate bone marrow function and calculated glomerular filtration rate (GFR) >50 ml/min were eligible. Forty-two patients were enrolled: 25 male; median age 62 (range 37-78) years. There were 26 patients (62%) with stage IV disease. One hundred and thirty-eight cycles of chemotherapy were delivered. Chemotherapy was well tolerated, allowing maintenance of planned dose intensity (DI) with mean dose delivered of 780.1 mg/m(2) (93%) and 25.6 mg/m(2) (96%) for G and C, respectively. The overall response rate was 43%. Median survival was 12.5 months with a median follow-up of 13.5 months. One year survival rate was 51%. G plus C both given on d1 and d8 (q21d) is a very active, well tolerated and convenient outpatient schedule, which maintains DI. PMID:18575742

  9. Combined Chemoradiation Therapy With Twice-Weekly Gemcitabine and Cisplatin for Organ Preservation in Muscle-Invasive Bladder Cancer: Long-Term Results of a Phase 1 Trial

    SciTech Connect

    Azria, David; Riou, Olivier; Rebillard, Xavier; Thezenas, Simon; Thuret, Rodolphe; Fenoglietto, Pascal; Pouessel, Damien; Culine, Stephane

    2014-03-15

    Purpose: Concomitant treatment with radiation therapy and cisplatin (CDDP) remains the gold standard for bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC). We present the long-term results of a phase 1 clinical trial to assess the association of twice-weekly gemcitabine with CDDP and radiation therapy in this setting. Methods and Materials: Patients with pT2-pT4N0M0 MIBC without hydronephrosis or diffuse carcinoma in situ were enrolled in this study. After maximal transurethral resection of the bladder tumor, patients received concomitant radiation therapy (63 Gy in 1.8 fractions) and chemotherapy (CDDP 20 mg/m²/day over 4 days every 21 days and gemcitabine twice a week). The starting dose of gemcitabine was 15 mg/m² with dose escalation to 20, 25, and 30 mg/m². The primary endpoint was the maximum tolerated dose (MTD). Secondary endpoints included toxicity and tumor control. Results: Fourteen patients were enrolled. Dose-limiting toxicity occurred in 2 patients treated with 30 mg/m² gemcitabine (grade 4 thrombocytopenia and severe impairment of World Health Organization performance status, respectively). Nine patients received the complete chemoradiation therapy protocol. The recommended dose of gemcitabine was 25 mg/m². The median follow-up time was 53 months, and the overall and disease-specific 5-year survival rates were 62% and 77%, respectively. Among the patients who received the complete treatment, bladder-intact survival was 76% at 5 years, and the median overall survival was 69.6 months. Conclusions: This regimen was well tolerated. The gemcitabine MTD was 25 mg/m². Bladder preservation and disease control were promising. A multicenter phase 2 randomized trial is ongoing.

  10. Combination 5-fluorouracil, folinic acid and cisplatin (LV5FU2-CDDP) followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: final results of a randomised strategic phase III trial (FFCD 0301)

    PubMed Central

    Bonnetain, Frank; Ychou, Marc; Mitry, Emmanuel; Gasmi, Mohamed; Raoul, Jean-Luc; Cattan, Stéphane; Phelip, Jean-Marc; Hammel, Pascal; Chauffert, Bruno; Michel, Pierre; Legoux, Jean-Louis; Rougier, Philippe; Bedenne, Laurent; Seitz, Jean-François

    2010-01-01

    Purpose Gemcitabine is the standard chemotherapy for patients with metastatic pancreatic adenocarcinoma. Although the 5-fluorouracil (5FU), folinic acid and cisplatin combination (LV5FU2-CDDP) is an option, the optimal order of the regimens must be determined. The first strategic phase III trial comparing LV5FU2-CDDP followed by gemcitabine versus gemcitabine followed by LV5FU2-CDDP was conducted. Methods Patients with metastatic pancreatic adenocarcinoma, performance status (PS) 0–2, without prior chemotherapy were randomly assigned (1:1) to receive either LV5FU2-CDDP followed by gemcitabine at disease progression or toxicity (Arm A), or the opposite sequence (Arm B). 202 patients had to be included and 170 deaths had to be observed to detect an expected improvement in median overall survival (OS) from 6.5 to 10 months in Arm A (two-sided α = 5% and β = 20%). Results 202 patients were included (Arm A, 102; Arm B, 100). Median age, male/female ratio, PS 0–1 and previous surgery were similar in the two arms. After a median follow-up of 44 months, median OS in Arm A was 6.6 months versus 8.0 months in Arm B (p = 0.85). Median progression-free survival was similar between Arms A and B. More grade 3/4 toxicities were observed when LV5FU2-CDDP was administered as a first-line treatment compared with gemcitabine: 79% versus 64% (p = 0.018). Conclusion This trial did not show any strategic advantage to using LV5FU2-CDDP as a first-line treatment and suggests that gemcitabine remains the standard first-line treatment. Sixty-one per cent of patients were able to receive a second line of chemotherapy. PMID:20947887

  11. Cisplatin plus oral etoposide (EoP) combination is more effective than paclitaxel in patients with advanced breast cancer pretreated with anthracyclines: a randomised phase III trial of Turkish Oncology Group

    PubMed Central

    Icli, F; Akbulut, H; Uner, A; Yalcin, B; Baltali, E; Altinbas, M; Coşkun, Ş; Komurcu, S; Erkisi, M; Demirkazik, A; Senler, F C; Sencan, O; Büyükcelik, A; Boruban, C; Onur, H; Zengin, N; Sak, S D

    2005-01-01

    Our objective was to determine whether oral etoposide and cisplatin combination (EoP) is superior to paclitaxel in the treatment of advanced breast cancer (ABC) patients pretreated with anthracyclines. From December 1997 to August 2003, 201 patients were randomised, 100 to EoP and 101 to paclitaxel arms. Four patients in each arm were ineligible. The doses of etoposide and cisplatin were 50 mg p.o. twice a day for 7 days and 70 mg m−2 intravenously (i.v.) on day 1, respectively, and it was 175 mg m−2 on day 1 for paclitaxel. Both treatments were repeated every 3 weeks. A median of four cycles of study treatment was given in both arms. The response rate obtained in the EoP arm was significantly higher (36.3 vs 22.2%; P=0.038). Median response duration was longer for the EoP arm (7 vs 4 months) (P=0.132). Also, time to progression was significantly in favour of the EoP arm (5.5 vs 3.9 months; P=0.003). Median overall survival was again significantly longer in the EoP arm (14 vs 9.5 months; P=0.039). Toxicity profile of both groups was similar. Two patients in each arm were lost due to febrile neutropenia. The observed activity and acceptable toxicity of EoP endorses the employment of this combination in the treatment of ABC following anthracyclines. PMID:15726120

  12. Etoposide Injection

    MedlinePlus

    ... other medications to treat a certain type of lung cancer (small cell lung cancer; SCLC). Etoposide is in a class of medications ... organs where eggs are formed), another type of lung cancer (non-small cell lung cancer; NSCLC), and Kaposi's ...

  13. Maintenance monotherapy with Gemcitabine following cisplatin-based primary combination chemotherapy in surgically treated advanced urothelial carcinoma: A matched-pair single institution analysis

    PubMed Central

    KALOGIROU, CHARIS; SVISTUNOV, ANDREY; KREBS, MARKUS; LAUSENMEYER, EVA MARIA; VERGHO, DANIEL; RIEDMILLER, HUBERTUS; KOCOT, ARKADIUS

    2016-01-01

    The role of maintenance therapy with Gemcitabine (GEM) following cisplatin-based combination chemotherapy (CBCC) in patients with surgically treated advanced urothelial carcinoma (UC) remains to be fully elucidated. In the present case control study, a retrospective analysis was performed to evaluate the role of GEM monotherapy following surgical intervention for advanced UC. Between 1999 and 2013, 38 patients were identified with surgically treated advanced UC after having completed CBCC, who were additionally treated quarterly with two consecutive GEM (1,250 mg/m2) infusions as maintenance therapy. This collective was matched by propensity score matching to a control collective (n=38) that received primary CBCC alone, and the overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS) rates were determined for the two collectives using Kaplan-Meier estimates and the log-rank test. Regression analysis was performed using the Cox proportional hazards model. The median follow-up time was 37 months (interquartile range: 9–148). Interestingly, patients treated with GEM following primary chemotherapy had a significantly improved outcome with respect to the 5-year OS (46.2 vs. 26.4%, P=0.0314) and 5-year CSS (61.3 vs. 33.4%, P=0.0386) rates. Notably, the 5-year PFS rate did not differ between the two groups (10.3 vs. 16.1%, P=0.134). It is proposed that additional GEM maintenance monotherapy is able to improve survival rates following primary CBCC in surgically treated patients with advanced UC, suggesting a possible treatment option for patients with, e.g., unclear disease status, or those who would require an active maintenance therapy in the future. Prospective studies should further determine the impact of GEM monotherapy with respect to PFS rates in groups comprising larger numbers of patients. PMID:27073682

  14. Association of xeroderma pigmentosum group D (Asp312Asn, Lys751Gln) and cytidine deaminase (Lys27Gln, Ala70Thr) polymorphisms with outcome in Chinese non-small cell lung cancer patients treated with cisplatin-gemcitabine.

    PubMed

    Zhou, M; Ding, Y J; Feng, Y; Zhang, Q R; Xiang, Y; Wan, H Y

    2014-01-01

    Xeroderma pigmentosum group D (XPD) plays a key role in the repair of DNA and platinum resistance lesions. Cytidine deaminase (CDA) genes determine the velocity of gemcitabine catalysis. This study aimed to investigate the relationship between XPD and CDA genotypes and outcome in non-small lung cancer (NSCLC) patients. We used polymerase chain reaction-restriction fragment length polymorphism to evaluate genetic polymorphisms of XPD (Asp312Asn and Lys751Gln) and CDA (Lys27Gln and Ala70Thr) in 93 NSCLC patients treated with a cisplatin-gemcitabine regimen. There were no significant correlations between the XPD polymorphisms Asp312Asn and Lys751Gln with clinical benefits (P>0.05). Time to progression (TTP) did not differ between patients with wild type genotypes and those heterozygous for the single nucleotide polymorphism loci of XPD. However, a significant difference was observed in overall survival (OS) between XPD Asp312Asp and XPD Asp312Asn individuals (20.0 vs 12.4 months, P=0.04). Furthermore, the OS of patients with wild type genotypes was longer (20.5 months) than that of patients carrying the XPD 751Lys/Gln polymorphism (11.5 months). No significant differences in TTP or OS were observed in patients carrying different genotypes of CDA Lys27Gln, and no mutations were observed at the CDA Ala70Thr site. These results provide suggestive evidence of a favorable effect for the XPD 312Asp/Asp and XPD 751Lys/Lys genotypes with respect to overall survival rates in platinum-treated NSCLC patients. However, the CDA 27 polymorphism does not appear to affect the efficacy of gemcitabine. PMID:24841663

  15. An open-label, dose-escalation study to evaluate the safety and pharmacokinetics of CEP-9722 (a PARP-1 and PARP-2 inhibitor) in combination with gemcitabine and cisplatin in patients with advanced solid tumors.

    PubMed

    Awada, Ahmad; Campone, Mario; Varga, Andrea; Aftimos, Philippe; Frenel, Jean-Sébastien; Bahleda, Rastilav; Gombos, Andrea; Bourbouloux, Emmanuelle; Soria, Jean-Charles

    2016-04-01

    Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors may potentiate chemotherapy by hindering DNA damage repair pathways. CEP-9722 is the prodrug of CEP-8983, a selective inhibitor of PARP-1 and PARP-2. Preclinical studies and a prior phase 1 study suggested that CEP-9722 may cause less myelosuppression than has been observed with other oral PARP inhibitors. The primary objective of this study was to determine the maximum-tolerated dose of CEP-9722 in combination with gemcitabine and cisplatin in patients with advanced solid tumors. All patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8 of a 21-day cycle. Patients who completed one cycle of chemotherapy alone continued chemotherapy in combination with CEP-9722 150, 200, 300, or 400 mg orally twice daily on days 2-7, with dose-limiting toxicity assessed in cycle 2. Patients experiencing clinical benefit could continue treatment until disease progression or unacceptable toxicity. Thirty-two patients enrolled; 18 patients completed cycle 1 and received chemotherapy plus CEP-9722. The median (range) treatment administration with CEP-9722 was five (1-12) cycles. No patient experienced dose-limiting toxicity with CEP-9722 treatment. Grade 3/4 hematologic adverse events included neutropenia (28%) and leukopenia (11%); adverse events led to discontinuation in 33% of patients. One patient achieved complete response, three had partial responses, and 11 had stable disease; however, the relative contribution of CEP-9722 and/or the chemotherapeutic agents cannot be determined from this single-arm design. This study was discontinued before determination of the maximum-tolerated dose because of highly variable CEP-8983 exposure in all cohorts and toxicity, particularly chemotherapy-induced myelosuppression. PMID:26796987

  16. Gemcitabine in patients with ovarian cancer.

    PubMed

    Poveda, Andres

    2005-01-01

    Standard first-line treatment of ovarian cancer (OC) consists of platinum-taxane combined chemotherapy. However, this regimen only cures about 25% of women with OC. Phase II studies have shown that platinum-gemcitabine doublet and platinum-taxane-gemcitabine triplet regimens are active first-line chemotherapy in advanced OC, with overall response rates (ORR) above 55%. Several phase III studies of gemcitabine-based doublet and triplet chemotherapy in OC are currently underway. Preliminary data show that these regimens are well-tolerated, with manageable haematological toxicity, and the efficacy results are eagerly awaited. Gemcitabine is also active as second-line monotherapy in women with recurrent OC, and studies combining gemcitabine with paclitaxel, docetaxel, liposomal doxorubicin or topotecan resulted in higher ORR than gemcitabine alone. Gemcitabine-cisplatin and gemcitabine-carboplatin are active in women with platinum-resistant recurrent OC suggesting in vivo synergy between these two classes of drug. These studies show that gemcitabine-based chemotherapy may have an important role as second-line treatment in women with platinum-resistant OC. Gemcitabine combinations are also highly recommended as they avoid the problems of neurotoxicity and alopecia seen with other regimens. In order to respect the quality of life of women with recurrent OC, assessment of prognostic factors is recommended so that the most appropriate chemotherapy can be administered. PMID:16360545

  17. Can thymidine phosphorylase be a predictive marker for gemcitabine and doxifluridine combination chemotherapy in cholangiocarcinoma?: case series.

    PubMed

    Kang, Myoung Hee; Lee, Won Sup; Go, Se-Il; Kim, Moon Jin; Lee, Un Seok; Choi, Hye Jung; Kim, Dong Chul; Lee, Jeong-Hee; Kim, Hoon-Gu; Bae, Kyung Soo; Cho, Jae Min

    2014-12-01

    Unresectable cholangiocarcinoma is poorly responded to chemotherapy, especially for the case refractory to gemcitabine and cisplatin. Here, we tested whether high expression of thymidine phosphorylase (TP) can be a predictive biomarker for the indicator for gemcitabine and doxifluridine combination chemotherapy in the cholangiocarcinoma refractory to gemcitabine and cisplatin. Immunohistochemical staining for TP was performed with a biopsy specimen. We accepted the result as positive when more than 10% of cancer cells were stained with moderate intensity. Here, we report 2 cases of TP-positive cholangiocarcinoma well controlled with gemcitabine and doxifluridine combination chemotherapy, which had been refractory to the first line treatment with gemcitabine and cisplatin combination chemotherapy. PMID:25526478

  18. [Therapeutic activity of gemcitabine in intracranial tumors].

    PubMed

    Stukov, A N; Filatova, L V; Latipova, D Kh; Bespalov, V G; Belyaeva, O A; Kireeva, G S; Vasilieva, I N; Alexandrov, V A; Maidin, M A; Semenov, A L; Vershinina, S F; Markochev, A B; Abduloeva, N Kh; Chubenko, V A; Semiglazova, T Yu

    2015-01-01

    Gemcitabine is known to exert a therapeutic effect on brain tumors despite the limited permeability of the blood-brain barrier (BBB). In our experimental research single intraperitoneal (i.p.) injection of gemcitabine 25 mg/kg provided increase in median survival of mice with intracranially transplanted Ehrlich carcinoma by 41-89% (p < 0.001). In this experimental model i.p. administration of gemcitabine (permeability of the BBB of less than 10%), carmustine (good permeability of the BBB), cyclophosphamide (poor permeability of the BBB) and cisplatin (doesn't penetrate through the BBB) increased median survival of mice by 88% (p < 0.001), 59% (p = 0.001), 35% (p = 0.005) and 18% (p = 0.302) respectively. Considering strong correlation between antitumor activity of the drugs (carmustine, cyclophosphamide and cisplatin) and their permeability of the BBB, efficacy of gemcitabine in intracranial tumors could be due to its wide range of therapeutic doses. PMID:26087611

  19. GDP (Gemcitabine, Dexamethasone, and Cisplatin) Is Highly Effective and Well-Tolerated for Newly Diagnosed Stage IV and Relapsed/Refractory Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type

    PubMed Central

    Wang, Jing-jing; Dong, Mei; He, Xiao-hui; Li, Ye-xiong; Wang, Wei-hu; Liu, Peng; Yang, Jian-liang; Gui, Lin; Zhang, Chang-gong; Yang, Sheng; Zhou, Sheng-yu; Shi, Yuan-kai

    2016-01-01

    Abstract This study was conducted to evaluate the effectiveness and tolerance of GDP (gemcitabine, dexamethasone, and cisplatin) regimen in patients with newly diagnosed stage IV and relapsed/refractory extranodal natural killer/T-cell lymphoma, nasal type (ENKTL). The study enrolled 41 ENKTL patients who received GDP regimen at the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 2008 and January 2015. The disease status was newly diagnosed stage IV in 15 patients and relapsed/refractory in 26 patients. The median number of cycles of chemotherapy per patient was 6 (range, 2–8 cycles). The overall response rate and complete-remission rate were 83.0% (34/41) and 41.5% (17/41), respectively. After a median follow-up of 16.2 months, 1-year progression-free survival rate and 1-year overall survival rate for the whole cohort were 54.5% and 72.7%. Grade 3 to 4 adverse events included neutropenia (34.1%), thrombocytopenia (19.5%), and anemia (14.6%). Our study has suggested high efficacy and low toxicity profile of GDP regimen in patients with newly diagnosed stage IV and relapsed/refractory ENKTL. PMID:26871836

  20. GDP (Gemcitabine, Dexamethasone, and Cisplatin) Is Highly Effective and Well-Tolerated for Newly Diagnosed Stage IV and Relapsed/Refractory Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type.

    PubMed

    Wang, Jing-Jing; Dong, Mei; He, Xiao-Hui; Li, Ye-Xiong; Wang, Wei-Hu; Liu, Peng; Yang, Jian-Liang; Gui, Lin; Zhang, Chang-Gong; Yang, Sheng; Zhou, Sheng-Yu; Shi, Yuan-Kai

    2016-02-01

    This study was conducted to evaluate the effectiveness and tolerance of GDP (gemcitabine, dexamethasone, and cisplatin) regimen in patients with newly diagnosed stage IV and relapsed/refractory extranodal natural killer/T-cell lymphoma, nasal type (ENKTL).The study enrolled 41 ENKTL patients who received GDP regimen at the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 2008 and January 2015.The disease status was newly diagnosed stage IV in 15 patients and relapsed/refractory in 26 patients. The median number of cycles of chemotherapy per patient was 6 (range, 2-8 cycles). The overall response rate and complete-remission rate were 83.0% (34/41) and 41.5% (17/41), respectively. After a median follow-up of 16.2 months, 1-year progression-free survival rate and 1-year overall survival rate for the whole cohort were 54.5% and 72.7%. Grade 3 to 4 adverse events included neutropenia (34.1%), thrombocytopenia (19.5%), and anemia (14.6%).Our study has suggested high efficacy and low toxicity profile of GDP regimen in patients with newly diagnosed stage IV and relapsed/refractory ENKTL. PMID:26871836

  1. Response of conventional chondrosarcoma to gemcitabine alone: a case report.

    PubMed

    Provenzano, Salvatore; Hindi, Nadia; Morosi, Carlo; Ghilardi, Mara; Collini, Paola; Casali, Paolo G; Stacchiotti, Silvia

    2015-01-01

    Conventional skeletal chondrosarcoma is a bone neoplasm, which is poorly sensitive to anthracyclines-based chemotherapy. We report on an 18-month-long tumour response to gemcitabine as single agent in a young patient with an advanced secondary peripheral conventional chondrosarcoma, previously treated unsuccessfully with anthracyclines, ifosfamide, platinum, etoposide. PMID:25793102

  2. Long Complete Remission Achieved with the Combination Therapy of Cisplatin and Gemcitabine in a Patient with Aggressive Natural Killer Cell Leukemia

    PubMed Central

    Koepke, John

    2015-01-01

    Aggressive natural killer cell leukemia (ANKL) is a rare and often lethal lymphoproliferative disorder. Patients may present with constitutional symptoms, jaundice, skin infiltration, lymphadenopathy, and hepatosplenomegaly. ANKL can progress quickly to multiorgan failure and survival is usually measured in weeks. Although a rapid and accurate diagnosis is critical, unfortunately there is no hallmark diagnostic marker of ANKL. We report a case of a 48-year-old male who was able to obtain a complete remission following cisplatin-based chemotherapy. We describe the details of the chemotherapy regimens used and a literature review of the treatment of ANKL. PMID:25694835

  3. Gemcitabine Injection

    MedlinePlus

    ... other chemotherapy drugs to treat a type of lung cancer (non-small cell lung cancer; NSCLC) that has spread to other parts of ... 3 weeks. When gemcitabine is used to treat lung cancer it is usually given on certain days every ...

  4. Comparison of the short-term efficacy of sequential treatment with intravesical single-port laparoscopic partial cystectomy with bladder preservation or open partial cystectomy in combination with cisplatin plus gemcitabine chemotherapy

    PubMed Central

    MAI, HAI-XING; LIU, JUN-LE; PEI, SHU-JUN; ZHAO, LI; QU, NAN; DONG, JIN-KAI; CHEN, BIAO; WANG, YA-LIN; HUANG, CHENG; CHEN, LI-JUN

    2015-01-01

    This study aimed to assess the short-term efficacy of sequential therapy for T2/T3a bladder cancer with intravesical single-port laparoscopic partial cystectomy or open partial cystectomy combined with cisplatin plus gemcitabine (GC) chemotherapy in a prospective randomized controlled study. Thirty patients with bladder cancer who underwent open partial cystectomy (group A) or single-port laparoscopic partial cystectomy (group B) and received standard GC chemotherapy were analyzed. Perioperative functional indicators and tumor recurrence during a 1-year postoperative follow-up were compared between the two groups. The baseline characteristics were comparable between the two groups. The mean operative time, amount of blood loss and duration of hospital stay were 90.3 min, 182.0 ml and 7.3 days, respectively, for group A, and 105.3 min, 49.3 ml and 5.8 days, respectively, for group B. No secondary postoperative bleeding, urine leakage, wound infection or other complications were observed in the two groups. Postoperative scarring was not evident in group B. The overall incidence of surgical complications, tumor recurrence rate and complications during chemotherapy in the postoperative follow-up period of 12 months were similar between the two groups. Single-port laparoscopic partial cystectomy surgery is an idea surgical method for the treatment of invasive bladder cancer, with good surgical effect, minimal invasiveness, rapid recovery and short hospital stay. The data from 1-year postoperative follow-up showed that laparoscopic surgery was superior with regard to perioperative bleeding, postoperative recovery and duration of indwelling urinary catheter use. However, regarding the tumor recurrence rate, long-term comparative details are required to determine the effect of laparoscopic surgery. PMID:26170915

  5. Cisplatin nanocapsules.

    PubMed

    de Kroon, Anton I P M; Staffhorst, Rutger W H M; Kruijff, Ben de; Burger, Koert N J

    2005-01-01

    Cisplatin nanocapsules represent a novel lipid formulation of the anticancer drug cis-diamminedichloroplatinum(II), in which nanoprecipitates of cisplatin are covered by a phospholipid bilayer coat consisting of an equimolar mixture of phosphatidylcholine and phosphatidylserine. Cisplatin nanocapsules are characterized by an unprecedented cisplatin-to-lipid molar ratio and exhibit strongly improved cytotoxicity against tumor cells in vitro compared with the free drug. Here, methods for preparing and characterizing cisplatin nanocapsules are reported. PMID:15721377

  6. The emerging role of pemetrexed (Alimta) and gemcitabine in non-small cell lung cancer.

    PubMed

    Le Chevalier, Thierry

    2003-08-01

    In recent years, several new cytotoxic agents have been investigated for the management of non-small cell lung cancer (NSCLC), including the antimetabolic gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and the new multitargeted antifolate pemetrexed (Alimta, Eli Lilly and Company), which are both among the most active agents in advanced NSCLC. Gemcitabine has become one of the key drugs in the management of NSCLC, alone or in association with platin compounds. Promising results have also been reported with pemetrexed used as a single-agent or in combination with cisplatin or gemcitabine. These results indicate that pemetrexed may also play a vital role in the treatment of NSCLC, malignant mesothelioma, and other solid tumors. Ongoing (and planned) trials are investigating the use of single-agent pemetrexed, or combinations with cisplatin, gemcitabine, and other cytotoxic agents in various malignancies. PMID:12947960

  7. In vitro antagonism between cisplatin and vinca alkaloids.

    PubMed Central

    Lee, K.; Tanaka, M.; Kanamaru, H.; Hashimura, T.; Yamamoto, I.; Konishi, J.; Kuze, F.

    1989-01-01

    The effects of the combination of cisplatin and other cytotoxic agents were studied in vitro. When A549 lung cancer cells were treated simultaneously with cisplatin and other cytotoxic agents, cisplatin additively increased the cytotoxic effects of etoposide, mitomycin C, adriamycin, 5-fluorouracil and 1-beta-D-arabinofuranosylcytosine, but antagonised those of vincristine, vindesine, vinblastine and podophyllotoxin. The antagonism between cisplatin and vincristine was also observed with HT29 colon cancer cells. NC65 renal carcinoma cells and A431 epidermoid carcinoma cells when these cells were simultaneously exposed to both agents. When A549 cells were exposed to cisplatin and vincristine sequentially, the antagonism between them was evident when cells were pretreated with cisplatin but not when treated in the opposite sequence. Therefore, when combination chemotherapy including cisplatin and vinca alkaloids is given, possible antagonism between them should be considered, especially in determining the schedule of drug administration. Images Figure 4 Figure 5 PMID:2757923

  8. Cost-effectiveness of paclitaxel plus cisplatin in advanced non-small-cell lung cancer

    PubMed Central

    Earle, C C; Evans, W K

    1999-01-01

    The aim of this study was to assess the cost-effectiveness of combination chemotherapy with paclitaxel/cisplatin, compared with standard etoposide/cisplatin in patients with advanced non-small cell lung cancer (NSCLC). We obtained the primary survival and resource utilization data from a large three-arm randomized trial comparing: paclitaxel 135 mg m−2 by 24-h intravenous (i.v.) infusion + cisplatin; paclitaxel 250 mg m−2 by 24-h i.v. infusion + cisplatin + granulocyte colony-stimulating factor (G-CSF); and standard etoposide/cisplatin in patients with stage IIIb or IV NSCLC. We also modelled the regimens with paclitaxel 135 mg m−2 + cisplatin administered as an outpatient by 3-h infusion, as clinical data suggest that this is equivalent to 24-h infusion. We collected costing data from the Ottawa Regional Cancer Centre and applied it to the resources consumed in the randomized trial. We integrated these data into the Statistics Canada POpulation HEalth Model (POHEM), which generated hypothetical cohorts of patients treated with each regimen. The POHEM model assigned diagnostic work-up, treatment, disease progression and survival characteristics to each individual in these cohorts and tabulated the costs associated with each. We did sensitivity analyses around the costs of chemotherapy and its administration, and the survival differences between the two regimens. All costs are in 1997 Canadian dollars ($1.00 Canadian ˜ £0.39 sterling). The perspective is that of the Canadian health care system. In the trial, the two paclitaxel-containing arms had almost identical survival curves with a median survival of 9.7 months compared with 7.4 months for etoposide/cisplatin. As administered in the trial, paclitaxel/cisplatin cost $76 370 per life-year gained (LYG) and paclitaxel/cisplatin/G-CSF $138 578 per LYG relative to etoposide/cisplatin. However, when modelled as an outpatient 3-h infusion, paclitaxel/cisplatin was moderately cost-effective at $30 619 per LYG

  9. Etoposide

    MedlinePlus

    ... cancer (cancer that begins in the female reproductive organs where eggs are formed). Talk to your doctor ... This branded product is no longer on the market. Generic alternatives may be available.

  10. Role of Insulin-Like Growth Factor-1 Signaling Pathway in Cisplatin-Resistant Lung Cancer Cells

    SciTech Connect

    Sun Yunguang; Zheng Siyuan; Torossian, Artour; Speirs, Christina K.; Schleicher, Stephen; Giacalone, Nicholas J.; Carbone, David P.; Zhao Zhongming; Lu Bo

    2012-03-01

    Purpose: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non-small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis. Methods and Materials: H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor. Results: Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation. Conclusions: The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment.

  11. Gemcitabine, Oxaliplatin, Tarceva &/or Cisplatin in HCC & Biliary Tree Cancers

    ClinicalTrials.gov

    2016-03-15

    Hepatocellular Carcinoma; Cholangiocellular Carcinoma; Cholangiocarcinoma of the Extrahepatic Bile Duct; Bile Duct Cancer; Periampullary Adenocarcinoma; Gallbladder Cancer; Extrahepatic Bile Duct Cancer

  12. Promising combination therapies with gemcitabine.

    PubMed

    Robinson, Blaine W; Ostruszka, Leo; Im, Michael M; Shewach, Donna S

    2004-04-01

    Because treatment regimens for breast cancer commonly include gemcitabine, we evaluated two promising combinations in preclinical studies: gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) with either ionizing radiation or docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Parsippany, NJ). In breast cancer cell lines that expressed either wild-type p53 (MCF-7) or mutant p53 (MCF-7/Adr), sensitivity to the cytotoxic effects of gemcitabine during a 24-hour incubation was similar (IC(50) values 80 and 60 nmol/L in MCF-7 and MCF-7/Adr, respectively). Both cell lines were well radiosensitized by gemcitabine at the corresponding IC(50), with radiation enhancement ratios of 1.6 to 1.7. Although the MCF-7 cells accumulated nearly twice as much gemcitabine triphosphate compared with the MCF-7/Adr cells, a similar reduction in 2'-deoxyadenosine 5'-triphosphate pools was observed. While the number of dying cells, as measured by sub-G1 DNA content or S-phase cells unable to replicate DNA, differed between the wild-type p53 or mutant p53-expressing cell lines, neither parameter correlated with radiosensitization. Docetaxel was a more potent cytotoxic agent than gemcitabine in MCF-7 cells (IC(50) = 1 nmol/L). Strong synergistic cytotoxicity was observed in cells treated with gemcitabine (24 hours) followed by docetaxel (24 hours) or the reverse sequence. However, simultaneous addition of the two drugs was antagonistic. To determine whether synergy with radiation or docetaxel was mediated by increased DNA damage, DNA double-strand breaks (double-strand breaks) were measured by immunostaining for phosphorylated H2AX. Ionizing radiation produced more double-strand breaks than gemcitabine alone, while no significant double-strand breaks formed with docetaxel alone. The addition of docetaxel or ionizing radiation to gemcitabine-treated cells did not increase H2AX foci formation. These results show that the combination of gemcitabine with ionizing radiation or docetaxel

  13. Pharmacokinetics and pharmacogenetics of Gemcitabine as a mainstay in adult and pediatric oncology: an EORTC-PAMM perspective.

    PubMed

    Ciccolini, Joseph; Serdjebi, Cindy; Peters, Godefridus J; Giovannetti, Elisa

    2016-07-01

    Gemcitabine is an antimetabolite ranking among the most prescribed anticancer drugs worldwide. This nucleoside analog exerts its antiproliferative action after tumoral conversion into active triphosphorylated nucleotides interfering with DNA synthesis and targeting ribonucleotide reductase. Gemcitabine is a mainstay for treating pancreatic and lung cancers, alone or in combination with several cytotoxic drugs (nab-paclitaxel, cisplatin and oxaliplatin), and is an option in a variety of other solid or hematological cancers. Several determinants of response have been identified with gemcitabine, i.e., membrane transporters, activating and inactivating enzymes at the tumor level, or Hedgehog signaling pathway. More recent studies have investigated how germinal genetic polymorphisms affecting cytidine deaminase, the enzyme responsible for the liver disposition of gemcitabine, could act as well as a marker for clinical outcome (i.e., toxicity, efficacy) at the bedside. Besides, constant efforts have been made to develop alternative chemical derivatives or encapsulated forms of gemcitabine, as an attempt to improve its metabolism and pharmacokinetics profile. Overall, gemcitabine is a drug paradigmatic for constant searches of the scientific community to improve its administration through the development of personalized medicine in oncology. PMID:27007129

  14. Drosophila melanogaster deoxyribonucleoside kinase activates gemcitabine

    SciTech Connect

    Knecht, Wolfgang; Mikkelsen, Nils Egil; Clausen, Anders Ranegaard; Willer, Mette; Gojkovic, Zoran

    2009-05-01

    Drosophila melanogaster multisubstrate deoxyribonucleoside kinase (Dm-dNK) can additionally sensitize human cancer cell lines towards the anti-cancer drug gemcitabine. We show that this property is based on the Dm-dNK ability to efficiently phosphorylate gemcitabine. The 2.2 A resolution structure of Dm-dNK in complex with gemcitabine shows that the residues Tyr70 and Arg105 play a crucial role in the firm positioning of gemcitabine by extra interactions made by the fluoride atoms. This explains why gemcitabine is a good substrate for Dm-dNK.

  15. Neuronal involvement in cisplatin neuropathy: prospective clinical and neurophysiological studies.

    PubMed

    Krarup-Hansen, A; Helweg-Larsen, S; Schmalbruch, H; Rørth, M; Krarup, C

    2007-04-01

    Although it is well known that cisplatin causes a sensory neuropathy, the primary site of involvement is not established. The clinical symptoms localized in a stocking-glove distribution may be explained by a length dependent neuronopathy or by a distal axonopathy. To study whether the whole neuron or the distal axon was primarily affected, we have carried out serial clinical and electrophysiological studies in 16 males with testicular cancer before or early and late during and after treatment with cisplatin, etoposide and bleomycin at limited (<400 mg/m2 cisplatin), conventional (approximately 400 mg/m2 cisplatin) or high (>400 mg/m2 cisplatin) doses. At cumulative doses of cisplatin higher than 300 mg/m2 the patients lost distal tendon and H-reflexes and displayed reduced vibration sense in the feet and the fingers. The amplitudes of sensory nerve action potentials (SNAP) from the fingers innervated by the median nerve and the dorsolateral side of the foot innervated by the sural nerve were 50-60% reduced, whereas no definite changes occurred at lower doses. The SNAP conduction velocities were reduced by 10-15% at cumulative doses of 400-700 mg/m2 consistent with loss of large myelinated fibres. SNAPs from primarily Pacinian corpuscles in digit 3 and the dorsolateral side of the foot evoked by a tactile probe showed similar changes to those observed in SNAPs evoked by electrical stimulation. At these doses, somatosensory evoked potentials (SEPs) from the tibial nerve had increased latencies of peripheral, spinal and central responses suggesting loss of central processes of large dorsal root ganglion cells. Motor conduction studies, autonomic function and warm and cold temperature sensation remained unchanged at all doses of cisplatin treatment. The results of these studies are consistent with degeneration of large sensory neurons whereas there was no evidence of distal axonal degeneration even at the lowest toxic doses of cisplatin. PMID:17301082

  16. Cyclopentenylcytosine does not enhance cisplatin-induced radiosensitization in human lung tumour cells

    PubMed Central

    RODERMOND, HANS M.; CATE, ROSEMARIE TEN; HAVEMAN, JAAP; VAN KUILENBURG, ANDRÉ; MEDEMA, JAN PAUL; VAN BREE, CHRIS; FRANKEN, NICOLAAS A.P.

    2010-01-01

    The search for agents that enhance the effect of ionizing radiation has been an object of study for decades. In this study, the sensitizing properties of cyclopentenylcytosine (CPEC) on radiation and cisplatin-induced radiosensitization in human squamous lung carcinoma cells were investigated. Human lung tumour SW-1573 cells (SWp, parental; SWg, gemcitabine-resistant) were incubated with CPEC and cisplatin and subsequently irradiated with different doses of γ-rays. Clonogenic survival was determined to measure the effectiveness of the treatments. CPEC (1 or 2 μM) treatment for 4 h decreased the plating efficiency to 75 and 50% in SWp and SWg cells, respectively. In the SWg cells, 0.1 and 1 μM CPEC for 4 h enhanced the cell killing effect of cisplatin. However, an increase was not noted in the SWp cells. Due to the moderate toxicity of 1 μM for 4 h, this CPEC dose was used in the radiosensitization experiments. However, CPEC neither radiosensitized the lung tumour cells nor enhanced the radiosensitizing effect of cisplatin. A 2-h incubation with 4 μM cisplatin also decreased the plating efficiency to 75–80% in the two cell lines. Using this cisplatin dose, radiosensitization was obtained in the two cell lines. Although cisplatin treatment clearly radiosensitized the lung tumour cells, CPEC treatment did not. Cisplatin-induced radiosensitization was also not enhanced by CPEC. PMID:22966339

  17. Etoposide sensitizes neuroblastoma cells expressing caspase 8 to TRAIL.

    PubMed

    Kim, Hye Ryung; Lee, Myoung Woo; Kim, Dae Seong; Jo, Ha Yeong; Lee, Soo Hyun; Chueh, Hee Won; Jung, Hye Lim; Yoo, Keon Hee; Sung, Ki Woong; Koo, Hong Hoe

    2012-01-01

    TRAIL [TNF (tumour necrosis factor)-related apoptosis-inducing ligand] is a promising agent for clinical use since it kills a wide range of tumour cells without affecting normal cells. We provide evidence that pretreatment with etoposide significantly enhanced TRAIL-mediated apoptosis via up-regulation of DR5 (death receptor 5 or TRAIL-R2) expression in the caspase 8 expressing neuroblastoma cell line, SK-N-MC. In addition, sequential treatment with etoposide and TRAIL increased caspases 8, 9 and 3 activation, Mcl-1 cleavage and Bid truncation, which suggests that the ability of etoposide and TRAIL to induce apoptosis is mediated through activation of an intrinsic signalling pathway. Although TRAIL-R2 expression increased in IMR-32 cells in response to etoposide treatment, cell death was not increased by concurrent treatment with TRAIL compared with etoposide alone, because the cells lacked caspase 8 expression. Restoration of caspase 8 expression by exposure to IFNγ (interferon γ) sensitizes IMR-32 cells to TRAIL. Moreover, pretreatment with etoposide increased TRAIL-induced apoptosis in caspase 8 restored IMR-32 cells through activation of a caspase cascade that included caspases 8, 9 and 3. These results indicate that the etoposide-mediated sensitization of neuroblastoma cells to TRAIL is associated with an increase in TRAIL-R2 expression and requires caspase 8 expression. These observations support the potential use of a combination of etoposide and TRAIL in future clinical trials. PMID:23124518

  18. Gemcitabine resistance in pancreatic ductal adenocarcinoma.

    PubMed

    Binenbaum, Yoav; Na'ara, Shorook; Gil, Ziv

    2015-11-01

    Pancreatic ductal adenocarcinoma (PDA) ranks fourth among cancer related deaths. The disappointing 5-year survival rate of below 5% stems from drug resistance to all known therapies, as well as from disease presentation at a late stage when PDA is already metastatic. Gemcitabine has been the cornerstone of PDA treatment in all stages of the disease for the last two decades, but gemcitabine resistance develops within weeks of chemotherapy initiation. From a mechanistic perspective, gemcitabine resistance may result from alterations in drug metabolism until the point that the cytidine analog is incorporated into the DNA, or from mitigation of gemcitabine-induced apoptosis. Both of these drug resistance modalities can be either intrinsic to the cancer cell, or influenced by the cancer microenvironment. Mechanisms of intrinsic gemcitabine resistance are difficult to tackle, as many of the genes that drive the carcinogenic process itself also interfere with gemcitabine-induced apoptosis. In this regard, recent understanding of the involvement of microRNAs in gemcitabine resistance may offer new opportunities to overcome intrinsic gemcitabine resistance. The characteristically fibrotic and immune infiltrated stroma of PDA that accompanies tumor inception and expansion is a lush ground for treatments aimed at targeting tumor microenvironment-mediated drug resistance. In the last couple of years, drugs interfering with tumor microenvironment have matured to clinical trials. Although drugs inducing 'stromal depletion' have yet failed to improve survival, they have greatly increased our understanding of tumor microenvironment-mediated drug resistance. In this review we summarize the current knowledge on intrinsic and environment-mediated gemcitabine resistance, and discuss the impact of these pathways on patient screening, and on future treatments aimed to potentiate gemcitabine activity. PMID:26690340

  19. Improvement in Gemcitabine-Induced Thrombotic Microangiopathy with Rituximab in a Patient with Ovarian Cancer: Mechanistic Considerations

    PubMed Central

    Murugapandian, Sangeetha; Bijin, Babitha; Mansour, Iyad; Daheshpour, Sepehr; Pillai, Biju G.; Thajudeen, Bijin; Salahudeen, Abdulla K.

    2015-01-01

    Gemcitabine is a potent and widely used anticancer drug. We report a case of gemcitabine-induced thrombotic microangiopathy (GCI-TMA), a known but not widely recognized complication of gemcitabine use, and our experience of treating GCI-TMA with rituximab. A 74-year-old woman was referred to our clinic for an evaluation of worsening renal function. She has recently been treated for ovarian cancer (diagnosed in 2011) with surgery (tumor debulking and bilateral salpingo-oophorectomy) along with cisplatin chemotherapy in 2012, followed by carboplatin/doxorubicin in 2013 and recent therapy for resistant disease with gemcitabine. Laboratory tests showed anemia, normal platelets and elevated lactate dehydrogenase. A peripheral smear revealed numerous schistocytes, and a kidney biopsy showed acute as well as chronic TMA. The patient continued on gemcitabine therapy, and treatment with plasma exchange was started. Since there was no response to treatment even after 5 sessions of plasma exchange, one dose of rituximab was given, which was associated with a drop in the creatinine level to 2 mg/dl. The pathogenesis of renal injury could be the effect of direct injury to the endothelium mediated by cytokines. Usual treatment includes withdrawing the drug and initiation of treatment with plasmapheresis with or without steroids. In cases resistant to plasmapheresis, treatment with rituximab can be tried. The mechanism of action of rituximab might be due to the reduced production of B-cell-dependent cytokines that drive endothelial dysfunction by depleting B cells. Patients receiving gemcitabine chemotherapy should be monitored for the development of TMA, and early treatment with plasma exchange along with rituximab might benefit these patients who already have a bad prognosis. PMID:26266248

  20. Therapeutic potential of sepantronium bromide YM155 in gemcitabine-resistant human urothelial carcinoma cells.

    PubMed

    Huang, Yen Ta; Cheng, Chuan Chu; Lin, Tzu Chun; Chiu, Ted H; Lai, Pei Chun

    2014-02-01

    Survivin is overexpressed in transitional cell carcinoma (TCC), the most common type of bladder cancer. Previous reports demonstrated that knockdown of survivin by siRNA induced apoptosis of TCC cells. The present study evaluated the therapeutic effects of sepantronium bromide (YM155), a novel small molecule survivin inhibitor under clinical trials, on TCC cells in vitro. BFTC905, a grade III TCC cell line derived from a patient of blackfoot disease in Taiwan, was the most gemcitabine-resistant cell line when compared to BFTC909, TSGH8301 and T24 in cytotoxicity assay, resulting from upregulation of securin and bcl-2 after gemcitabine treatment. YM155 caused potent concentration‑dependent cytotoxicity in 4 TCC cell lines (IC50s ≤20 nM), but exhibited no cytotoxicity in survivin-null primary human urothelial cells. For BFTC905 cells, addition of gemcitabine and/or cisplatin, the standard TCC chemotherapy regimen, to YM155 did not exert additive cytotoxic effects. Molecular analyses indicated that YM155 inhibited the proliferation of BFTC905 cells by increasing p27kip1, suppressing Ki-67, and inducing quiescence. In addition, YM155 elicited apoptosis manifested with DNA fragmentation through suppressing the expression of survivin, securin and bcl-2. Furthermore, YM155 induced autophagy in BFTC905 cells as autophagic inhibitor, 3-methyladenine, attenuated YM155-induced LC3B-II levels and reversed the cytotoxicity of YM155. mTOR inhibitors sirolimus and everolimus did not increase YM155-induced expression of LC3B-II nor augment YM155-induced cytotoxicity. These results indicate that YM155 exerts its lethal effect on BFTC905 cells via apoptotic and autophagic death pathways and suggest that YM155 may be a potential drug for the therapy of gemcitabine-resistant bladder cancer. PMID:24297644

  1. Modulation of PKM alternative splicing by PTBP1 promotes gemcitabine resistance in pancreatic cancer cells

    PubMed Central

    Calabretta, Sara; Bielli, Pamela; Passacantilli, Ilaria; Pilozzi, Emanuela; Fendrich, Volker; Capurso, Gabriele; Delle Fave, Gianfranco; Sette, Claudio

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and incurable disease. Poor prognosis is due to multiple reasons, including acquisition of resistance to gemcitabine, the first line chemotherapeutic approach. Thus, there is a strong need for novel therapies, targeting more directly the molecular aberrations of this disease. We found that chronic exposure of PDAC cells to gemcitabine selected a subpopulation of cells that are drug-resistant (DR-PDAC cells). Importantly, alternative splicing of the pyruvate kinase gene (PKM) was differentially modulated in DR-PDAC cells, resulting in promotion of the cancer-related PKM2 isoform, whose high expression also correlated with shorter recurrence free survival in PDAC patients. Switching PKM splicing by antisense oligonucleotides to favour the alternative PKM1 variant rescued sensitivity of DR-PDAC cells to gemcitabine and cisplatin, suggesting that PKM2 expression is required to withstand drug-induced genotoxic stress. Mechanistically, up-regulation of the polypyrimidine-tract binding protein (PTBP1), a key modulator of PKM splicing, correlated with PKM2 expression in DR-PDAC cell lines. PTBP1 was recruited more efficiently to PKM pre-mRNA in DR- than in parental PDAC cells. Accordingly, knockdown of PTBP1 in DR-PDAC cells reduced its recruitment to the PKM pre-mRNA, promoted splicing of the PKM1 variant and abolished drug resistance. Thus, chronic exposure to gemcitabine leads to up-regulation of PTBP1 and modulation of PKM alternative splicing in PDAC cells, conferring resistance to the drug. These findings point to PKM2 and PTBP1 as new potential therapeutic targets to improve response of PDAC to chemotherapy. PMID:26234680

  2. Modulation of PKM alternative splicing by PTBP1 promotes gemcitabine resistance in pancreatic cancer cells.

    PubMed

    Calabretta, S; Bielli, P; Passacantilli, I; Pilozzi, E; Fendrich, V; Capurso, G; Fave, G Delle; Sette, C

    2016-04-21

    Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and incurable disease. Poor prognosis is due to multiple reasons, including acquisition of resistance to gemcitabine, the first-line chemotherapeutic approach. Thus, there is a strong need for novel therapies, targeting more directly the molecular aberrations of this disease. We found that chronic exposure of PDAC cells to gemcitabine selected a subpopulation of cells that are drug-resistant (DR-PDAC cells). Importantly, alternative splicing (AS) of the pyruvate kinase gene (PKM) was differentially modulated in DR-PDAC cells, resulting in promotion of the cancer-related PKM2 isoform, whose high expression also correlated with shorter recurrence-free survival in PDAC patients. Switching PKM splicing by antisense oligonucleotides to favor the alternative PKM1 variant rescued sensitivity of DR-PDAC cells to gemcitabine and cisplatin, suggesting that PKM2 expression is required to withstand drug-induced genotoxic stress. Mechanistically, upregulation of the polypyrimidine-tract binding protein (PTBP1), a key modulator of PKM splicing, correlated with PKM2 expression in DR-PDAC cell lines. PTBP1 was recruited more efficiently to PKM pre-mRNA in DR- than in parental PDAC cells. Accordingly, knockdown of PTBP1 in DR-PDAC cells reduced its recruitment to the PKM pre-mRNA, promoted splicing of the PKM1 variant and abolished drug resistance. Thus, chronic exposure to gemcitabine leads to upregulation of PTBP1 and modulation of PKM AS in PDAC cells, conferring resistance to the drug. These findings point to PKM2 and PTBP1 as new potential therapeutic targets to improve response of PDAC to chemotherapy. PMID:26234680

  3. Novel approaches to deliver gemcitabine to cancers.

    PubMed

    Reddy, L Harivardhan; Couvreur, Patrick

    2008-01-01

    Univ. Paris-Sud XI, Faculté de Pharmacie, UMR CNRS 8612, 92296 Châtenay-Malabry Cedex, France. patrick.couvreur@u-psud.fr The objective of this review is to discuss the strategies adopted to improve the delivery of gemcitabine to tumors. Concomitant research in this area has implemented a wide variety of approaches such as, aerosolized formulations, prodrug conjugates, liposomes, nanoparticles and beads. Some of these strategies were also aimed at overcoming the rapid metabolization and drug resistance associated with gemcitabine. Aerosolized formulations were employed to treat the local tumors, while other approaches were aimed at the systemic therapy of cancers. The liposomal formulations considerably increased the half-life and the area under the curve (AUC) of gemcitabine, and simultaneously caused a marked improvement in the anticancer activity against experimental solid tumors developed orthotopically or at subcutaneous site. Alternatively, the prodrug conjugates of gemcitabine displayed considerable activity in vivo against various tumors. Especially, in the case of leukemia in which gemcitabine was demonstrated to be inactive, the lipidic conjugates displayed marked efficiency following systemic and oral administration. These conjugates induced greater apoptosis and also caused resistance reversal in the resistant leukemia types. Altogether, the delivery strategies adopted for gemcitabine led to a considerable improvement in the treatment of cancers at the preclinical stage, and some of them are potential candidates for clinical trials. PMID:18473859

  4. [Digital ischaemia and gemcitabine. Two new cases].

    PubMed

    Blaise, S; Appeltants, H; Carpentier, P H; Debru, J L

    2005-02-01

    Chemotherapy generates numerous adverse effects, but digital ischemia is usually associated with a paraneoplastic mechanism. In addition to thrombotic microangiopathy or hepatic or pulmonary venoocclusive disease gemcitabine appears to induce this type of complication. This study presents two cases of digital ischemia, which are very likely attributable to gemcitabine. The first case involved a 56-year-old female patient with lymph node metastatic squamous cell carcinoma, for which no primitive tumor could be identified. This carcinoma had been treated at a second stage with gemcitabine at a cumulative dose of 14 390 mg. Search for etiology revealed toxic vascularitis. Response was favourable after interruption of gemcitabine and prescription of a suitable medical treatment. The second case was a 74-year-old male patient with an infiltrating bladder urothelium carcinoma with lymph node metastasis. He had been treated by surgery and chemotherapy (gemcitabine and carboplatine). Gemcitabine-induced arterial thrombosis was diagnosed. Nine other cases of digital ischemia were identified in the literature. This rare adverse effect is probably underestimated. The other reported vascular side-effects are thrombotic microangiopathy, with an estimated occurrence of 1 per 6,000 patients and two cases of veno-occlusive disease. The pathogenic mechanisms have still not been fully elucidated. Precautions before use are necessary, especially in case of associated micro or macroangiopathy. PMID:15924070

  5. Nab-Paclitaxel Plus Gemcitabine for Metastatic Pancreatic Cancer

    Cancer.gov

    A summary of results from a phase III trial that compared the combination of albumin-bound paclitaxel (nab-paclitaxel [Abraxane®]) and gemcitabine (Gemzar®) versus gemcitabine alone in patients with metastatic pancreatic cancer.

  6. SL-01, an oral gemcitabine derivative, inhibited human cancer growth more potently than gemcitabine

    SciTech Connect

    Zhao, Cuirong; Yue, Bin; Liu, Huiping; Sun, Cuicui; Li, Wenbao; Qu, Xianjun

    2012-08-01

    SL-01, an oral gemcitabine derivative, was synthesized by introducing the moiety of 3-(dodecyloxycarbonyl)pyrazine-2-carbonyl at the N4-position on the cytidine ring of gemcitabine. Our goal in this study was to evaluate the efficacy of SL-01 on the growth of human cancers with gemcitabine as control. Experiments were performed on human non-small cell lung cancer NCI-H460 and colon cancer HCT-116 both in vitro and in vivo. In vitro assays, SL-01 significantly inhibited the growth of cancer cells as determined by the 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay. Further studies indicated that SL-01 induced the cancer cells to apoptosis showing chromatin condensation and externalization of phosphatidylserine. In in vivo studies, we evaluated the efficacy of SL-01 in nude mice bearing human cancer xenografts. SL-01 effectively delayed the growth of NCI-H460 and HCT-116 without significant loss of body weight. Molecular analysis indicated that the high efficacy of SL-01 was associated with its ability to induce apoptosis as evidenced by increase of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining cells, activation of caspase-9, caspase-3 and cleaved poly ADP-ribose polymerase (PARP) in tumor tissues. SL-01 also increased Bax/Bcl-2 ratio in cancer cells. These biological activities of SL-01 were more potential than that of gemcitabine. Based on these in vitro and in vivo results, SL-01 is proposed as a potent oral anticancer agent that may supplant the use of gemcitabine in the clinic. -- Highlights: ► An oral gemcitabine derivative SL-01 was synthesized. ► The effects of SL-01 were evaluated and its efficacy was compared with gemcitabine. ► The biological activities of SL-01 were more potent than that of gemcitabine. ► SL-01 could replace gemcitabine for clinical use.

  7. Interstitial Pneumonitis from Treatment with Gemcitabine

    PubMed Central

    Poole, Brolin B.; Brockman, Megan M.; Byrd, Debbie C.

    2014-01-01

    Introduction: The use of gemcitabine may lead to numerous adverse effects ranging from mild to very severe, such as interstitial pneumonitis. The diagnosis of this complication is based on multiple laboratory findings, radiographic evidence, and high clinical suspicion. Presented is a case report of a patient who met these criteria and had onset consistent with drug-induced interstitial pneumonitis. Case Presentation: A 76-year-old White female was treated with gemcitabine for pancreatic cancer. Two months after the initiation of therapy, she was admitted to the hospital for worsening dyspnea and cough. High clinical suspicion, bilateral interstitial opacities on chest x-ray, worsening pulmonary status, and onset 2 months after initiation of therapy led to the diagnosis of gemcitabine-induced interstitial pneumonitis. Steroid therapy with prednisone was initiated, and the patient’s clinical symptoms and radiographic findings improved. Discussion: Gemcitabine-induced interstitial pneumonitis is well described in the literature. It is a rare but serious complication associated with gemcitabine therapy in which patients present with worsening dyspnea. Most patients only require supportive care and discontinuation of the drug for treatment, but in severe cases supplemental oxygen and steroid therapy must be used before resolution of symptoms. It is important to obtain an accurate medication history to evaluate for other potentially pulmonary toxic medications. Radiographic findings such as bilateral infiltrates should be completely resolved after therapy. Conclusion: Radiographic findings, clinical symptoms, and clinical suspicion can lead to early recognition of interstitial pneumonitis from gemcitabine. Physician awareness of this adverse effect and early recognition are keys to providing prompt treatment in resolving symptoms and decreasing mortality. PMID:25477616

  8. Mismatch repair proficiency is not required for radioenhancement by gemcitabine

    SciTech Connect

    Bree, Chris van . E-mail: c.vanbree@amc.uva.nl; Rodermond, Hans M.; Vos, Judith de; Haveman, Jaap; Franken, Nicolaas

    2005-08-01

    Purpose: Mismatch repair (MMR) proficiency has been reported to either increase or decrease radioenhancement by 24-h incubations with gemcitabine. This study aimed to establish the importance of MMR for radioenhancement by gemcitabine after short-exposure, high-dose treatment and long-exposure, low-dose treatment. Methods and Materials: Survival of MMR-deficient HCT116 and MMR-proficient HCT116 + 3 cells was analyzed by clonogenic assays. Mild, equitoxic gemcitabine treatments (4 h, 0.1 {mu}M vs. 24 h, 6 nM) were combined with {gamma}-irradiation to determine the radioenhancement with or without recovery. Gemcitabine metabolism and cell-cycle effects were evaluated by high-performance liquid chromatography analysis and bivariate flow cytometry. Results: Radioenhancement after 4 h of 0.1 {mu}M of gemcitabine was similar in both cell lines, but the radioenhancement after 24 h of 6 nM of gemcitabine was reduced in MMR-proficient cells. No significant differences between both cell lines were observed in the gemcitabine metabolism or cell-cycle effects after these treatments. Gemcitabine radioenhancement after recovery was also lower in MMR-proficient cells than in MMR-deficient cells. Conclusion: Mismatch repair proficiency decreases radioenhancement by long incubations of gemcitabine but does not affect radioenhancement by short exposures to a clinically relevant gemcitabine dose. Our data suggest that MMR contributes to the recovery from gemcitabine treatment.

  9. Gemcitabine induces cell senescence in human pancreatic cancer cell lines.

    PubMed

    Song, Yao; Baba, Tomohisa; Mukaida, Naofumi

    2016-08-26

    Patients with pancreatic ductal adenocarcinoma (PDAC) commonly require chemotherapy because they frequently develop metastatic disease or locally advanced tumors. Gemcitabine, an analogue of cytosine arabinoside, is commonly used for PDAC treatment. We observed that gemcitabine induced senescence phenotypes characterized by enhanced senescence-associated β-galactosidase (SA β-Gal) staining and increased expression of senescence-associated molecules in two human pancreatic cancer cell lines, Miapaca-2 and Panc-1, which exhibit resistance to gemcitabine but not L3.pl cells with a high sensitivity to gemcitabine. Gemcitabine-induced cell senescence can be inhibited by reactive oxygen species inhibitor, N-acetyl cysteine. Although gemcitabine also enhanced CXCL8 expression, anti-CXCL8 antibody failed to reduce gemcitabine-induced increases in SA β-Gal-positive cell numbers. These observations would indicate that cell senescence can proceed independently of CXCL8 expression, a characteristic feature of senescence-associated secretion phenotype. PMID:27311854

  10. Gemcitabine-Based Combination Chemotherapy Followed by Radiation With Capecitabine as Adjuvant Therapy for Resected Pancreas Cancer

    SciTech Connect

    Desai, Sameer; Ben-Josef, Edgar; Griffith, Kent A.; Simeone, Diane; Greenson, Joel K.; Francis, Isaac R.; Hampton, Janet; Colletti, Lisa; Chang, Alfred E.; Lawrence, Theodore S.; Zalupski, Mark M.

    2009-12-01

    Purpose: To report outcomes for patients with resected pancreas cancer treated with an adjuvant regimen consisting of gemcitabine-based combination chemotherapy followed by capecitabine and radiation. Patients and Methods: We performed a retrospective review of a series of patients treated at a single institution with a common postoperative adjuvant program. Between January 2002 and August 2006, 43 resected pancreas cancer patients were offered treatment consisting of 4, 21-day cycles of gemcitabine 1 g/m{sup 2} intravenously over 30 min on Days 1 and 8, with either cisplatin 35 mg/m{sup 2} intravenously on Days 1 and 8 or capecitabine 1500 mg/m{sup 2} orally in divided doses on Days 1-14. After completion of combination chemotherapy, patients received a course of radiotherapy (54 Gy) with concurrent capecitabine (1330 mg/m{sup 2} orally in divided doses) day 1 to treatment completion. Results: Forty-one patients were treated. Median progression-free survival for the entire group was 21.7 months (95% confidence interval 13.9-34.5 months), and median overall survival was 45.9 months. In multivariate analysis a postoperative CA 19-9 level of >=180 U/mL predicted relapse and death. Toxicity was mild, with only two hospitalizations during adjuvant therapy. Conclusions: A postoperative adjuvant program using combination chemotherapy with gemcitabine and either cisplatin or capecitabine followed by radiotherapy with capecitabine is tolerable and efficacious and should be considered for Phase III testing in this group of patients.

  11. Differential Gene and MicroRNA Expression between Etoposide Resistant and Etoposide Sensitive MCF7 Breast Cancer Cell Lines

    PubMed Central

    Moitra, Karobi; Im, Kate; Limpert, Katy; Borsa, Alexander; Sawitzke, Julie; Robey, Rob; Yuhki, Naoya; Savan, Ram; Huang, Da Wei; Lempicki, Richard A.; Bates, Susan; Dean, Michael

    2012-01-01

    In order to develop targeted strategies for combating drug resistance it is essential to understand it’s basic molecular mechanisms. In an exploratory study we have found several possible indicators of etoposide resistance operating in MCF7VP cells, including up-regulation of ABC transporter genes, modulation of miRNA, and alteration in copy numbers of genes. PMID:23028896

  12. Curcumin enhances the cytogenotoxic effect of etoposide in leukemia cells through induction of reactive oxygen species

    PubMed Central

    Papież, Monika A; Krzyściak, Wirginia; Szade, Krzysztof; Bukowska-Straková, Karolina; Kozakowska, Magdalena; Hajduk, Karolina; Bystrowska, Beata; Dulak, Jozef; Jozkowicz, Alicja

    2016-01-01

    Curcumin may exert a more selective cytotoxic effect in tumor cells with elevated levels of free radicals. Here, we investigated whether curcumin can modulate etoposide action in myeloid leukemia cells and in normal cells of hematopoietic origin. HL-60 cell line, normal myeloid progenitor cluster of differentiation (CD)-34+ cells, and granulocytes were incubated for 4 or 24 hours at different concentrations of curcumin and/or etoposide. Brown Norway rats with acute myeloid leukemia (BNML) were used to prove the influence of curcumin on etoposide action in vivo. Rats were treated with curcumin for 23 days and etoposide was administered for the final 3 days of the experiment. Curcumin synergistically potentiated the cytotoxic effect of etoposide, and it intensified apoptosis and phosphorylation of the histone H2AX induced by this cytostatic drug in leukemic HL-60 cells. In contrast, curcumin did not significantly modify etoposide-induced cytotoxicity and H2AX phosphorylation in normal CD34+ cells and granulocytes. Curcumin modified the cytotoxic action of etoposide in HL-60 cells through intensification of free radical production because preincubation with N-acetyl-l-cysteine (NAC) significantly reduced the cytotoxic effect of curcumin itself and a combination of two compounds. In contrast, NAC did not decrease the cytotoxic effect of etoposide. Thus, oxidative stress plays a greater role in the cytotoxic effect of curcumin than that of etoposide in HL-60 cells. In vitro results were confirmed in a BNML model. Pretreatment with curcumin enhanced the antileukemic activity of etoposide in BNML rats (1.57-fold tumor reduction versus etoposide alone; P<0.05) and induced apoptosis of BNML cells more efficiently than etoposide alone (1.54-fold change versus etoposide alone; P<0.05), but this treatment protected nonleukemic B-cells from apoptosis. Thus, curcumin can increase the antileukemic effect of etoposide through reactive oxygen species in sensitive myeloid leukemia

  13. Dose Escalation of Gemcitabine Is Possible With Concurrent Chest Three-Dimensional Rather Than Two-Dimensional Radiotherapy: A Phase I Trial in Patients With Stage III Non-Small-Cell Lung Cancer

    SciTech Connect

    Zinner, Ralph G. Cox, James D.; Glisson, Bonnie S.; Pisters, Katherine M.W.; Herbst, Roy S.; Kies, Merril; Hong, Waun K.; Fossella, Frank V.

    2009-01-01

    Purpose: To determine in a Phase I study the maximum tolerated dose of weekly gemcitabine concurrent with radiotherapy in locally advanced non-small-cell lung cancer (NSCLC), as well as the relationship between the volume of the esophagus irradiated and severe esophagitis. Methods and Materials: Twenty-one patients with Stage III NSCLC received gemcitabine initially at 150 mg/m{sup 2}/wk over 7 weeks concurrently with chest radiotherapy to 63 Gy in 34 fractions. The first 9 patients underwent treatment with two-dimensional (2D) radiotherapy; the remaining 12 patients, with three-dimensional conformal radiotherapy (3D-CRT) and target volume reduced to clinically apparent disease. Consolidation was 4 cycles of gemcitabine at 1000 mg/m{sup 2}/wk and cisplatin 60 mg/m{sup 2}. Results: In the 2D group, the dose-limiting toxicity, Grade 3 esophagitis, occurred in 3 of 6 patients in the 150-mg/m{sup 2}/wk cohort and 2 of 3 patients in the 125-mg/m{sup 2}/wk cohort. No cases of Grade 3 esophagitis occurred at these doses in the 3D group. At gemcitabine 190 mg/m{sup 2}/wk, 2 of 6 patients in the 3D cohort had Grade 3 esophagitis. The mean percentages of esophagus irradiated to 60 Gy were 68% in the 2D cohort and 18% in the 3D cohort. Conclusions: We could not escalate the dose of gemcitabine with concurrent radiotherapy when using 2D planning because of severe acute esophagitis. However, we could escalate the dose of gemcitabine to 190 mg/m{sup 2}/wk when using 3D planning. The Phase II dose is 150 mg/m{sup 2}/wk. Three-dimensional CRT permitted the use of higher doses of gemcitabine.

  14. Liposomal squalenoyl-gemcitabine: formulation, characterization and anticancer activity evaluation

    NASA Astrophysics Data System (ADS)

    Pili, Barbara; ReddyCurrent Address: Sanofi-Aventis, 13 Quai Jules-Guesdes, 94403, Vitry-Sur-Seine, France., L. Harivardhan; Bourgaux, Claudie; Lepêtre-Mouelhi, Sinda; Desmaële, Didier; Couvreur, Patrick

    2010-08-01

    A new prodrug of gemcitabine, based on the covalent coupling of squalene to gemcitabine (GemSQ), has been designed to enhance the anticancer activity of gemcitabine, a nucleoside analogue active against a wide variety of tumors. In the present study, the feasibility of encapsulating GemSQ into liposomes either PEGylated or non-PEGylated has been investigated. The in vivo anticancer activity of these formulations has been tested on subcutaneous grafted L1210wt leukemia model and compared to that of free gemcitabine. The liposomal GemSQ appears to be a potential delivery system for the effective treatment of tumors.

  15. Oral treatment with etoposide in small cell lung cancer – dilemmas and solutions

    PubMed Central

    Rezonja, Renata; Knez, Lea; Cufer, Tanja; Mrhar, Ales

    2013-01-01

    Background Etoposide is a chemotherapeutic agent, widely used for the treatment of various malignancies, including small cell lung cancer (SCLC), an aggressive disease with poor prognosis. Oral etoposide administration exhibits advantages for the quality of life of the patient as well as economic benefits. However, widespread use of oral etoposide is limited by incomplete and variable bioavailability. Variability in bioavailability was observed both within and between patients. This suggests that some patients may experience suboptimal tumor cytotoxicity, whereas other patients may be at risk for excess toxicity. Conclusions The article highlights dilemmas as well as solutions regarding oral treatment with etoposide by presenting and analyzing relevant literature data. Numerous studies have shown that bioavailability of etoposide is influenced by genetic, physiological and environmental factors. Several strategies were explored to improve bioavailability and to reduce pharmacokinetic variability of oral etoposide, including desired and undesired drug interactions (e.g. with ketoconazole), development of suitable drug delivery systems, use of more water-soluble prodrug of etoposide, and influence on gastric emptying. In addition to genotype-based dose administration, etoposide is suitable for pharmacokinetically guided dosing, which enables dose adjustments in individual patient. Further, it is established that oral and intravenous schedules of etoposide in SCLC patients do not result in significant differences in treatment outcome, while results of toxicity are inconclusive. To conclude, the main message of the article is that better prediction of the pharmacokinetics of oral etoposide may encourage its wider use in routine clinical practice. PMID:23450046

  16. Nab-paclitaxel and Gemcitabine vs Gemcitabine Alone as Adjuvant Therapy for Patients With Resected Pancreatic Cancer (the "Apact" Study)

    ClinicalTrials.gov

    2016-06-22

    Pancreatic Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Digestive System Diseases; Endocrine System Diseases; Gemcitabine; Antimetabolites, Antineoplastic

  17. Gemcitabine Hydrochloride and Cisplatin or High-Dose Methotrexate, Vinblastine, Doxorubicin Hydrochloride, and Cisplatin in Treating Patients With Urothelial Cancer

    ClinicalTrials.gov

    2014-01-27

    Anterior Urethral Cancer; Localized Transitional Cell Cancer of the Renal Pelvis and Ureter; Posterior Urethral Cancer; Recurrent Bladder Cancer; Recurrent Urethral Cancer; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Stage III Bladder Cancer; Transitional Cell Carcinoma of the Bladder; Ureter Cancer; Urethral Cancer Associated With Invasive Bladder Cancer

  18. Defective hCNT1 Transport Contributes to Gemcitabine Chemoresistance in Ovarian Cancer Subtypes: Overcoming Transport Defects Using a Nanoparticle Approach

    PubMed Central

    Hung, Sau Wai; Marrache, Sean; Cummins, Shannon; Bhutia, Yangzom D.; Mody, Hardik; Hooks, Shelley B.; Dhar, Shanta; Govindarajan, Rajgopal

    2015-01-01

    Nucleoside analogs are used as chemotherapeutic options for the treatment of platinum-resistant ovarian cancers. Human concentrative nucleoside transporter 1 (hCNT1) is implicated in sensitizing solid tumors to nucleoside analogs although its role in determining drug efficacy in ovarian cancers remains unclear. Here we examined the functional expression of hCNT1 and compared its contributions towards gemcitabine efficacy in histological subtypes of ovarian cancer. Radioactivity analysis identified hCNT1-mediated 3H-gemcitabine transport in ovarian cancer cells to be significantly reduced compared with that of normal ovarian surface epithelial cells. Biochemical and immunocytochemical analysis identified that unlike normal ovarian cells which expressed high levels of hCNT1 at the apical cell surface, the transporter was either diminished in expression and/or mislocalized in cell lines of various subtypes of ovarian cancer. Retroviral expression of hCNT1 selectively rescued gemcitabine transport in cell lines representing serous, teratocarcinoma, and endometrioid subtypes, but not clear cell carcinoma (CCC). In addition, exogenous hCNT1 predominantly accumulated in intracytoplasmic vesicles in CCC suggesting defective cellular trafficking of hCNT1 as a contributing factor to transport deficiency. Despite diminution of hCNT1 transport in the majority of ovarian cancers and apparent trafficking defects with CCC, the chemotherapeutic efficacy of gemcitabine was broadly enhanced in all subtypes when delivered via engineered nanoparticles (NPs). Additionally, by bypassing the transport requirement, the delivery of a gemcitabine-cisplatin combination in NP formulation increased their synergistic interactions. These findings uncover hCNT1 as a putative determinant for nucleoside analog chemoresistance in ovarian cancer and may help rationalize drug selection and delivery strategies for various histological subtypes of ovarian cancer. PMID:25600708

  19. Pharmacokinetically guided dosing of carboplatin and etoposide during peritoneal dialysis and haemodialysis.

    PubMed Central

    English, M. W.; Lowis, S. P.; Peng, B.; Boddy, A.; Newell, D. R.; Price, L.; Pearson, A. D.

    1996-01-01

    Two patients with relapsed Wilms' tumour and renal failure requiring dialysis were given carboplatin and etoposide by pharmacokinetically guided dosing. The target area under the drug plasma concentration vs time curve (AUC) was 6 mg ml-1 min for carboplatin and 18 and 21 mg ml-1 min for etoposide. On course 1 measured AUCs of carboplatin and etoposide were 6 and 20 mg ml-1 min for patient 1 and 6 and 21 mg ml-1 min for patient 2 respectively. Peritoneal dialysis did not remove carboplatin or etoposide from the plasma, however carboplatin but not etoposide was cleared by haemodialysis. Therapy with carboplatin and etoposide is possible in children and adults with renal failure who require dialysis, but in this situation pharmacokinetic monitoring is essential. PMID:8611379

  20. Oral etoposide (VP16) in platinum-resistant epithelial ovarian cancer (EOC).

    PubMed

    Alici, Süleyman; Saip, Pinar; Eralp, Yeşim; Aydiner, Adnan; Topuz, Erkan

    2003-08-01

    This phase II study evaluates the efficacy and toxicity of a prolonged schedule second-line and third-line treatment of oral VP16 in patients with measurable advanced ovarian cancer resistant to, or relapsed following, platinum-based chemotherapy. Twenty-two eligible women with progressive or relapsed ovarian cancer resistant to platinum-based therapy were included in this study. All the patients had received more than one prior treatment, and had evidence of disease progression within 6 months of the previous chemotherapy. Eleven patients had received more than two different chemotherapy regimens. Fifteen patients had received consolidation therapy with intraperitoneal cisplatin after an initial treatment course with six cycles of a platinum-based combination regimen. All patients with measurable disease observed in abdominal computed tomography scans were given oral VP16 at a daily dose of 50 mg/m2 for 14 consecutive days with 4 weekly intervals. Among 22 assessable patients, there were one complete response (CR) and three partial responses (PR), so the objective response rate, which is the addition of CR and PR rates, was 18%. Seven patients (32%) had stable disease. Median duration of response and stable disease was 2.5 months (range: 1-10 months). Overall median survival was 11 months from study entry (range: 3-36 months). Toxicity for most patients was mild, but a few severe myelotoxicities occurred, and there were no treatment-related deaths. According to World Health Organization toxicity criteria grade III/IV thrombocytopenia was seen in 4 of 22 patients, grade III/IV neutropenia in 6 of 22 patients, and grade III anemia was observed in 3 of 22 patients. Nonhematologic toxicity was mild, and mucositis was the most frequently observed nonhematologic toxicity. Oral etoposide has considerable activity with a tolerable toxicity profile for the treatment of platinum-resistant epithelial ovarian cancer. PMID:12902885

  1. A multicentre phase II study of carboplatin and prolonged oral etoposide in the treatment of cancer of unknown primary site (CUPS).

    PubMed Central

    Warner, E.; Goel, R.; Chang, J.; Chow, W.; Verma, S.; Dancey, J.; Franssen, E.; Dulude, H.; Girouard, M.; Correia, J.; Gallant, G.

    1998-01-01

    Cisplatin-based combination chemotherapy is frequently used to treat patients with carcinoma of unknown primary site (CUPS). Response rates in the literature range from 12% to 26% and median survival from 5 to 7 months. The goal of this study was to evaluate the combination of carboplatin and prolonged oral etoposide in patients with CUPS, with the hope of minimizing toxicity but improving efficacy and convenience. Treatment consisted of carboplatin, 300 mg m(-2) on day 1, and oral etoposide 50 mg on days 1-20, every 4 weeks for up to nine cycles. A total of 33 patients were treated and all were evaluable for toxicity. Non-haematological toxicity was mild to moderate, with the exception of one case of grade 4 stomatitis. Grade 4 leucopenia was observed in eight (24%) patients and sepsis in four (12%), with two and possibly three treatment-related deaths. For the 26 patients evaluable for response, the response rate was 23% with responses lasting a median of 11 months (range 7-13 months), with one patient still responding at 12 months. An additional nine patients (35%) had stable disease. Median survival for all patients was 5.6 months (range 2 weeks to 33 months). The combination of carboplatin with prolonged oral etoposide has moderate activity similar to that of other platinum-based regimens and is a well tolerated, convenient, outpatient regimen. Dosing according to estimated creatinine clearance to achieve a carboplatin AUC of 6.0 mg ml(-1) min might have decreased the incidence of severe myelotoxicity without compromising the regimen's efficacy. PMID:9649162

  2. Ribonucleotide reductase is an effective target to overcome gemcitabine resistance in gemcitabine-resistant pancreatic cancer cells with dual resistant factors.

    PubMed

    Minami, Kentaro; Shinsato, Yoshinari; Yamamoto, Masatatsu; Takahashi, Homare; Zhang, Shaoxuan; Nishizawa, Yukihiko; Tabata, Sho; Ikeda, Ryuji; Kawahara, Kohich; Tsujikawa, Kazutake; Chijiiwa, Kazuo; Yamada, Katsushi; Akiyama, Shin-ichi; Pérez-Torras, Sandra; Pastor-Anglada, Marcal; Furukawa, Tatsuhiko; Yasuo, Takeda

    2015-03-01

    Gemcitabine is widely used for pancreatic, lung, and bladder cancer. However, drug resistance against gemcitabine is a large obstacle to effective chemotherapy. Nucleoside transporters, nucleoside and nucleotide metabolic enzymes, and efflux transporters have been reported to be involved in gemcitabine resistance. Although most of the resistant factors are supposed to be related to each other, it is unclear how one factor can affect the other one. In this study, we established gemcitabine-resistant pancreatic cancer cell lines. Gemcitabine resistance in these cells is caused by two major processes: a decrease in gemcitabine uptake and overexpression of ribonucleotide reductase large subunit (RRM1). Knockdown of RRM1, but not the overexpression of concentrative nucleoside transporter 1 (CNT1), could completely overcome the gemcitabine resistance. RRM1 knockdown in gemcitabine-resistant cells could increase the intracellular accumulation of gemcitabine by increasing the nucleoside transporter expression. Furthermore, a synergistic effect was observed between hydroxyurea, a ribonucleotide reductase (RR) inhibitor, and gemcitabine on the gemcitabine-resistant cells. Here we indicate that RR is one of the most promising targets to overcome gemcitabine resistance in gemcitabine-resistant cells with dual resistant factors. PMID:25837929

  3. Leucovorin, 5-fluorouracil, and gemcitabine: a phase I study.

    PubMed

    Poplin, E; Roberts, J; Tombs, M; Grant, S; Rubin, E

    1999-01-01

    Gemcitabine is a chemotherapy agent with efficacy in the treatment of lung, pancreas, bladder and breast cancer. It inhibits DNA synthesis by interfering with cytidine triphosphate production and also inhibits the activity of ribonucleotide reductase. Gemcitabine may potentiate fluorouracil's inhibition of thymidylate synthase. This inhibition would be expected to be sequence dependent, occurring only if gemcitabine were administered following fluorouracil (5FU). The combination of leucovorin, 5-FU, and gemcitabine was assessed in this phase I trial. Eligibility requirements included refractory solid tumor malignancy; adequate hematologic, renal and hepatic reserve; no prior therapy with the combination of leucovorin and 5FU, or with gemcitabine; ECOG performance status 0-2, and signed informed consent. Eleven men and nine women were eligible. The median age was 52.5 years and the median performance status was 1. All but three patients had prior chemotherapy. The starting doses were leucovorin 20 mg/m2, 5FU 255 mg/m2 and gemcitabine 600 mg/m2. 5FU and gemcitabine were escalated in tandem to 340 mg/m2 and 800 mg/m2 and thereafter to 425 mg/m2 and 1000 mg/m2, respectively. Gemcitabine administration always followed that of 5FU by 30 minutes. The median number of cycles was 2 (range 1-32). Two patients at the starting dose had disease progression within the first cycle with one death on day 28. One patient with cholangiocarcinoma had a partial response and remained on study for 40 months. There were no other responses. The maximum tolerated dose is leucovorin 20 mg/m2, 5FU 340 mg/m2, and gemcitabine 800 mg/m2. The impact of drug sequence remains undetermined. PMID:10555123

  4. Radiation Therapy Plus Cisplatin and Gemcitabine in Treating Patients With Cervical Cancer

    ClinicalTrials.gov

    2014-12-23

    Cervical Adenocarcinoma; Cervical Adenosquamous Carcinoma; Cervical Small Cell Carcinoma; Cervical Squamous Cell Carcinoma; Stage IB Cervical Cancer; Stage IIA Cervical Cancer; Stage IIB Cervical Cancer; Stage III Cervical Cancer; Stage IVA Cervical Cancer

  5. Gemcitabine Hydrochloride and Cisplatin With or Without Bevacizumab in Treating Patients With Advanced Urinary Tract Cancer

    ClinicalTrials.gov

    2016-09-15

    Bladder Urothelial Carcinoma; Distal Urethral Carcinoma; Infiltrating Bladder Urothelial Carcinoma Associated With Urethral Carcinoma; Metastatic Urothelial Carcinoma of the Renal Pelvis and Ureter; Proximal Urethral Carcinoma; Recurrent Bladder Carcinoma; Recurrent Prostate Carcinoma; Recurrent Urethra Carcinoma; Recurrent Urothelial Carcinoma of the Renal Pelvis and Ureter; Regional Urothelial Carcinoma of the Renal Pelvis and Ureter; Stage IV Bladder Cancer; Stage IV Prostate Cancer; Stage IV Urethral Cancer; Ureter Carcinoma

  6. Ricolinostat, Gemcitabine Hydrochloride, and Cisplatin in Treating Patients With Unresectable or Metastatic Cholangiocarcinoma

    ClinicalTrials.gov

    2016-08-02

    Non-Resectable Cholangiocarcinoma; Recurrent Cholangiocarcinoma; Stage III Extrahepatic Bile Duct Cancer; Stage III Intrahepatic Cholangiocarcinoma; Stage IIIA Hilar Cholangiocarcinoma; Stage IIIB Hilar Cholangiocarcinoma; Stage IVA Extrahepatic Bile Duct Cancer; Stage IVA Hilar Cholangiocarcinoma; Stage IVA Intrahepatic Cholangiocarcinoma; Stage IVB Extrahepatic Bile Duct Cancer; Stage IVB Hilar Cholangiocarcinoma; Stage IVB Intrahepatic Cholangiocarcinoma; Unresectable Extrahepatic Bile Duct Carcinoma

  7. Zidovudine, an anti-viral drug, resensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine by inhibition of the Akt-GSK3β-Snail pathway.

    PubMed

    Namba, T; Kodama, R; Moritomo, S; Hoshino, T; Mizushima, T

    2015-01-01

    Pancreatic cancer is one of the most difficult malignancies to treat owing to the rapid acquisition of resistance to chemotherapy. Gemcitabine, a first-line treatment for pancreatic cancer, prolongs patient survival by several months, and combination treatment with gemcitabine and other anti-cancer drugs in the clinic do not show any significant effects on overall survival. Thus, identification of a drug that resensitizes gemcitabine-resistant pancreatic cancer to gemcitabine and a better understanding of the molecular mechanisms of gemcitabine resistance are critical to develop new therapeutic options for pancreatic cancer. Here, we report that zidovudine resensitizes gemcitabine-resistant pancreatic cancer to gemcitabine as shown by screening a compound library, including clinical medicine, using gemcitabine-resistant cells. In analyzing the molecular mechanisms of zidovudine effects, we found that the epithelial-to-mesenchymal transition (EMT)-like phenotype and downregulation of human equilibrative nucleoside transporter 1 (hENT1) are essential for the acquisition of gemcitabine resistance, and zidovudine restored these changes. The chemical biology investigations also revealed that activation of the Akt-GSK3β-Snail1 pathway in resistant cells is a key signaling event for gemcitabine resistance, and zidovudine resensitized resistant cells to gemcitabine by inhibiting this activated pathway. Moreover, our in vivo study demonstrated that co-administration of zidovudine and gemcitabine strongly suppressed the formation of tumors by gemcitabine-resistant pancreatic cancer and prevented gemcitabine-sensitive pancreatic tumors from acquiring gemcitabine-resistant properties, inducing an EMT-like phenotype and downregulating hENT1 expression. These results suggested that co-treatment with zidovudine and gemcitabine may become a novel therapeutic strategy for pancreatic cancer by inhibiting chemoresistance-specific signaling. PMID:26111057

  8. Zidovudine, an anti-viral drug, resensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine by inhibition of the Akt-GSK3β-Snail pathway

    PubMed Central

    Namba, T; Kodama, R; Moritomo, S; Hoshino, T; Mizushima, T

    2015-01-01

    Pancreatic cancer is one of the most difficult malignancies to treat owing to the rapid acquisition of resistance to chemotherapy. Gemcitabine, a first-line treatment for pancreatic cancer, prolongs patient survival by several months, and combination treatment with gemcitabine and other anti-cancer drugs in the clinic do not show any significant effects on overall survival. Thus, identification of a drug that resensitizes gemcitabine-resistant pancreatic cancer to gemcitabine and a better understanding of the molecular mechanisms of gemcitabine resistance are critical to develop new therapeutic options for pancreatic cancer. Here, we report that zidovudine resensitizes gemcitabine-resistant pancreatic cancer to gemcitabine as shown by screening a compound library, including clinical medicine, using gemcitabine-resistant cells. In analyzing the molecular mechanisms of zidovudine effects, we found that the epithelial-to-mesenchymal transition (EMT)-like phenotype and downregulation of human equilibrative nucleoside transporter 1 (hENT1) are essential for the acquisition of gemcitabine resistance, and zidovudine restored these changes. The chemical biology investigations also revealed that activation of the Akt-GSK3β-Snail1 pathway in resistant cells is a key signaling event for gemcitabine resistance, and zidovudine resensitized resistant cells to gemcitabine by inhibiting this activated pathway. Moreover, our in vivo study demonstrated that co-administration of zidovudine and gemcitabine strongly suppressed the formation of tumors by gemcitabine-resistant pancreatic cancer and prevented gemcitabine-sensitive pancreatic tumors from acquiring gemcitabine-resistant properties, inducing an EMT-like phenotype and downregulating hENT1 expression. These results suggested that co-treatment with zidovudine and gemcitabine may become a novel therapeutic strategy for pancreatic cancer by inhibiting chemoresistance-specific signaling. PMID:26111057

  9. Theranostic etoposide phosphate/indium nanoparticles for cancer therapy and imaging

    NASA Astrophysics Data System (ADS)

    Srinivas, Ramishetti; Satterlee, Andrew; Wang, Yuhua; Zhang, Yuan; Wang, Yongjun; Huang, Leaf

    2015-11-01

    Etoposide phosphate (EP), a water-soluble anticancer prodrug, is widely used for treatment of many cancers. After administration it is rapidly converted to etoposide, its parent compound, which exhibits anticancer activity. Difficulty in parenteral administration necessitates the development of a suitable nanoparticle delivery system for EP. Here we have used indium both as a carrier to deliver etoposide phosphate to tumor cells and as a SPECT imaging agent through incorporation of 111In. Etoposide phosphate was successfully encapsulated together with indium in nanoparticles, and exhibited dose dependent cytotoxicity and induction of apoptosis in cultured H460 cancer cells via G2/M cell cycle arrest. In a mouse xenograft lung cancer model, etoposide phosphate/indium nanoparticles induce tumor cell apoptosis, leading to significant enhancement of tumor growth inhibition compared to the free drug.

  10. A Phase II Study of Weekly Paclitaxel Plus Gemcitabine as a Second-Line Therapy in Patients with Metastatic or Recurrent Small Cell Lung Cancer

    PubMed Central

    Yun, Tak; Kim, Heung Tae; Han, Ji-Youn; Yoon, Sung Jin; Kim, Hyae Young; Nam, Byung-Ho; Lee, Jin Soo

    2016-01-01

    Purpose Paclitaxel (P) and gemcitabine (G) are clinically synergistic in small cell lung cancer (SCLC). We evaluated the efficacy of PG as a salvage treatment for SCLC patients whose disease progressed after a platinum-containing regimen. Materials and Methods Eligibility included histologically confirmed SCLC, one dimensionally measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and progressive disease after platinum-based chemotherapy. Treatment consisted of P (80 mg/m2) and G (1,000 mg/m2) on days 1 and 8 of each cycle of 21 days until disease progression. Results Thirty-three patients seen between December 2005 and February 2009 were selected into this study. Thirty patients (91%) had received irinotecan-platinum, and three had received etoposide-platinum. Sixteen patients (49%) had a treatment-free interval of less than 3 months. The overall response rate was 30.3% (29.4% in sensitive relapse and 31.3% in refractory relapse). The median time to progression was 12.0 weeks and median overall survival (OS) 31.0 weeks, with a 1-year OS rate of 30.3%. Toxicities were moderate and manageable with 18.2% grade (G) 4 neutropenia, 24.2% G3 thrombocytopenia, 6.1% G3 sensory neuropathy, and 3% G3 asthenia. One patient developed febrile neutropenia. Conclusion Second-line paclitaxel and gemcitabine were well-tolerated and moderately active in SCLC patients previously treated with platinum-based chemotherapy. PMID:26044164

  11. Transport properties of pancreatic cancer describe gemcitabine delivery and response

    PubMed Central

    Koay, Eugene J.; Truty, Mark J.; Cristini, Vittorio; Thomas, Ryan M.; Chen, Rong; Chatterjee, Deyali; Kang, Ya’an; Bhosale, Priya R.; Tamm, Eric P.; Crane, Christopher H.; Javle, Milind; Katz, Matthew H.; Gottumukkala, Vijaya N.; Rozner, Marc A.; Shen, Haifa; Lee, Jeffery E.; Wang, Huamin; Chen, Yuling; Plunkett, William; Abbruzzese, James L.; Wolff, Robert A.; Varadhachary, Gauri R.; Ferrari, Mauro; Fleming, Jason B.

    2014-01-01

    Background. The therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) is partly ascribed to ineffective delivery of chemotherapy to cancer cells. We hypothesized that physical properties at vascular, extracellular, and cellular scales influence delivery of and response to gemcitabine-based therapy. Methods. We developed a method to measure mass transport properties during routine contrast-enhanced CT scans of individual human PDAC tumors. Additionally, we evaluated gemcitabine infusion during PDAC resection in 12 patients, measuring gemcitabine incorporation into tumor DNA and correlating its uptake with human equilibrative nucleoside transporter (hENT1) levels, stromal reaction, and CT-derived mass transport properties. We also studied associations between CT-derived transport properties and clinical outcomes in patients who received preoperative gemcitabine-based chemoradiotherapy for resectable PDAC. Results. Transport modeling of 176 CT scans illustrated striking differences in transport properties between normal pancreas and tumor, with a wide array of enhancement profiles. Reflecting the interpatient differences in contrast enhancement, resected tumors exhibited dramatic differences in gemcitabine DNA incorporation, despite similar intravascular pharmacokinetics. Gemcitabine incorporation into tumor DNA was inversely related to CT-derived transport parameters and PDAC stromal score, after accounting for hENT1 levels. Moreover, stromal score directly correlated with CT-derived parameters. Among 110 patients who received preoperative gemcitabine-based chemoradiotherapy, CT-derived parameters correlated with pathological response and survival. Conclusion. Gemcitabine incorporation into tumor DNA is highly variable and correlates with multiscale transport properties that can be derived from routine CT scans. Furthermore, pretherapy CT-derived properties correlate with clinically relevant endpoints. Trial registration. Clinicaltrials.gov NCT01276613

  12. Elevated Cellular PD1/PD-L1 Expression Confers Acquired Resistance to Cisplatin in Small Cell Lung Cancer Cells.

    PubMed

    Yan, Fei; Pang, Jiuxia; Peng, Yong; Molina, Julian R; Yang, Ping; Liu, Shujun

    2016-01-01

    Although small cell lung cancer (SCLC) is highly responsive to chemotherapies (e.g., cisplatin-etoposide doublet), virtually almost all responsive SCLC patients experience disease recurrence characterized by drug resistance. The mechanisms underlying cisplatin resistance remain elusive. Here we report that cell-intrinsic expression of PD1 and PD-L1, two immune checkpoints, is required for sustained expansion of SCLC cells under cisplatin selection. Indeed, PD1 and PD-L1 were expressed at a higher level in lung cancer cell lines, tumor tissues, and importantly, in SCLC cells resistant to cisplatin (H69R, H82R), when compared to respective controls. Genetic abrogation of PD1 and PD-L1 in H69R and H82R cells decreased their proliferation rate, and restored their sensitivity to cisplatin. Mechanistically, PD-L1 upregulation in H69R and H82R cells was attributed to the overexpression of DNA methyltransferase 1 (DNMT1) or receptor tyrosine kinase KIT, as knockdown of DNMT1 or KIT in H69R and H82R cells led to PD-L1 downregulation. Consequently, combined knockdown of PD-L1 with KIT or DNMT1 resulted in more pronounced inhibition of H69R and H82R cell growth. Thus, cell intrinsic PD1/PD-L1 signaling may be a predictor for poor efficacy of cisplatin treatment, and targeting the cellular PD1/PD-L1 axis may improve chemosensitization of aggressive SCLC. PMID:27610620

  13. Synergistic antiviral activity of gemcitabine and ribavirin against enteroviruses.

    PubMed

    Kang, Hyunju; Kim, Chonsaeng; Kim, Dong-eun; Song, Jae-Hyoung; Choi, Miri; Choi, Kwangman; Kang, Mingu; Lee, Kyungjin; Kim, Hae Soo; Shin, Jin Soo; Kim, Janghwan; Han, Sang-Bae; Lee, Mi-Young; Lee, Su Ui; Lee, Chong-Kyo; Kim, Meehyein; Ko, Hyun-Jeong; van Kuppeveld, Frank J M; Cho, Sungchan

    2015-12-01

    Enteroviruses are major causative agents of various human diseases, and some of them are currently considered to be an enormous threat to public health. However, no effective therapy is currently available for the treatment of these infections. We identified gemcitabine, a nucleoside-analog drug used for cancer treatment, from a screen of bioactive chemicals as a novel inhibitor of coxsackievirus B3 (CVB3) and enterovirus 71 (EV71). Gemcitabine potently inhibited the proliferation of CVB3 and EV71, as well as the replication of CVB3 and EV71 replicons, in cells with a low micromolar IC50 (1-5 μM). Its strong inhibitory effect was also observed in cells infected with human rhinoviruses, demonstrating broad-spectrum antiviral effects on enteroviruses. Mechanistically, an extensive analysis excluded the involvement of 2C, 3A, IRES-dependent translation, and also that of polyprotein processing in the antiviral effects of gemcitabine. Importantly, gemcitabine in combination with ribavirin, an antiviral drug currently being used against a few RNA viruses, exhibited a synergistic antiviral effect on the replication of CVB3 and EV71 replicons. Consequently, our results clearly demonstrate a new indication for gemcitabine as an effective broad-spectrum inhibitor of enteroviruses and strongly suggest a new therapeutic strategy using gemcitabine alone or in combination with ribavirin for the treatment of various diseases associated with enterovirus infection. PMID:26526589

  14. Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer

    PubMed Central

    Borad, Mitesh J.; Reddy, Shantan G.; Bahary, Nathan; Uronis, Hope E.; Sigal, Darren; Cohn, Allen L.; Schelman, William R.; Stephenson, Joe; Chiorean, E. Gabriela; Rosen, Peter J.; Ulrich, Brian; Dragovich, Tomislav; Del Prete, Salvatore A.; Rarick, Mark; Eng, Clarence; Kroll, Stew; Ryan, David P.

    2015-01-01

    Purpose TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer. Patients and Methods Patients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m2), gemcitabine plus TH-302 240 mg/m2 (G+T240), or gemcitabine plus TH-302 340 mg/m2 (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety. Results Two hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (−5,398 v −549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302–related AEs but were not associated with treatment discontinuation. Conclusion PFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study

  15. Wogonin potentiates the antitumor action of etoposide and ameliorates its adverse effects.

    PubMed

    Enomoto, Riyo; Koshiba, Chika; Suzuki, Chie; Lee, Eibai

    2011-05-01

    Wogonin, a flavone in the roots of Scutellaria baicalensis, reduced etoposide-induced apoptotic cell death in normal cells, such as bone marrow cells and thymocytes. On the other hand, wogonin potentiated the proapoptotic or cytotoxic action of etoposide in tumor cells, such as Jurkat, HL-60, A549, and NCI-H226. These contradictory actions of wogonin on apoptosis are distinguished by normal or cancer cell types. Wogonin had no effect on apoptosis induced by other anticancer agents in the tumor cells. Thus, the potentiation effect of wogonin was observed only in etoposide-induced apoptosis in tumor cells. In a functional assay for P-glycoprotein (P-gp), wogonin suppressed excretion of calcein, a substrate for P-gp, in these tumor cells. Moreover, wogonin decreased the excretion of radiolabeled etoposide and accordingly increased intracellular content of this agent in the cells. P-gp inhibitors showed a similar potentiation effect on etoposide-induced apoptosis in these tumor cells. Thus, wogonin is likely to potentiate the anticancer action of etoposide due to P-gp inhibition and accumulation of this agent. These findings suggest that wogonin may be a useful chemotherapeutic adjuvant to potentiate the pharmacological action of etoposide and ameliorate its adverse effects. PMID:20658136

  16. Spectroscopic detection of etoposide binding to chromatin components: The role of histone proteins

    NASA Astrophysics Data System (ADS)

    Chamani, Elham; Rabbani-Chadegani, Azra; Zahraei, Zohreh

    2014-12-01

    Chromatin has been introduced as a main target for most anticancer drugs. Etoposide is known as a topoisomerase II inhibitor, but its effect on chromatin components is unknown. This report, for the first time, describes the effect of etoposide on DNA, histones and DNA-histones complex in the structure of nucleosomes employing thermal denaturation, fluorescence, UV absorbance and circular dichroism spectroscopy techniques. The results showed that the binding of etoposide decreased UV absorbance and fluorescence emission intensity, altered secondary structure of chromatin and hypochromicity was occurred in thermal denaturation profiles. The drug exhibited higher affinity to chromatin compared to DNA. Quenching of drug chromophores with tyrosine residues of histones indicated that globular domain of histones is the site of etoposide binding. Moreover, the binding of etoposide to histones altered their secondary structure accompanied with hypochromicity revealing compaction of histones in the presence of the drug. From the results it is concludes that apart from topoisomerase II, chromatin components especially its protein moiety can be introduced as a new site of etoposide binding and histone proteins especially H1 play a fundamental role in this process and anticancer activity of etoposide.

  17. [Severe Hyponatremia after Cisplatin-Based Chemotherapy : Two Case Reports].

    PubMed

    Ohtaka, Mari; Hattori, Yusuke; Kumano, Yohei; Maeda, Yoko; Kondo, Takuya; Mochizuki, Taku; Kawahara, Takashi; Teranishi, Jun-Ichi; Miyoshi, Yasuhide; Yumura, Yasushi; Uemura, Hiroji

    2016-07-01

    Hyponatremia is one of the common electrolyte disorders associated with cisplatin (CDDP) administration. We report here two cases of hyponatremia associated with CDDP. Case 1 : A 75-year-old man with urothelial carcinoma of bladder (cT3N1M0) underwent neoadjuvant chemotherapy with CDDP and gemcitabine. He lost consciousness on the eighth day after the chemotherapy. Blood tests showed severe hyponatremia (Na 113 mEq/l), low plasma osmolality and high level of plasma vasopressin. Urine tests showed low osmolality. These findings were consistent with the syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH). His consciousness level was improved after saline infusion and fluid restriction. Case 2 : A 54-year-old man with penile cancer (cT3N2M0) underwent neoadjuvant chemotherapy with CDDP, paclitaxel and fluorouracil. He lost consciousness on the seventh day after the chemotherapy. Blood tests showed hyponatremia(Na 121 mEq/l) with renal dysfunction. We concluded that the hyponatremia is due to the renal salt wasting syndrome (RSWS) based on renal dysfunction and high urinary sodium excretion. His consciousness level was improved after saline infusion. Although it is difficult to distinguish between SIADH and RSWS, correct evaluation is necessary for appropriate management of hyponatremia after CDDP administration. PMID:27569354

  18. Cisplatin stimulates protein tyrosine phosphorylation in macrophages.

    PubMed

    Kumar, R; Shrivastava, A; Sodhi, A

    1995-03-01

    Cisplatin [cis-dichlorodiamine platinum (II)], a potent anti-tumor compound, stimulates immune responses by activating monocyte-macrophages and other cells of the immune system. The mechanism by which cisplatin activates these cells is poorly characterized. Since protein tyrosine phosphorylation appears to be a major intracellular signalling event that mediates cellular responses, we examined whether cisplatin alters tyrosine phosphorylation in macrophages. We found that cisplatin increased tyrosine phosphorylation of several proteins in peritoneal macrophages and in P388D1 and IC-21 macrophage cell lines. Treatment of macrophages with tyrosine kinase inhibitors, genestein and lavendustin A, inhibited cisplatin-stimulated protein tyrosine phosphorylation in macrophages. Macrophages treated with cisplatin also exhibit increased fluorescence with anti-phosphotyrosine-FITC antibody. These data indicate that protein tyrosine phosphorylation plays a role in cisplatin-induced activation of macrophages. PMID:7539662

  19. 76 FR 16445 - In the Matter of Certain Gemcitabine and Products Containing Same; Notice of Investigation

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-23

    ... COMMISSION In the Matter of Certain Gemcitabine and Products Containing Same; Notice of Investigation AGENCY... the sale within the United States after importation of certain gemcitabine and products containing... after importation of certain gemcitabine and products containing same by reason of infringement of...

  20. Etoposide incorporated into camel milk phospholipids liposomes shows increased activity against fibrosarcoma in a mouse model.

    PubMed

    Maswadeh, Hamzah M; Aljarbou, Ahmad N; Alorainy, Mohammed S; Alsharidah, Mansour S; Khan, Masood A

    2015-01-01

    Phospholipids were isolated from camel milk and identified by using high performance liquid chromatography and gas chromatography-mass spectrometry (GC/MS). Anticancer drug etoposide (ETP) was entrapped in liposomes, prepared from camel milk phospholipids, to determine its activity against fibrosarcoma in a murine model. Fibrosarcoma was induced in mice by injecting benzopyrene (BAP) and tumor-bearing mice were treated with various formulations of etoposide, including etoposide entrapped camel milk phospholipids liposomes (ETP-Cam-liposomes) and etoposide-loaded DPPC-liposomes (ETP-DPPC-liposomes). The tumor-bearing mice treated with ETP-Cam-liposomes showed slow progression of tumors and increased survival compared to free ETP or ETP-DPPC-liposomes. These results suggest that ETP-Cam-liposomes may prove to be a better drug delivery system for anticancer drugs. PMID:25821817

  1. The effect of food and concurrent chemotherapy on the bioavailability of oral etoposide.

    PubMed Central

    Harvey, V. J.; Slevin, M. L.; Joel, S. P.; Johnston, A.; Wrigley, P. F.

    1985-01-01

    There is no information on the effect of food or concurrent drug administration on the bioavailability of oral etoposide, despite the fact that treatment is frequently administered over several days and most often in combination with other cytotoxic agents. The influence of these factors has been studied in 11 patients, receiving combination cytotoxic therapy for extensive small cell lung carcinoma. Neither food nor concurrent oral or intravenous chemotherapy had a significant effect on the mean plasma concentrations of etoposide, achieved following oral administration. Wide variation in peak plasma concentrations and in area under the concentration time curve (AUC) occurred both between and within patients. It appears unnecessary for patients receiving etoposide (at 100 mg) to fast prior to drug administration. Furthermore, oral etoposide (at 100 mg and at 400 mg) may be given in combination with other cytotoxic agents without compromising its bioavailability. PMID:2994705

  2. The effect of quercetin on oxidative DNA damage and myelosuppression induced by etoposide in bone marrow cells of rats.

    PubMed

    Papież, Monika A

    2014-01-01

    There is increasing evidence for the existence of an association between the presence of etoposide phenoxyl radicals and the development of treatment-related acute myeloid leukemia (t-AML), which occurs in a few percent of patients treated with this chemotherapeutic agent. The most common side effect caused by etoposide is myelosuppression, which limits the use of this effective drug. The goal of the study was to investigate the influence of antioxidant querectin on myelosuppression and oxidative DNA damage caused by etoposide. The influence of quercetin and/or etoposide on oxidative DNA damage was investigated in LT-12 cell line and bone marrow cells of rats via comet assay. The effect of quercetin on myelosuppression induced by etoposide was invetsigated by cytological analysis of bone marrow smears stained with May-Grünwald-Giemsa stain. Etoposide caused a significant increase in oxidative DNA damage in bone marrow cells and LT-12 cell line in comparison to the appropriate controls. Quercetin significantly reduced the oxidative DNA damage caused by etoposide both in vitro and in vivo. Quercetin also significantly protected against a decrease in the percentage of myeloid precursors and erythroid nucleated cells caused by etoposide administration in comparison to the group treated with etoposide alone. The results of the study indicate that quercetin could be considered a protectively acting compound in bone marrow cells during etoposide therapy. PMID:24644549

  3. Stability of etoposide solutions in disposable infusion devices for day hospital cancer practices.

    PubMed

    Klasen, Alison; Kessari, Romain; Mercier, Lionel; Valade, Cyril; Grill, Jacques; Desmaris, Romain; Paci, Angelo

    2014-03-01

    In a context of day hospital care of cancer patients, a protocol combining etoposide and carboplatin is used in paediatrics. Disposable infusion devices can be used to improve patient quality of life and to optimize nursing time. Stability data are available for carboplatin in these devices but not for etoposide. The aim of this study was to determine the stability of etoposide solutions in these devices by monitoring the changing etoposide concentration. To study the changing etoposide concentration, we investigated three different concentrations, each in two different solvents: sodium chloride (NaCl) 0.9 % and dextrose 5 %, in Intermate(®) disposable infusion devices. Quantitative analyses were performed by high-performance liquid chromatography coupled with ultraviolet (UV) detection on samples collected over a 24-h study period. The results showed that 100 mg/L etoposide solutions were stable for 24 h in NaCl 0.9 % and for 12 h in dextrose 5 %, whatever the temperature. The 400-mg/L solutions were stable for 24 h in both diluents, whatever the temperature, whereas the 600-mg/L solutions when diluted in NaCl 0.9 % and dextrose 5 % in water were stable for 8 and 6 h, respectively. We found that precipitation was the main phenomenon responsible for decreased etoposide concentrations. This study allowed us to conclude that etoposide solutions prepared in Intermate(®) infusion devices are stable for day hospital administration in paediatrics. It will also allow us to conduct a future clinical study that will focus on the medico-economic feasibility of this protocol and on the evaluation of patient and nurse satisfaction. PMID:24627337

  4. Anti-mutagenic activity of Salvia merjamie extract against gemcitabine.

    PubMed

    Alanazi, Khalid Mashay

    2015-01-01

    Gemcitabine is an anti-cancer drug with clinically uses in the treatment of various neoplasms, including breast, ovarian, non-small cell lung, pancreaticand cervical cancers, T-cell malignancies, germ cell tumours, and hepatocellular carcinomas. However, it has also been reported to have many adverse effects. Naturally occurring anti-mutagenic effects, especially those of plant origin, have recently become a subject of intensive research. The present study was therefore designed to investigate the anti-mutagenic effects of Salvia merjamie (Family: Lamiaceae) plant extracts against the mutagenic effects of gemcitabine. The anti-mutagenic properties of Salvia merjamie were tested in Inbred SWR/J male and female mice bone marrow cells. The mice were treated in four groups; a control group treated with 30 mg/kg body weight gemcitabine and three treatment groups, each with 30 mg/kg body weight gemcitabine together with, respectively, 50, 100 and 150 mg/kg body weight Salvia merjamie extract. Chromosomal aberration and mitotic index assays were performed with the results demonstrating that Salvia merjamie extract protects bone marrow cells in mice against gemcitabine induced mutagenicity. This information can be used for the development of a potential therapeutic anti-mutagenic agents. PMID:25743821

  5. Etoposide selectively ablates activated T cells to control the immunoregulatory disorder hemophagocytic lymphohistiocytosis.

    PubMed

    Johnson, Theodore S; Terrell, Catherine E; Millen, Scott H; Katz, Jonathan D; Hildeman, David A; Jordan, Michael B

    2014-01-01

    Hemophagocytic lymphohistiocytosis (HLH) is an inborn disorder of immune regulation caused by mutations affecting perforin-dependent cytotoxicity. Defects in this pathway impair negative feedback between cytotoxic lymphocytes and APCs, leading to prolonged and pathologic activation of T cells. Etoposide, a widely used chemotherapeutic drug that inhibits topoisomerase II, is the mainstay of treatment for HLH, although its therapeutic mechanism remains unknown. We used a murine model of HLH, involving lymphocytic choriomeningitis virus infection of perforin-deficient mice, to study the activity and mechanism of etoposide for treating HLH and found that it substantially alleviated all symptoms of murine HLH and allowed prolonged survival. This therapeutic effect was relatively unique among chemotherapeutic agents tested, suggesting distinctive effects on the immune response. We found that the therapeutic mechanism of etoposide in this model system involved potent deletion of activated T cells and efficient suppression of inflammatory cytokine production. This effect was remarkably selective; etoposide did not exert a direct anti-inflammatory effect on macrophages or dendritic cells, and it did not cause deletion of quiescent naive or memory T cells. Finally, etoposide's immunomodulatory effects were similar in wild-type and perforin-deficient animals. Thus, etoposide treats HLH by selectively eliminating pathologic, activated T cells and may have usefulness as a novel immune modulator in a broad array of immunopathologic disorders. PMID:24259502

  6. The expression of vimentin in HL-60 cells induced with etoposide using immunofluorescence and immunogold methods.

    PubMed

    Grzanka, A

    2001-01-01

    HL-60 leukemic cells were treated with 6 different doses of etoposide for 72 hours. Changes in the distribution of vimentin were found to be dependent on the concentration of etoposide. As compared with control cells there were distinct changes in cells incubated with 100 and 200 microM/L of the drug. The size of cells treated with 100 microM/L and especially with 200 microM/L increased, but the number of cells decreased. In control cells and those treated with 0.02, 0.2 and 2 microM/L etoposide, vimentin was seen rather as a ring often with the increased concentration near one pole of the cells. Cells at 20 microM/L etoposide showed the same staining pattern but more brighter cells were found. The addition of 100 microM/L and 200 microM/L etoposide to cells resulted in diffusely distributed fluorescence staining, which often appeared as a quite dense network around the nucleus. Immunogold labelling was observed in cells treated with all doses of etoposide and control cells. Labelling was localized in the nucleus but also in the cytoplasm but rather in the area of the nucleus. PMID:11915179

  7. Membrane Transition Temperature Determines Cisplatin Response.

    PubMed

    Raghunathan, Krishnan; Ahsan, Aarif; Ray, Dipankar; Nyati, Mukesh K; Veatch, Sarah L

    2015-01-01

    Cisplatin is a classical chemotherapeutic agent used in treating several forms of cancer including head and neck. However, cells develop resistance to the drug in some patients through a range of mechanisms, some of which are poorly understood. Using isolated plasma membrane vesicles as a model system, we present evidence suggesting that cisplatin induced resistance may be due to certain changes in the bio-physical properties of plasma membranes. Giant plasma membrane vesicles (GPMVs) isolated from cortical cytoskeleton exhibit a miscibility transition between a single liquid phase at high temperature and two distinct coexisting liquid phases at low temperature. The temperature at which this transition occurs is hypothesized to reflect the magnitude of membrane heterogeneity at physiological temperature. We find that addition of cisplatin to vesicles isolated from cisplatin-sensitive cells result in a lowering of this miscibility transition temperature, whereas in cisplatin-resistant cells such treatment does not affect the transition temperature. To explore if this is a cause or consequence of cisplatin resistance, we tested if addition of cisplatin in combination with agents that modulate GPMV transition temperatures can affect cisplatin sensitivity. We found that cells become more sensitive to cisplatin when isopropanol, an agent that lowers GPMV transition temperature, was combined with cisplatin. Conversely, cells became resistant to cisplatin when added in combination with menthol that raises GPMV transition temperatures. These data suggest that changes in plasma membrane heterogeneity augments or suppresses signaling events initiated in the plasma membranes that can determine response to cisplatin. We postulate that desired perturbations of membrane heterogeneity could provide an effective therapeutic strategy to overcome cisplatin resistance for certain patients. PMID:26484687

  8. Membrane Transition Temperature Determines Cisplatin Response

    PubMed Central

    Raghunathan, Krishnan; Ahsan, Aarif; Ray, Dipankar; Nyati, Mukesh K.; Veatch, Sarah L.

    2015-01-01

    Cisplatin is a classical chemotherapeutic agent used in treating several forms of cancer including head and neck. However, cells develop resistance to the drug in some patients through a range of mechanisms, some of which are poorly understood. Using isolated plasma membrane vesicles as a model system, we present evidence suggesting that cisplatin induced resistance may be due to certain changes in the bio-physical properties of plasma membranes. Giant plasma membrane vesicles (GPMVs) isolated from cortical cytoskeleton exhibit a miscibility transition between a single liquid phase at high temperature and two distinct coexisting liquid phases at low temperature. The temperature at which this transition occurs is hypothesized to reflect the magnitude of membrane heterogeneity at physiological temperature. We find that addition of cisplatin to vesicles isolated from cisplatin-sensitive cells result in a lowering of this miscibility transition temperature, whereas in cisplatin-resistant cells such treatment does not affect the transition temperature. To explore if this is a cause or consequence of cisplatin resistance, we tested if addition of cisplatin in combination with agents that modulate GPMV transition temperatures can affect cisplatin sensitivity. We found that cells become more sensitive to cisplatin when isopropanol, an agent that lowers GPMV transition temperature, was combined with cisplatin. Conversely, cells became resistant to cisplatin when added in combination with menthol that raises GPMV transition temperatures. These data suggest that changes in plasma membrane heterogeneity augments or suppresses signaling events initiated in the plasma membranes that can determine response to cisplatin. We postulate that desired perturbations of membrane heterogeneity could provide an effective therapeutic strategy to overcome cisplatin resistance for certain patients. PMID:26484687

  9. Obatoclax, saliphenylhalamide, and gemcitabine inhibit influenza a virus infection.

    PubMed

    Denisova, Oxana V; Kakkola, Laura; Feng, Lin; Stenman, Jakob; Nagaraj, Ashwini; Lampe, Johanna; Yadav, Bhagwan; Aittokallio, Tero; Kaukinen, Pasi; Ahola, Tero; Kuivanen, Suvi; Vapalahti, Olli; Kantele, Anu; Tynell, Janne; Julkunen, Ilkka; Kallio-Kokko, Hannimari; Paavilainen, Henrik; Hukkanen, Veijo; Elliott, Richard M; De Brabander, Jef K; Saelens, Xavier; Kainov, Denis E

    2012-10-12

    Influenza A viruses (IAVs) infect humans and cause significant morbidity and mortality. Different treatment options have been developed; however, these were insufficient during recent IAV outbreaks. Here, we conducted a targeted chemical screen in human nonmalignant cells to validate known and search for novel host-directed antivirals. The screen validated saliphenylhalamide (SaliPhe) and identified two novel anti-IAV agents, obatoclax and gemcitabine. Further experiments demonstrated that Mcl-1 (target of obatoclax) provides a novel host target for IAV treatment. Moreover, we showed that obatoclax and SaliPhe inhibited IAV uptake and gemcitabine suppressed viral RNA transcription and replication. These compounds possess broad spectrum antiviral activity, although their antiviral efficacies were virus-, cell type-, and species-specific. Altogether, our results suggest that phase II obatoclax, investigational SaliPhe, and FDA/EMEA-approved gemcitabine represent potent antiviral agents. PMID:22910914

  10. ETOPOSIDE INDUCES CHROMOSOMAL ABNORMALITIES IN SPERMATOCYTES AND SPERMATOGONIAL STEM CELLS

    SciTech Connect

    Marchetti, F; Pearson, F S; Bishop, J B; Wyrobek, A J

    2005-07-15

    Etoposide (ET) is a chemotherapeutic agent widely used in the treatment of leukemia, lymphomas and many solid tumors, such as testicular and ovarian cancers, that affect patients in their reproductive years. The purpose of the study was to use sperm FISH analyses to characterize the long-term effects of ET on male germ cells. We used a mouse model to characterize the induction of chromosomal aberrations (partial duplications and deletions) and whole chromosomal aneuploidies in sperm of mice treated with a clinical dose of ET. Semen samples were collected at 25 and 49 days after dosing to investigate the effects of ET on meiotic pachytene cells and spermatogonial stem-cells, respectively. ET treatment resulted in major increases in the frequencies of sperm carrying chromosomal aberrations in both meiotic pachytene (27- to 578-fold) and spermatogonial stem-cells (8- to 16-fold), but aneuploid sperm were induced only after treatment of meiotic cells (27-fold) with no persistent effects in stem cells. These results demonstrate that male meiotic germ cells are considerably more sensitive to ET than spermatogonial stem-cell and that increased frequencies of sperm with structural aberrations persist after spermatogonial stem-cell treatment. These findings predict that patients who undergo chemotherapy with ET may have transient elevations in the frequencies of aneuploid sperm, but more importantly, may have persistent elevations in the frequencies of sperm with chromosomal aberrations, placing them at higher risk for abnormal reproductive outcomes long after the end of their chemotherapy.

  11. Distribution of Gemcitabine Is Nearly Homogenous in Two Orthotopic Murine Models of Pancreatic Cancer.

    PubMed

    Kramer, Robin M; Russell, James; Humm, John L

    2015-09-01

    Pancreatic cancer is one of the leading causes of cancer-related death in the United States. Gemcitabine is a common treatment, but response rates are low, perhaps due in part to tumor hypoxia. We utilized (14)C-labeled gemcitabine to map distribution of the drug with respect to perfused and hypoxic regions of the tumor microenvironment in two orthotopic xenograft models of pancreatic cancer. There was only a slight reduction in gemcitabine in hypoxic areas, with ∼78% of the drug present in hypoxic compared to perfused areas. In addition, only a 4% reduction in gemcitabine was measured at >100 μm from perfused blood vessels. Thus, despite significant areas of hypoxia in these tumors, gemcitabine distribution is relatively homogenous. Ours is the first study to directly measure gemcitabine distribution within tumor tissue, demonstrating that in these models, tumor tissue does not represent a barrier to gemcitabine penetration. PMID:26203552

  12. In vitro cross-resistance and collateral sensitivity in seven resistant small-cell lung cancer cell lines: preclinical identification of suitable drug partners to taxotere, taxol, topotecan and gemcitabin.

    PubMed Central

    Jensen, P. B.; Holm, B.; Sorensen, M.; Christensen, I. J.; Sehested, M.

    1997-01-01

    coefficient (CC) for a given pair of compounds indicates a similar pattern in response in the set of cell lines. Such data corroborate the view that there is cross-resistance among the drugs. A numerically low coefficient indicates that the two drugs are acting in different ways, suggesting a lack of cross-resistance between the drugs, and a negative correlation coefficient implies that two drugs exhibit collateral sensitivity. The most negative CCs (%) to the new drug leads were: taxotere-carmustine (BCNU) (-75), taxol-cisplatin (-58), ara-C-taxol (-25), gemcitabin-doxorubicin (-32), camptotecin-VM26 (-41) and topotecan-VP16 (-17). The most negative correlations to the clinically important agent VP-16 were: cisplatin (-70); BCNU (-68); camptothecin (-38); bleomycin (-33), gemcitabin (-32); ara-C (-21); topotecan (-17); melphalan (-3); and to the other main drug in SCLC treatment cisplatin were: doxorubicin (-70); VP-16 (-70); VM-26 (-69); mAMSA (-64); taxotere (-58); taxol (-58). Taxol and taxotere were highly correlated (cross-resistant) to VP-16 (0.76 and 0.81 respectively) and inversely correlated to cisplatin (both -0.58). Similarly, camptothecin and topotecan were correlated to cisplatin but inversely correlated to VP-16 and other topo II poisons. From the sensitivity data, we conclude that collateral sensitivity and lack of cross-resistance favours a cisplatin-taxane or topo I-topo II poison combination, whereas patterns of cross-resistance suggest that epipodophyllotoxin-taxane or topo I poison-cisplatin combinations may be disadvantageous. PMID:9062409

  13. Nanoscale Coordination Polymers Codeliver Chemotherapeutics and siRNAs to Eradicate Tumors of Cisplatin-Resistant Ovarian Cancer.

    PubMed

    He, Chunbai; Poon, Christopher; Chan, Christina; Yamada, S Diane; Lin, Wenbin

    2016-05-11

    Drug resistance impedes the successful treatment of many types of cancers, especially ovarian cancer (OCa). To counter this problem, we developed novel long-circulating, self-assembled core-shell nanoscale coordination polymer (NCP) nanoparticles that efficiently deliver multiple therapeutics with different mechanisms of action to enhance synergistic therapeutic effects. These NCP particles contain high payloads of chemotherapeutics cisplatin or cisplatin plus gemcitabine in the core and pooled siRNAs that target multidrug resistant (MDR) genes in the shell. The NCP particles possess efficient endosomal escape via a novel carbon dioxide release mechanism without compromising the neutral surface charge required for long blood circulation and effectively downregulate MDR gene expression in vivo to enhance chemotherapeutic efficacy by several orders of magnitude. Even at low doses, intraperitoneal injections of nanoparticles led to effective and long-lasting tumor regression/eradication in subcutaneous and intraperitoneal xenograft mouse models of cisplatin-resistant OCa. By silencing MDR genes in tumors, self-assembled core-shell nanoparticles promise a more effective chemotherapeutic treatment for many challenging cancers. PMID:27088560

  14. Biweekly gemcitabine and paclitaxel in patients with relapsed or metastatic squamous cell carcinoma of the head and neck

    PubMed Central

    Sukari, Ammar; Al-Hajeili, Marwan; Salem, Mohamed; Heilbrun, Lance; Smith, Daryn; Yoo, George; Jacobs, John R; Lin, Ho-Sheng; Kucuk, Omer

    2015-01-01

    Purpose: We conducted a Phase II, clinical trial to evaluate the efficacy and safety of a biweekly gemcitabine and paclitaxel (GEMTAX) regimen as second-line treatment in patients with recurrent or metastatic unresectable, squamous cell carcinoma of the head and neck (SCCHN). The primary endpoint was response rate. Patients and Methods: Patients with recurrent unresectable or metastatic platinum refractory SCCHN, who had performance status ≤2 and adequate organ function, were eligible. Gemcitabine (3000 mg/m2 intravenous) and paclitaxel (150 mg/m2 intravenous) was given on days 1 and 15of 4 weeks cycle, until patients had disease progression or unacceptable toxicity. Results: Disease control (partial response [PR] + complete response [CR] + stable disease [SD]) was noted in 19 patients (54%) and overall response (CR + PR) was noted in 8 patients (23%). However, the most frequent response outcomes were progressive disease in 16 patients (46%) and SD in 11 patients (31%). The most frequent Grade 3–4 adverse events were lymphopenia in 38 patients (75%), anemia in 20 patients (39%), and infection in 16 patients (31%). Median progression-free survival was 3.6 months; median overall survival was 6.3 months. Conclusion: The biweekly GEMTAX regimen has statistically significant grade 3 and 4 adverse events and has meaningful clinical activity as a second-line treatment in patients with recurrent or metastatic SCCHN who have received prior chemotherapy. This regimen may particularly be a useful treatment option in patients who progressed in less than 6 months of concurrent chemoradiotherapy with high-dose cisplatin and/or have recurrent/metastatic platinum refractory SCCHN. PMID:25878965

  15. Etoposide selectively ablates activated T cells to control the immunoregulatory disorder hemophagocytic lymphohistiocytosis

    PubMed Central

    Johnson, Theodore S.; Terrell, Catherine E.; Millen, Scott H.; Katz, Jonathan D.; Hildeman, David A.; Jordan, Michael B.

    2014-01-01

    Hemophagocytic lymphohistiocytosis (HLH) is an inborn disorder of immune regulation caused by mutations affecting perforin-dependent cytotoxicity. Defects of this pathway impair negative feedback between cytotoxic lymphocytes and APCs, leading to prolonged and pathologic activation of T cells. Etoposide, a widely used chemotherapeutic drug which inhibits topoisomerase II, is the mainstay of treatment for HLH, though its therapeutic mechanism remains unknown. We utilized a murine model of HLH, involving lymphocytic choriomeningitis virus infection of perforin deficient mice to study the activity and mechanism of etoposide for treating HLH and found that it substantially alleviated all symptoms of murine HLH and allowed prolonged survival. This therapeutic effect was relatively unique among chemotherapeutic agents tested, suggesting distinctive effects on the immune response. We found that the therapeutic mechanism of etoposide in this model system involved potent deletion of activated T cells and efficient suppression of inflammatory cytokine production. This effect was remarkably selective; etoposide did not exert a direct anti-inflammatory effect on macrophages or dendritic cells and it did not cause deletion of quiescent naive or memory T cells. Finally, etoposide’s immunomodulatory effects were similar in wild type and perforin deficient animals. Thus, etoposide treats HLH by selectively eliminating pathologic, activated T cells and may have utility as a novel immune modulator in a broad array of immunopathologic disorders. PMID:24259502

  16. Actin distribution patterns in HL-60 leukemia cells treated with etoposide.

    PubMed

    Grzanka, A

    2001-10-01

    Localization of actin was studied in HL-60 leukemia cells after treatment with the anticancer agent etoposide for 3 days in a range of concentrations (0.02-200 microM). Significant changes in morphology of the cells and F-actin distribution patterns labelled with TRITC-phalloidin occurred only after treatment with 100 and 200 microM etoposide. In comparison with control cells, the number of cells decreased, cells were larger and almost all treated cells had irregular surfaces with lamellipodia. F-actin was distributed in a punctate pattern throughout the cytoplasm after treatment. In some treated cells, fluorescence appeared as a bright haze, whereas in other cells it formed a network. Treated cells also showed bright fluorescence at their periphery. Immunogold labelling of actin was observed in cells whether or not treated with etoposide. Labelling was found in the nucleus and also in the cytoplasm. At the ultrastructural level, cells treated with 100 and 200 microM etoposide showed increased positivity for actin in relation with blebbing, margination of nuclear chromatin and bodies containing recognizable nuclear fragments. These findings indicate that alterations in expression of actin in HL-60 cells after treatment with etoposide is dose-dependent and related with apoptosis. PMID:11700950

  17. Evaluating Cytotoxicity of Hyaluronate Targeted Solid Lipid Nanoparticles of Etoposide on SK-OV-3 Cells

    PubMed Central

    Varshosaz, Jaleh; Sadeghi Aliabadi, Hojatollah

    2014-01-01

    The epithelial ovarian carcinoma is one of the most fatal gynecological cancers. Etoposide is used in treating platinum-resistant ovarian cancer. Sodium hyaluronate is a substance that binds to the CD44 receptors overexpressed in SK-OV-3 cells of epithelial ovarian carcinoma. The aim of the present work was to study the cytotoxicity effect of hyaluronate targeted solid lipid nanoparticles (SLNs) of etoposide on SK-OV-3 cells. The cytotoxicity of the targeted and nontargeted SLNs of etoposide was compared to free drug on the SK-OV-3 cells by MTT assay method. The cellular uptake of the targeted and nontargeted nanoparticles containing sodium fluorescein was also studied. The difference of cell vitality between nontargeted nanoparticles and also targeted nanoparticles with free drug was significant. Targeted nanoparticles also caused more toxicity than nontargeted nanoparticles (P < 0.05). After 4 hours of incubating, the fluorescence was remarkably higher in the cells treated by targeted SLNs rather than nontargeted ones, and there was no observable fluorescence in cells incubated with pure sodium fluorescein. Hyaluronate targeted SLNs containing etoposide increased the cytotoxicity of etoposide on SK-OV-3 cells which may be a worthwhile potential method for reducing the prescribed dose and systemic side effects of this drug in epithelial ovarian carcinoma. PMID:24868467

  18. Patients with Advanced Ovarian Cancer Administered Oral Etoposide following Taxane as Maintenance Chemotherapy

    PubMed Central

    Nagano, Hiroaki; Tachibana, Yasunari; Kawakami, Megumi; Ueno, Mariko; Morita, Yoshihiro; Muraoka, Mitsue; Takagi, Koichiro

    2016-01-01

    Introduction The concept of maintenance therapy is one of the highly relevant approaches in the management of advanced ovarian cancer. The fundamental goal of maintenance therapy is to improve survival outcomes. We attempted to reinforce maintenance chemotherapy by adding oral etoposide following taxane administration. Cases We retrospectively evaluated 14 patients with advanced ovarian cancer who had achieved clinically defined complete response to a primary platinum/taxane chemotherapy regimen and who were administered oral etoposide (50 mg/day × 21 days per cycle monthly for 3–5 cycles) following paclitaxel or docetaxel administration as maintenance chemotherapy. With regard to oral etoposide toxicity, grade 2 oral mucositis and grade 3 anemia were observed in 1 patient each. Three to five cycles of etoposide were administered to all patients, though daily dosage was reduced to 25 mg in 2 patients due to toxicity. The median progression-free survival was 43.5 months, the median overall survival was 86 months, and 5-year overall survival was 77.1%. Conclusion The results from this ovarian cancer treatment evaluation suggest that oral etoposide may be administered safely following paclitaxel or docetaxel as maintenance chemotherapy. We expect this regimen to contribute to the improvement in the survival outcomes of patients with advanced ovarian cancer. PMID:27099605

  19. Suberoylanilide hydroxamic acid synergistically enhances the antitumor activity of etoposide in Ewing sarcoma cell lines.

    PubMed

    Unland, Rebekka; Clemens, Dagmar; Heinicke, Ulrike; Potratz, Jenny C; Hotfilder, Marc; Fulda, Simone; Wardelmann, Eva; Frühwald, Michael C; Dirksen, Uta

    2015-09-01

    Ewing sarcomas (ES) are highly malignant tumors arising in bone and soft tissues. Given the poor outcome of affected patients with primary disseminated disease or at relapse, there is a clear need for new targeted therapies. The HDAC inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA, Vorinostat) inhibits ES tumor growth and induces apoptosis in vitro and in vivo. Thus, SAHA may be considered a novel treatment. However, it is most likely that not a single agent but a combination of agents with synergistic mechanisms will help improve the prognosis in high-risk ES patients. Therefore, the aim of the present study was to assess a putative synergistic effect of SAHA in combination with conventional chemotherapeutic agents. The antitumor activity of SAHA in combination with conventional chemotherapeutics (doxorubicin, etoposide, rapamycin, topotecan) was assessed using an MTT cell proliferation assay on five well-characterized ES cell lines (CADO-ES-1, RD-ES, TC-71, SK-ES-1, SK-N-MC) and a newly established ES cell line (DC-ES-15). SAHA antagonistically affected the antiproliferative effect of doxorubicin and topotecan in the majority of the ES cell lines, but synergistically enhanced the antiproliferative activity of etoposide. In functional analyses, pretreatment with SAHA significantly increased the effects of etoposide on apoptosis and clonogenicity. The in-vitro analyses presented in this work show that SAHA synergistically enhances the antitumor activity of etoposide in ES cells. Sequential treatment with etoposide combined with SAHA may represent a new therapeutic approach in ES. PMID:26053276

  20. Phase I studies of gemcitabine combined with carboplatin or paclitaxel.

    PubMed

    Pedersen, A G

    1997-04-01

    Gemcitabine is a novel nucleoside analogue with a unique mechanism of action. In light of its good single-agent activity in several solid tumors, generally mild toxicity profile, and potential for synergy, combination phase I studies with other active chemotherapeutic agents have been conducted. In two studies the combination of gemcitabine and carboplatin was used to treat patients with non-small cell lung cancer. Gemcitabine was administered weekly x 3 every 4 weeks, and carboplatin was given on day 1. Although dose-limiting myelotoxicity was observed, encouraging activity was noted. In other studies patients with recurrent or persistent ovarian cancer or with refractory solid tumors were treated with weekly gemcitabine and paclitaxel on a 28-day schedule or with both drugs given every 2 weeks. Dose escalation was possible and toxicities were manageable. The effect of sequence of drug administration on the toxicity profile was also examined. Further trials to establish the efficacy of these promising approaches as well as combinations of all three drugs are needed. PMID:9194483

  1. Prognostic factors for gemcitabine-refractory patients with advanced pancreatic cancer: a retrospective analysis of a multicentre study (Anatolian Society of Medical Oncology)

    PubMed Central

    Kos, F. Tuba; Algın, Efnan; Yıldız, Ramazan; Berk, Veli; Unek, İlkay T.; Colak, Dilsen; Dane, Faysal; Geredeli, Caglayan; Isıkdogan, Abdurrahman

    2015-01-01

    Aim of the study Systemic chemotherapy for patients with pancreatic cancer has limited impact on overall survival (OS). Patients eligible for chemotherapy should be selected carefully. The aim of the study was to search for prognostic factors for survival in patients with gemcitabine (Gem)-refractory or with gemcitabine and cisplatin (GemCis)-refractory advanced pancreatic cancer. Material and methods We retrospectively evaluated patients with Gem- or GemCis-refractory advanced pancreatic cancer. Sixteen potential prognostic variables were chosen for analysis in this study. Univariate and multivariate analyses were conducted to identify prognostic factors associated with survival. Univariate and multivariate statistical methods were used to determine prognostic factors. Results Multivariate analysis included the four prognostic significance factors in univariate analysis. Multivariate analysis showed that liver metastasis and second-line chemotherapy were considered independent prognostic factors for survival. Conclusions Liver metastasis and second-line chemotherapy were identified as important prognostic factors in advanced pancreatic cancer patients refractory to treatment with Gem or GemCis. This prognostic factors may also facilitate pretreatment prediction of survival and can be used for selecting patients for treatment. PMID:26034390

  2. Gemcitabine-based chemotherapy in sarcomas: A systematic review of published trials.

    PubMed

    Ducoulombier, Agnès; Cousin, Sophie; Kotecki, Nuria; Penel, Nicolas

    2016-02-01

    Gemcitabine is largely used in the management of sarcomas. We have systematically reviewed all of the fully published trials that investigated a gemcitabine-based regimen in the management of sarcomas and then provided a grade of recommendations and a level of evidence for every recommendation. Because of conflicting results from successive non-randomized phase II trials, gemcitabine activity alone in unselected pretreated soft tissue sarcomas could not be properly assessed. Gemcitabine alone and gemcitabine-docetaxel appeared to both be active in pretreated uterine and non-uterine leiomyosarcoma (1B;I). Gemcitabine-dacarbazine appeared to be active in pretreated unselected soft tissue sarcomas (1B;I). According the GeDDIS phase III trial (not yet fully published), gemcitabine-docetaxel appeared slightly less active than doxorubicine and more toxic than doxorubicine in chemo-naïve metastatic soft tissue sarcoma patients. Because of the absence of controlled randomized trials, the benefit of gemcitabine-docetaxel as an adjuvant treatment in high-grade uterine leiomyosarcoma could not be appropriately assessed. The level of activity of gemcitabine/docetaxel in bone sarcomas cannot be ascertained with the available data. The level of evidence supporting the use of gemcitabine-based regimens in sarcoma management is limited. Confirmatory phase III trials are warranted when phase II trials suggest some preliminary activity. PMID:26555460

  3. The development of cisplatin resistance in neuroblastoma is accompanied by epithelial to mesenchymal transition in vitro.

    PubMed

    Piskareva, Olga; Harvey, Harry; Nolan, John; Conlon, Ross; Alcock, Leah; Buckley, Patrick; Dowling, Paul; Henry, Michael; O'Sullivan, Finbarr; Bray, Isabella; Stallings, Raymond L

    2015-08-10

    Neuroblastoma is a challenging childhood malignancy, with a very high percentage of patients relapsing following acquisition of drug resistance, thereby necessitating the identification of mechanisms of drug resistance as well as new biological targets contributing to the aggressive pathogenicity of the disease. In order to investigate the molecular pathways that are involved with drug resistance in neuroblastoma, we have developed and characterised cisplatin resistant sublines SK-N-ASCis24, KellyCis83 and CHP-212Cis100, integrating data of cell behaviour, cytotoxicity, genomic alterations and modulation of protein expression. All three cisplatin resistant cell lines demonstrated cross resistance to temozolomide, etoposide and irinotecan, all of which are drugs in re-initiation therapy. Array CGH analysis indicated that resistant lines have acquired additional genomic imbalances. Differentially expressed proteins were identified by mass spectrometry and classified by bioinformatics tools according to their molecular and cellular functions and their involvement into biological pathways. Significant changes in the expression of proteins involved with pathways such as actin cytoskeletal signalling (p = 9.28E-10), integrin linked kinase (ILK) signalling (p = 4.01E-8), epithelial adherens junctions signalling (p = 5.49E-8) and remodelling of epithelial adherens junctions (p = 5.87E-8) pointed towards a mesenchymal phenotype developed by cisplatin resistant SK-N-ASCis24. Western blotting and confocal microscopy of MYH9, ACTN4 and ROCK1 coupled with invasion assays provide evidence that elevated levels of MYH9 and ACTN4 and reduced levels of ROCK1 contribute to the increased ROCK1-independent migratory potential of SK-N-ASCis24. Therefore, our results suggest that epithelial-to-mesenchymal transition is a feature during the development of drug resistance in neuroblastoma. PMID:25960282

  4. Eltrombopag with gemcitabine-based chemotherapy in patients with advanced solid tumors: a randomized phase I study.

    PubMed

    Winer, Eric S; Safran, Howard; Karaszewska, Boguslawa; Richards, Donald A; Hartner, Lee; Forget, Frederic; Ramlau, Rodryg; Kumar, Kirushna; Mayer, Bhabita; Johnson, Brendan M; Messam, Conrad A; Mostafa Kamel, Yasser

    2015-01-01

    Preventing chemotherapy-induced thrombocytopenia could avoid chemotherapy dose reductions and delays. The safety and maximum tolerated dose of eltrombopag, an oral thrombopoietin receptor agonist, with gemcitabine-based therapy was evaluated. Patients with advanced solid tumors and platelets ≤300 × 10(9) /L receiving gemcitabine plus cisplatin or carboplatin (Group A) or gemcitabine monotherapy (Group B) were randomized 3:1 to receive eltrombopag or placebo at a starting dose of 100 mg daily administered on days -5 to -1 and days 2-6 starting from cycle 2 of treatment. Nineteen patients (Group A, n = 9; Group B, n = 10) received eltrombopag 100 mg and seven (Group A, n = 3; Group B, n = 4) received matching placebo. Nine eltrombopag patients in Group A and eight in Group B had 38 and 54 occurrences of platelet counts ≥400 × 10(9) /L, respectively. Mean platelet nadirs across cycles 2-6 were 115 × 10(9) /L and 143 × 10(9) /L for eltrombopag-treated patients versus 53 × 10(9) /L and 103 × 10(9) /L for placebo-treated patients in Groups A and B, respectively. No dose-limiting toxicities were reported for eltrombopag; however, due to several occurrences of thrombocytosis, a decision was made not to dose-escalate eltrombopag to >100 mg daily. In Groups A and B, 14% of eltrombopag versus 50% of placebo patients required chemotherapy dose reductions and/or delays for any reason across cycles 3-6. Eltrombopag 100 mg once daily administered 5 days before and after day 1 of chemotherapy was well tolerated with an acceptable safety profile, and will be further tested in a phase II trial. Fewer patients receiving eltrombopag required chemotherapy dose delays and/or reductions compared with those receiving placebo. PMID:25165041

  5. Manganoporphyrins and Ascorbate Enhance Gemcitabine Cytotoxicity in Pancreatic Cancer

    PubMed Central

    Cieslak, John A.; Strother, Robert K.; Rawal, Malvika; Du, Juan; Doskey, Claire M.; Schroeder, Samuel R.; Button, Anna; Wagner, Brett A.; Buettner, Garry R.; Cullen, Joseph J.

    2015-01-01

    Pharmacological ascorbate (AscH−) selectively induces cytotoxicity in pancreatic cancer cells vs. normal cells via the generation of extracellular hydrogen peroxide (H2O2), producing double-stranded DNA breaks and ultimately cell death. Catalytic manganoporphyrins (MnPs) can enhance ascorbate-induced cytotoxicity by increasing the rate of AscH− oxidation and therefore the rate of generation of H2O2. We hypothesized that combining MnPs and AscH− with the chemotherapeutic agent gemcitabine would further enhance pancreatic cancer cell cytotoxicity without increasing toxicity in normal pancreatic cells or other organs. Redox active MnPs were combined with AscH− and administered with or without gemcitabine to human pancreatic cancer cell lines, as well as immortalized normal pancreatic ductal epithelial cells. The MnPs MnT2EPyP (Mn(III)meso-tetrakis(N-ethylpyridinium-2-yl) porphyrin pentachloride) and MnT4MPyP (Mn(III)tetrakis(N-methylpyridinium-4-yl) porphyrin pentachloride) were investigated. Clonogenic survival was significantly decreased in all pancreatic cancer cell lines studied when treated with MnP + AscH− + gemcitabine, whereas non-tumorigenic cells were resistant. The concentration of ascorbate radical (Asc•−, an indicator of oxidative flux) was significantly increased in treatment groups containing MnP and AscH−. Furthermore, MnP + AscH− increased double stranded DNA breaks in gemcitabine treated cells. These results were abrogated by extracellular catalase, further supporting the role of the flux of H2O2. In vivo growth was inhibited and survival increased in mice treated with MnT2EPyP, AscH−, and gemcitabine without a concomitant increase in systemic oxidative stress. These data suggest a promising role for the use of MnPs in combination with pharmacologic AscH− and chemotherapeutics in pancreatic cancer. PMID:25725418

  6. [Influence of Acetylcysteine on Cytogenetic Effects of Etoposide in Mouse Oocytes].

    PubMed

    Pligina, K L; Zhanataev, A K; Kulakova, A V; Chaika, Z V; Durnev, A D

    2016-02-01

    The influence of N-acetylcysteine (ACC) on the cytogenetic effects of etoposide in F1 CBA x C57BL/6 mice was studied. Etoposide introduced intraperitoneally in doses of 10, 20, 40, and 60 mg/kg has a dose-dependent clastogenic activity and has an aneugenic effect with the induction of mainly hypohaploid oocytes. ACC significantly decreases the aneugenic and clastogenic activity of etoposide (20 mg/kg) in oocytes of 6-, 9-, and 12-week-old mice during triple introduction at a dose 200 mg/kg per os. The most pronounced anticlastogenic ACC activity (an 80% decrease) was registered in 9-week-old females; a 100% decrease in aneugenesis was detected in 6-week-old female mice. PMID:27215036

  7. Insights into RNA binding by the anticancer drug cisplatin from the crystal structure of cisplatin-modified ribosome.

    PubMed

    Melnikov, Sergey V; Söll, Dieter; Steitz, Thomas A; Polikanov, Yury S

    2016-06-01

    Cisplatin is a widely prescribed anticancer drug, which triggers cell death by covalent binding to a broad range of biological molecules. Among cisplatin targets, cellular RNAs remain the most poorly characterized molecules. Although cisplatin was shown to inactivate essential RNAs, including ribosomal, spliceosomal and telomeric RNAs, cisplatin binding sites in most RNA molecules are unknown, and therefore it remains challenging to study how modifications of RNA by cisplatin contributes to its toxicity. Here we report a 2.6Å-resolution X-ray structure of cisplatin-modified 70S ribosome, which describes cisplatin binding to the ribosome and provides the first nearly atomic model of cisplatin-RNA complex. We observe nine cisplatin molecules bound to the ribosome and reveal consensus structural features of the cisplatin-binding sites. Two of the cisplatin molecules modify conserved functional centers of the ribosome-the mRNA-channel and the GTPase center. In the mRNA-channel, cisplatin intercalates between the ribosome and the messenger RNA, suggesting that the observed inhibition of protein synthesis by cisplatin is caused by impaired mRNA-translocation. Our structure provides an insight into RNA targeting and inhibition by cisplatin, which can help predict cisplatin-binding sites in other cellular RNAs and design studies to elucidate a link between RNA modifications by cisplatin and cisplatin toxicity. PMID:27079977

  8. Nanoparticle formulations of cisplatin for cancer therapy.

    PubMed

    Duan, Xiaopin; He, Chunbai; Kron, Stephen J; Lin, Wenbin

    2016-09-01

    The genotoxic agent cisplatin, used alone or in combination with radiation and/or other chemotherapeutic agents, is an important first-line chemotherapy for a broad range of cancers. The clinical utility of cisplatin is limited both by intrinsic and acquired resistance and dose-limiting normal tissue toxicity. That cisplatin shows little selectivity for tumor versus normal tissue may be a critical factor limiting its value. To overcome the low therapeutic ratio of the free drug, macromolecular, liposomal, and nanoparticle drug delivery systems have been explored toward leveraging the enhanced permeability and retention effect and promoting delivery of cisplatin to tumors. Here, we survey recent advances in nanoparticle formulations of cisplatin, focusing on agents that show promise in preclinical or clinical settings. WIREs Nanomed Nanobiotechnol 2016, 8:776-791. doi: 10.1002/wnan.1390 For further resources related to this article, please visit the WIREs website. PMID:26848041

  9. Specific Biomarkers Are Associated with Docetaxeland Gemcitabine-Resistant NSCLC Cell Lines1

    PubMed Central

    Pasini, Alice; Paganelli, Giulia; Tesei, Anna; Zoli, Wainer; Giordano, Emanuele; Calistri, Daniele

    2012-01-01

    Five-year survival rate for lung cancer is limited to 10% to 15%. Therefore, the identification of novel therapeutic prognostic factors is an urgent requirement. The aim of this study is thus to highlight specific biomarkers in chemoresistant non-small cell lung cancer cell lines. Therefore, we checked—in the control condition as well as after short-term pharmacological treatment with either docetaxel or gemcitabine—the expression of genes such as tumor suppressor genes (CDKN2A, DAPK, FHIT, GSTP1, MGMT, RARβ2, RASSF1A, and TIMP3), genes associated with drug resistance (BRCA1, COX2, ERCC1, IGFBP3, RRM1, and TUBB3), and stemness-related genes (CD133, OCT4, and SLUG) in two cellular models of squamous carcinoma (CAEP) and adenocarcinoma (RAL) of the lung originally established. Their promoter methylation profile was also evaluated. Drug-related genes were upregulated. Cisplatin resistance matched with high levels of BRCA1 and ERCC1 in both cell lines; docetaxel sensitivity of CAEP cells was associated to levels of TUBB3 lower than RAL cells. Although CAEP cells were more sensitive to gemcitabine, both cell lines showed high levels of RRM1. Stemness-related genes were downregulated in the control condition but became upregulated in docetaxel-resistant cells, indicating the selection of a population with stemness features. We did not find an unequivocal correspondence between gene expression and respective DNA promoter methylation status, suggesting the involvement of additional mechanisms of gene expression regulation. These results highlight specific biomarkers consistent with the different responses of the two cell lines to standard pharmacological treatments and indicate specific molecular traits for their chemoresistance. PMID:23397475

  10. Antagonism between curcumin and the topoisomerase II inhibitor etoposide

    PubMed Central

    Saleh, Ekram M.; El-awady, Raafat A; Eissa, Nadia A.; Abdel-Rahman, Wael M.

    2012-01-01

    The use of combinations of chemotherapy and natural products has recently emerged as a new method of cancer therapy, relying on the capacity of certain natural compounds to trigger cell death with low doses of chemotherapeutic agents and few side effects. The current study aims to evaluate the modulatory effects of curcumin (CUR), Nigella sativa (NS) and taurine on etoposide (ETP) cytotoxicity in a panel of cancer cell lines and to identify their underlying mechanisms. CUR alone showed potent antitumor activity, but surprisingly, its interaction with ETP was antagonistic in four out of five cancer cell lines. Neither taurine nor Nigella sativa affect the sensitivity of cancer cells to ETP. Examination of the DNA damage response machinery (DDR) showed that both ETP and CUR elicited DNA double-strand breaks (DSB) and evoked γ-H2AX foci formation at doses as low as 1 µg/ml. Cell cycle analysis revealed S phase arrest after ETP or CUR application, whereas co-treatment with ETP and CUR led to increased arrest of the cell cycle in S phase (MCF-7 cells) or the accumulation of cells in G2/M phases (HCT116, and HeLa cells). Furthermore, cotreatment with ETP and CUR resulted in modulation of the level of DNA damage induction and repair compared with either agent alone. Electron microscopic examination demonstrated that different modalities of cell death occurred with each treatment. CUR alone induced autophagy, apoptosis and necrosis, whereas ETP alone or in combination with CUR led to apoptosis and necrosis. Conclusions: Cotreatment with ETP and CUR resulted in an antagonistic interaction. This antagonism is related, in part, to the enhanced arrest of tumor cells in both S and G2/M phases, which prevents the cells from entering M-phase with damaged DNA and, consequently, prevents cell death from occurring. This arrest allows time for the cells to repair DNA damage so that cell cycle -arrested cells can eventually resume cell cycle progression and continue their

  11. Enhancement of etoposide and methotrexate sensitivity by indomethacin in vitro.

    PubMed

    Maca, R D

    1991-11-01

    The possibility of increasing the activity of etoposide (VP-16) by combining this anti-cancer agent with indomethacin (Indo) was investigated by treating murine and human cultured tumor cells with a combination of Indo and VP-16 and quantitating VP-16 cytotoxicity by the [3H]thymidine incorporation assay. Non-toxic concentrations of Indo were found to enhance the sensitivity to VP-16 in cultured Lewis lung carcinoma (LLC), YAC-1, P815, CCRF-CEM and K562 cells which were all relatively sensitive to VP-16. With the LLC, the Indo effect was dose dependent and near maximal at an Indo concentration of 0.5 micrograms/ml. Indo also increased the response of LLC cells to methotrexate, but not to bleomycin. Ibuprofen was less effective than Indo in enhancing VP-16 sensitivity in LLC cells. The enhanced sensitivity of VP-16 by Indo was not reversed by the prostaglandins PGE2 and PGD2, the analogs carbocyclic thromboxane A2 and carba-prostacyclin or conditioned medium removed after 24 h or 48 h of culture from near confluent LLC cell monolayers. This finding suggests that Indo is not augmenting VP-16 cytotoxicity by inhibiting cyclo-oxygenase activity and prostaglandin production. The lipoxygenase inhibitor, eicosatetraynoic acid (ETYA), was also ineffective in reversing the Indo augmentation of VP-16 sensitivity. This finding indicates that Indo is not acting by inhibiting cyclo-oxygenase and converting larger amounts of arachidonic acid to lipoxygenase products, such as leukotrienes, that could then interact with VP-16 to increase its sensitivity. In other studies, Indo was found to significantly increase the steady state accumulation of [3H]-VP-16 in all five cell lines studied. With the LLC cells, this increased steady state was achieved within 15 min after the addition of Indo to these cells and this enhanced VP-16 uptake was not reversed by the addition of prostaglandin E2 or prostaglandin D2. Thus, taken together, these studies indicate that Indo most likely enhances

  12. Bortezomib and etoposide combinations exert synergistic effects on the human prostate cancer cell line PC-3

    PubMed Central

    ARAS, BEKIR; YERLIKAYA, AZMI

    2016-01-01

    Novel treatment modalities are urgently required for androgen-independent prostate cancer. In order to develop an alternative treatment for prostate cancer, the cytotoxic effects of the 26S proteasome inhibitor bortezomib, either alone or in combination with the two commonly used chemotherapeutic agents irinotecan and etoposide, on the human prostate cancer cell line PC-3 were evaluated in the present study. The PC-3 cell line was maintained in Dulbecco's modified Eagle's medium with 10% fetal bovine serum and treated with various doses of bortezomib, irinotecan, etoposide or their combinations. The growth inhibitory and cytotoxic effects were determined by water-soluble tetrazolium (WST)-1 assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay or iCELLigence system. The combination index values were determined by the Chou-Talalay method. The half maximal inhibitory concentration (IC50) value of bortezomib on the PC-3 cell line was determined to be 53.4 nM by WST-1 assay, whereas the IC50 values of irinotecan and etoposide were determined to be 2.1 and 26.5 µM, respectively. These results suggest that the 26S proteasome inhibitor bortezomib is more potent, compared with irinotecan and etoposide, in the androgen-insensitive and tumor protein p53-null cell line PC-3. The combined effects of bortezomib+irinotecan and bortezomib+etoposide were also tested on PC-3 cells. The effect of bortezomib+irinotecan combination was not significantly different than that produced by either monotherapy, according to the results of iCELLigence system and MTT assay. However, 40 nM bortezomib+5 µM etoposide or 40 nM bortezomib+20 µM etoposide combinations were observed to be more effective than each drug tested alone. The results of the current study suggest that bortezomib and etoposide combination may be additionally evaluated in clinical trials for the treatment of hormone-refractory prostate cancer. PMID:27123085

  13. Toxicity and Efficacy of Concurrent Gemcitabine and Radiotherapy for Locally Advanced Pancreatic Cancer.

    PubMed

    Crane, Christopher; Janjan, N; Evans, D; Wolff, R; Ballo, M; Milas, L; Mason, K; Charnsangavej, C; Pisters, P; Lee, J; Lenzi, R; Vauthey, J; Wong, A; Phan, T; Nguyen, Q; Abbruzzese, J

    2001-01-01

    Gemcitabine has been demonstrated to be a potentradiosensitizer in the laboratory and in the clinic (1-7)and has proven clinical systemic activity to pancreaticcancer. Responses to systemic gemcitabine inpatients with metastatic pancreatic adenocarcinomahave been documented in phase I, phase II, and phaseIII clinical settings (8,9). Moreover, a recent randomizedtrial of gemcitabine vs 5-FU as first-linetherapy in patients with advanced pancreatic adenocarcinomademonstrated a modest median survivalbenefit (4.41 vs 5.65 mo,p= 0.0025) for those patientswho received gemcitabine compared to those whoreceived 5-FU (10). In addition, gemcitabine wasshown to improve cancer-related symptoms and performancestatus as assessed by a quantitative clinicalbenefit scale in both untreated and previouslytreated patients with metastatic adenocarcinoma ofthe pancreas (10,11). Based on these data, the FDAapproved gemcitabine as a first-line agent for patientswith advanced adenocarcinoma of the pancreas. PMID:12754400

  14. Mechanisms of cisplatin-induced muscle atrophy

    SciTech Connect

    Sakai, Hiroyasu; Sagara, Atsunobu; Arakawa, Kazuhiko; Sugiyama, Ryoto; Hirosaki, Akiko; Takase, Kazuhide; Jo, Ara; Sato, Ken; Chiba, Yoshihiko; Yamazaki, Mitsuaki; Matoba, Motohiro; Narita, Minoru

    2014-07-15

    Fatigue is the most common side effect of chemotherapy. However, the mechanisms of “muscle fatigue” induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3 mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only the muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggest that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue. - Highlights: • Cisplatin decreased mass and myofiber diameter in quadriceps muscle. • The mRNA of MAFbx, MuRF1 and FOXO3 were increased by the cisplatin. • The mRNA of myostatin and p21 were upregulated by cisplatin. • The phosphorylation of Akt and FOXO3a was decreased by cisplatin.

  15. Insights into RNA binding by the anticancer drug cisplatin from the crystal structure of cisplatin-modified ribosome

    PubMed Central

    Melnikov, Sergey V.; Söll, Dieter; Steitz, Thomas A.; Polikanov, Yury S.

    2016-01-01

    Cisplatin is a widely prescribed anticancer drug, which triggers cell death by covalent binding to a broad range of biological molecules. Among cisplatin targets, cellular RNAs remain the most poorly characterized molecules. Although cisplatin was shown to inactivate essential RNAs, including ribosomal, spliceosomal and telomeric RNAs, cisplatin binding sites in most RNA molecules are unknown, and therefore it remains challenging to study how modifications of RNA by cisplatin contributes to its toxicity. Here we report a 2.6Å-resolution X-ray structure of cisplatin-modified 70S ribosome, which describes cisplatin binding to the ribosome and provides the first nearly atomic model of cisplatin–RNA complex. We observe nine cisplatin molecules bound to the ribosome and reveal consensus structural features of the cisplatin-binding sites. Two of the cisplatin molecules modify conserved functional centers of the ribosome—the mRNA-channel and the GTPase center. In the mRNA-channel, cisplatin intercalates between the ribosome and the messenger RNA, suggesting that the observed inhibition of protein synthesis by cisplatin is caused by impaired mRNA-translocation. Our structure provides an insight into RNA targeting and inhibition by cisplatin, which can help predict cisplatin-binding sites in other cellular RNAs and design studies to elucidate a link between RNA modifications by cisplatin and cisplatin toxicity. PMID:27079977

  16. Gemcitabine-induced CXCL8 expression counteracts its actions by inducing tumor neovascularization

    SciTech Connect

    Song, Yao; Baba, Tomohisa; Li, Ying-Yi; Furukawa, Kaoru; Tanabe, Yamato; Matsugo, Seiichi; Sasaki, Soichiro; Mukaida, Naofumi

    2015-03-06

    Patients with pancreatic ductal adenocarcinoma (PDAC) are frequently complicated with metastatic disease or locally advanced tumors, and consequently need chemotherapy. Gemcitabine is commonly used for PDAC treatment, but with limited efficacy. The capacity of gemcitabine to generate reactive oxygen species (ROS) in human pancreatic cancer cells, prompted us to examine its effects on the expression of pro-inflammatory cytokines and chemokines. We observed that gemcitabine enhanced selectively the expression of CXCL8 in human pancreatic cancer cells through ROS generation and NF-κB activation. In vitro blocking of CXCL8 failed to modulate gemcitabine-mediated inhibition of cell proliferation in human pancreatic cancer cells. Gemcitabine also enhanced CXCL8 expression in pancreatic cancer cells in xenografted tumor tissues. Moreover, anti-CXCL8 antibody treatment in vivo attenuated tumor formation as well as intra-tumoral vascularity in nude mice, which were transplanted with Miapaca-2 cells and treated with gemcitabine. Thus, gemcitabine-induced CXCL8 may counteract the drug through inducing neovascularization. - Highlights: • Gemcitabine induced CXCL8 expression in human pancreatic cancer cells. • CXCL8 expression required ROS generation and NF-κB activation. • CXCL8 did not affect in vitro proliferation of human pancreatic cancer cells. • CXCL8 in vivo counteracted gemcitabine by inducing neovascularization.

  17. Enhanced Tumor Delivery of Gemcitabine via PEG-DSPE/TPGS Mixed Micelles

    PubMed Central

    2015-01-01

    Gemcitabine is a potent anticancer drug approved for the treatment of pancreatic, non-small-cell lung, breast, and ovarian cancers. The major deficiencies of current gemcitabine therapy, however, are its rapid metabolic inactivation and narrow therapeutic window. Herein, we employed polyethylene glycol-b-distearoylphosphatidylethanolamine (PEG-DSPE)/tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles as a delivery system, to improve the pharmacokinetic characteristics of gemcitabine and enhance its antitumor efficacy. By conjugating stearic acid to gemcitabine and subsequently encapsulating stearoyl gemcitabine (GemC18) within PEG-DSPE/TPGS mixed micelles, the deamination of gemcitabine was delayed in vitro and in vivo. Importantly, compared to free gemcitabine, GemC18-loaded micelles pronouncedly prolonged the circulation time of gemcitabine and elevated its concentration in the tumor by 3-fold, resulting in superior antitumor efficacy in mice bearing human pancreatic cancer BxPC-3 xenografts. Our findings demonstrate the promise of PEG-DSPE/TPGS mixed micelles as a nanocarrier system for the delivery of gemcitabine to achieve safer and more efficacious therapeutic outcomes. PMID:24579673

  18. Silodosin inhibits the growth of bladder cancer cells and enhances the cytotoxic activity of cisplatin via ELK1 inactivation

    PubMed Central

    Kawahara, Takashi; Ide, Hiroki; Kashiwagi, Eiji; Patterson, John D; Inoue, Satoshi; Shareef, Hasanain Khaleel; Aljarah, Ali Kadhim; Zheng, Yichun; Baras, Alexander S; Miyamoto, Hiroshi

    2015-01-01

    Silodosin, a selective α1A-adrenergic blocker prescribed for the symptomatic treatment of benign prostatic hyperplasia, was previously shown to decrease the expression of ELK1, a c-fos proto-oncogene regulator and a well-described downstream target of the PKC/Raf-1/ERK pathway, in human prostate smooth muscle cells. PKC/Raf-1/ERK activation has also been implicated in drug resistance. In the current study, we assessed the effects of silodosin on ELK1 expression/activity in bladder cancer cells as well as on their proliferation in the presence or absence of chemotherapeutic drugs, including cisplatin and gemcitabine. In bladder cancer cell lines, silodosin reduced the expression of ELK1 (mRNA/protein) and its downstream target, c-fos gene, as well as the transcriptional activity of ELK1. While silodosin alone (up to 10 μM) insignificantly affected the growth of bladder cancer cells cultured in androgen depleted conditions or those expressing ELK1-short hairpin RNA, it considerably inhibited the viability of androgen receptor (AR)-positive/ELK1-positive cells in the presence of androgens. Silodosin also inhibited the migration of ELK1-positive cells with or without a functional AR, but not that of ELK1 knockdown cells. Interestingly, silodosin treatment or ELK1 silencing resulted in increases in drug sensitivity to cisplatin, but not to gemcitabine, even in AR-negative cells or AR-positive cells cultured in an androgen-depleted condition. In addition, silodosin decreased the expression of NF-κB, a key regulator of chemoresistance, and its transcriptional activity. Moreover, immunohistochemistry in bladder cancer specimens from patients who received neoadjuvant chemotherapy revealed that phospho-ELK1 positivity strongly correlated with chemoresistance. Silodosin was thus found to not only inhibit cell viability and migration but also enhance the cytotoxic activity of cisplatin in bladder cancer lines via inactivating ELK1. Our results suggest that combined

  19. Gemcitabine-loaded liposomes: rationale, potentialities and future perspectives

    PubMed Central

    Federico, Cinzia; Morittu, Valeria M; Britti, Domenico; Trapasso, Elena; Cosco, Donato

    2012-01-01

    This review describes the strategies used in recent years to improve the biopharmaceutical properties of gemcitabine, a nucleoside analog deoxycytidine antimetabolite characterized by activity against many kinds of tumors, by means of liposomal devices. The main limitation of using this active compound is the rapid inactivation of deoxycytidine deaminase following administration in vivo. Consequently, different strategies based on its encapsulation/complexation in innovative vesicular colloidal carriers have been investigated, with interesting results in terms of increased pharmacological activity, plasma half-life, and tumor localization, in addition to decreased side effects. This review focuses on the specific approaches used, based on the encapsulation of gemcitabine in liposomes, with particular attention to the results obtained during the last 5 years. These approaches represent a valid starting point in the attempt to obtain a novel, commercializable drug formulation as already achieved for liposomal doxorubicin (Doxil®, Caelyx®). PMID:23139626

  20. pH-sensitive strontium carbonate nanoparticles as new anticancer vehicles for controlled etoposide release

    PubMed Central

    Qian, Wen-Yu; Sun, Dong-Mei; Zhu, Rong-Rong; Du, Xi-Ling; Liu, Hui; Wang, Shi-Long

    2012-01-01

    Strontium carbonate nanoparticles (SCNs), a novel biodegradable nanosystem for the pH-sensitive release of anticancer drugs, were developed via a facile mixed solvent method aimed at creating smart drug delivery in acidic conditions, particularly in tumor environments. Structural characterization of SCNs revealed that the engineered nanocarriers were uniform in size and presented a dumbbell-shaped morphology with a dense mass of a scale-like spine coating, which could serve as the storage structure for hydrophobic drugs. Chosen as a model anticancer agent, etoposide was effectively loaded into SCNs based on a simultaneous process that allowed for the formation of the nanocarriers and for drug storage to be accomplished in a single step. The etoposide-loaded SCNs (ESCNs) possess both a high loading capacity and efficient encapsulation. It was found that the cumulative release of etoposide from ESCNs is acid-dependent, and that the release rate is slow at a pH of 7.4; this rate increases significantly at low pH levels (5.8, 3.0). Meanwhile, it was also found that the blank SCNs were almost nontoxic to normal cells, and ESCN systems were evidently more potent in antitumor activity compared with free etoposide, as confirmed by a cytotoxicity test using an MTT assay and an apoptosis test with fluorescence-activated cell sorter (FACS) analysis. These findings suggest that SCNs hold tremendous promise in the areas of controlled drug delivery and targeted cancer therapy. PMID:23185118

  1. EZH2 inhibition re-sensitizes multidrug resistant B-cell lymphomas to etoposide mediated apoptosis

    PubMed Central

    Smonskey, Matthew; Lasorsa, Elena; Rosario, Spencer; Kirk, Jason S.; Hernandez-Ilizaliturri, Francisco J.; Ellis, Leigh

    2016-01-01

    Reactivation of apoptotic pathways is an attractive strategy for patients with treatment-resistant B-cell lymphoma. The tumor suppressor, p53 is central for apoptotic response to multiple DNA damaging agents used to treat aggressive B-cell lymphomas, including etoposide. It has been demonstrated that etoposide induced DNA damage and therapeutic efficacy is enhanced by combination with inhibitors of the histone methyltransferase, enhancer of zeste homolog 2 (EZH2). Further, EZH2 was identified to regulate cell fate decisions in response to DNA damage. Using B-cell lymphoma cell lines resistant to etoposide induced cell death; we show that p53 is dramatically down regulated and MDMX, a negative regulator of p53, is significantly up regulated. However, these cell lines remain responsive to etoposide mediated DNA damage and exhibit cell cycle inhibition and induction of senescence. Furthermore, chemical inhibition of EZH2 directs DNA damage to a predominant p53 dependent apoptotic response associated with loss of MDMX and BCL-XL. These data provide confirmation of EZH2 in determining cell fate following DNA damage and propose a novel therapeutic strategy for patients with aggressive treatment-resistant B-cell lymphoma. PMID:26973857

  2. Biodegradability of the anticancer drug etoposide and identification of the transformation products.

    PubMed

    Kosjek, Tina; Negreira, Noelia; Heath, Ester; de Alda, Miren López; Barceló, Damià

    2016-08-01

    Etoposide susceptibility to microbiological breakdown was studied in a batch biotransformation system, in the presence or absence of artificial wastewater containing nutrients, salts and activated sludge at two concentration levels. The primary focus of the present study was to study etoposide transformation products by ultra-high performance liquid chromatography coupled to high-resolution hybrid quadrupole-Orbitrap tandem mass spectrometry (MS/MS). Data-dependent experiments combining full-scan MS data with product ion spectra were acquired to identify the molecular ions of etoposide transformation products, to propose the molecular formulae and to elucidate their chemical structures. Due to the complexity of the matrix, visual inspection of the chromatograms showed no clear differences between the controls and the treated samples. Therefore, the software package MZmine was used to facilitate the identification of the transformation products and speed up the data analysis. In total, we propose five transformation products; among them, four are described as etoposide transformation products for the first time. Even though the chemical structures of these new compounds cannot be confirmed due to the lack of standards, their molecular formulae can be used to target them in monitoring studies. PMID:27215983

  3. Combining disulfiram and poly(l-glutamic acid)-cisplatin conjugates for combating cisplatin resistance.

    PubMed

    Song, Wantong; Tang, Zhaohui; Shen, Na; Yu, Haiyang; Jia, Yanjie; Zhang, Dawei; Jiang, Jian; He, Chaoliang; Tian, Huayu; Chen, Xuesi

    2016-06-10

    A poly(l-glutamic acid) graft polyethylene glycol-cisplatin complex (PGA-CisPt) performs well in reducing the toxicity of free cisplatin and greatly enhances the accumulation and retention of cisplatin in solid tumors. However, there is a lack of effective treatment options for cisplatin-resistant tumors. A major reason for this is the dense PEG shell, which ensures that the PGA-CisPt maintains a long retention time in the blood that may result in it bypassing the tumor cells or failing to be endocytosed within the tumor microenvironment. Consequently, the cisplatin from PGA-CisPt is released to the extracellular space in the presence of cisplatin-resistant tumor cells and the resistant problem to free cisplatin still valid. Therefore, we devised a strategy to combat the resistance of cisplatin in the tumor microenvironment using nanoparticles-loaded disulfiram (NPs-DSF) as a modulator. In vitro, cisplatin, in combination with DSF, had a synergistic effect and decreased cell survival rate of cisplatin-resistant A549DDP cells. This effect was also observed when combining PGA-CisPt with NPs-DSF. Similarly, in Balb/C nude mice with A549DDP xenografts, NPs-DSF improved PGA-CisPt effectiveness in inhibiting tumor growth while maintaining low toxicity. Our data demonstrate that DSF reduces intracellular glutathione (GSH) levels, inhibits NFκB activity, and modulates the expression of apoptosis-related proteins Bcl-2 and Bax, thereby improves the effectiveness of cisplatin in resistant cell lines. Here, we provide a promising method for overcoming cisplatin resistance in tumors, while maintaining the in vivo benefits of the PGA-CisPt complex. PMID:26928530

  4. Thermosensitive gemcitabine-magnetoliposomes for combined hyperthermia and chemotherapy

    NASA Astrophysics Data System (ADS)

    Ferreira, Roberta V.; da Mata Martins, Thaís Maria; Goes, Alfredo Miranda; Fabris, José D.; Cavalcante, Luis Carlos D.; Eugenio Fernandez Outon, Luis; Domingues, Rosana Z.

    2016-02-01

    The combination of magnetic hyperthermia therapy with the controlled release of chemotherapeutic agents in tumors may be an efficient therapeutic with few side effects because the bioavailability, tolerance and amount of the drug can be optimized. Here, we prepared magnetoliposomes consisting of magnetite nanoparticle cores and the anticancer drug gemcitabine encapsulated by a phospholipid bilayer. The potential of these magnetoliposomes for controlled drug release and cancer treatment via hyperthermic behavior was investigated. The magnetic nanoparticle encapsulation efficiency was dependent on the initial amount of magnetite nanoparticles present at the encapsulation stage; the best formulation was 66%. We chose this formulation to characterize the physicochemical properties of the magnetoliposomes and to encapsulate gemcitabine. The mean particle size and distribution were determined by dynamic light scattering (DLS), and the zeta potential was measured. The magnetoliposome formulations all had acceptable characteristics for systemic administration, with a mean size of approximately 150 nm and a polydispersity index <0.2. The magnetoliposomes were stable in aqueous suspension for at least one week, as determined by DLS. Temperature increases due to the dissipation energy of magnetoliposome suspensions subjected to an applied alternating magnetic field (AMF) were measured at different magnetic field intensities, and the values were appropriated for cancer treatments. The drug release profile at 37 °C showed that 17% of the gemcitabine was released after 72 h. Drug release from magnetoliposomes exposed to an AMF for 5 min reached 70%.

  5. Distribution of actin in etoposide-induced human leukemia cell line K-562 using fluorescence and immunoelectron microscopy technique.

    PubMed

    Grzanka, Alina; Grzanka, Dariusz

    2002-01-01

    Localization of actin was studied in erythroleukemic cell line K-562 after treatment with etoposide for 72 hours in a range of concentrations 0.02-200 microM/L. Actin was visualised by fluorescence microscopy and streptavidingold method. These findings indicate that changes in actin after treatment with etoposide were dose-dependent. Significant changes in the cellular distribution of F-actin in K-562 cells were obtained after treatment with 20 and 200 microM/L etoposide. In comparison with control cells, the number of the cells decreased and cells were larger especially at 200 microM/L. F-actin was diffusely distributed throughout the cell at 20 microM/L. Treatment of cells with 200 microM/L etoposide showed F-actin diffusely distributed throughout the cell with local actin assemblies and also at the cell periphery. Immunogold labelling of actin was observed in cells treated with all doses of etoposide and control cells. Labelling was found in the nucleus and also in the cytoplasm. At the ultrastructural level, cells treated with 200 microM/L etoposide showed protrusions at the surface, in which increase of actin was often observed. Etoposide causes changes in actin distribution of K-562 cells, and the changes in expression of actin were not only restricted to cell with features of apoptosis. PMID:12140866

  6. Preparation of hierarchical mesoporous CaCO3 by a facile binary solvent approach as anticancer drug carrier for etoposide

    PubMed Central

    2013-01-01

    To develop a nontoxic system for targeting therapy, a new highly ordered hierarchical mesoporous calcium carbonate nanospheres (CCNSs) as small drug carriers has been synthesized by a mild and facile binary solvent approach under the normal temperature and pressure. The hierarchical structure by multistage self-assembled strategy was confirmed by TEM and SEM, and a possible formation process was proposed. Due to the large fraction of voids inside the nanospheres which provides space for physical absorption, the CCNSs can stably encapsulate the anticancer drug etoposide with the drug loading efficiency as high as 39.7 wt.%, and etoposide-loaded CCNS (ECCNS) nanoparticles can dispersed well in the cell culture. Besides, the drug release behavior investigated at three different pH values showed that the release of etoposide from CCNSs was pH-sensitive. MTT assay showed that compared with free etoposide, ECCNSs exhibited a higher cell inhibition ratio against SGC-7901 cells and also decreased the toxicity of etoposide to HEK 293 T cells. The CLSM image showed that ECCNSs exhibited a high efficiency of intracellular delivery, especially in nuclear invasion. The apoptosis test revealed that etoposide entrapped in CCNSs could enhance the delivery efficiencies of drug to achieve an improved inhibition effect on cell growth. These results clearly implied that the CCNSs are a promising drug delivery system for etoposide in cancer therapy. PMID:23849350

  7. Concurrent IMRT and weekly cisplatin followed by GDP chemotherapy in newly diagnosed, stage IE to IIE, nasal, extranodal NK/T-Cell lymphoma.

    PubMed

    Ke, Q-H; Zhou, S-Q; Du, W; Liang, G; Lei, Y; Luo, F

    2014-01-01

    On the basis of the benefits of frontline radiation in early-stage, extranodal natural killer (NK)/T-cell lymphoma (ENKTL), we conducted the trial of concurrent chemoradiotherapy (CCRT) followed by three cycles of gemcitabine, dexamethasone and cisplatin (GDP). Thirty-two patients with newly diagnosed, stage IE to IIE, nasal ENKTL received CCRT (that is, all patients received intensity-modulated radiotherapy 56 Gy and cisplatin 30 mg/m(2) weekly, 3-5 weeks). Three cycles of GDP (gemcitabine 1000 mg/m(2) intravenously (i.v.) on days 1 and 8, dexamethasone 40 mg orally on days 1-4 and cisplatin 75 mg/m(2) i.v. on day 1 (GDP), every 21 days as an outpatient were scheduled after CCRT. All patients completed CCRT, which resulted in 100% response that included 24 complete responses (CRs) and eight partial responses. The CR rate after CCRT was 75.0% (that is, 24 of 32 responses). Twenty-eight of the 32 patients completed the planned three cycles of GDP, whereas four patients did not because they withdrew (n = 1) or because they had an infection (n = 3). The overall response rate and the CR rate were 90.6% (that is, 29 of 32 responses) and 84.4% (that is, 27 of 32 responses), respectively. Only two patient experienced grade 3 toxicity during CCRT (nausea), whereas 13 of the 30 patients experienced grade 4 neutropenia. The estimated 3-year overall survival and progression-free rates were 87.50% and 84.38%, respectively. In conclusion, CCRT followed by GDP chemotherapy can be a feasible and effective treatment strategy for stage IE to IIE nasal ENKTL. PMID:25501024

  8. Suramin protects from cisplatin-induced acute kidney injury.

    PubMed

    Dupre, Tess V; Doll, Mark A; Shah, Parag P; Sharp, Cierra N; Kiefer, Alex; Scherzer, Michael T; Saurabh, Kumar; Saforo, Doug; Siow, Deanna; Casson, Lavona; Arteel, Gavin E; Jenson, Alfred Bennett; Megyesi, Judit; Schnellmann, Rick G; Beverly, Levi J; Siskind, Leah J

    2016-02-01

    Cisplatin, a commonly used cancer chemotherapeutic, has a dose-limiting side effect of nephrotoxicity. Approximately 30% of patients administered cisplatin suffer from kidney injury, and there are limited treatment options for the treatment of cisplatin-induced kidney injury. Suramin, which is Federal Drug Administration-approved for the treatment of trypanosomiasis, improves kidney function after various forms of kidney injury in rodent models. We hypothesized that suramin would attenuate cisplatin-induced kidney injury. Suramin treatment before cisplatin administration reduced cisplatin-induced decreases in kidney function and injury. Furthermore, suramin attenuated cisplatin-induced expression of inflammatory cytokines and chemokines, endoplasmic reticulum stress, and apoptosis in the kidney cortex. Treatment of mice with suramin 24 h after cisplatin also improved kidney function, suggesting that the mechanism of protection is not by inhibition of tubular cisplatin uptake or its metabolism to nephrotoxic species. If suramin is to be used in the context of cancer, then it cannot prevent cisplatin-induced cytotoxicity of cancer cells. Suramin did not alter the dose-response curve of cisplatin in lung adenocarcinoma cells in vitro. In addition, suramin pretreatment of mice harboring lung adenocarcinomas did not alter the initial cytotoxic effects of cisplatin (DNA damage and apoptosis) on tumor cells. These results provide evidence that suramin has potential as a renoprotective agent for the treatment/prevention of cisplatin-induced acute kidney injury and justify future long-term preclinical studies using cotreatment of suramin and cisplatin in mouse models of cancer. PMID:26661653

  9. Cisplatin induces stemness in ovarian cancer.

    PubMed

    Wiechert, Andrew; Saygin, Caner; Thiagarajan, Praveena S; Rao, Vinay S; Hale, James S; Gupta, Nikhil; Hitomi, Masahiro; Nagaraj, Anil Belur; DiFeo, Analisa; Lathia, Justin D; Reizes, Ofer

    2016-05-24

    The mainstay of treatment for ovarian cancer is platinum-based cytotoxic chemotherapy. However, therapeutic resistance and recurrence is a common eventuality for nearly all ovarian cancer patients, resulting in poor median survival. Recurrence is postulated to be driven by a population of self-renewing, therapeutically resistant cancer stem cells (CSCs). A current limitation in CSC studies is the inability to interrogate their dynamic changes in real time. Here we utilized a GFP reporter driven by the NANOG-promoter to enrich and track ovarian CSCs. Using this approach, we identified a population of cells with CSC properties including enhanced expression of stem cell transcription factors, self-renewal, and tumor initiation. We also observed elevations in CSC properties in cisplatin-resistant ovarian cancer cells as compared to cisplatin-naïve ovarian cancer cells. CD49f, a marker for CSCs in other solid tumors, enriched CSCs in cisplatin-resistant and -naïve cells. NANOG-GFP enriched CSCs (GFP+ cells) were more resistant to cisplatin as compared to GFP-negative cells. Moreover, upon cisplatin treatment, the GFP signal intensity and NANOG expression increased in GFP-negative cells, indicating that cisplatin was able to induce the CSC state. Taken together, we describe a reporter-based strategy that allows for determination of the CSC state in real time and can be used to detect the induction of the CSC state upon cisplatin treatment. As cisplatin may provide an inductive stress for the stem cell state, future efforts should focus on combining cytotoxic chemotherapy with a CSC targeted therapy for greater clinical utility. PMID:27105520

  10. 76 FR 55110 - In the Matter of Certain Gemcitabine and Products Containing Same; Notice of Commission...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-06

    ... Lilly and Company (``Lilly''). 76 FR 16445. The complaint alleges violations of section 337 of the... COMMISSION In the Matter of Certain Gemcitabine and Products Containing Same; Notice of Commission... importation, and the sale within the United States after importation of certain gemcitabine and...

  11. [Gemcitabine Monotherapy for Advanced Mycosis Fungoides--Two Case Reports and a Literature Review].

    PubMed

    Masuzawa, Mamiko; Takasu, Hiroshi; Amoh, Yasuyuki

    2015-12-01

    Gemcitabine, a pyrimidine nucleoside analogue, is gaining recognition as a potential therapeutic agent for advanced-stage and refractory cutaneous T-cell lymphoma (CTCL). We report of 2 patients whose advanced-stage mycosis fungoides was not sufficiently controlled by prior CHOP therapy. Both patients showed great improvement in the skin lesions with weekly gemcitabine therapy (1,000-1,200 mg/m2). The patients received four and 8 cycles of gemcitabine monotherapy, respectively, and no grade 3-4 hematological or hepatic adverse events occurred. This is the first report of the efficacy of gemcitabine for CTCL in Japan. Gemcitabine is well tolerated and is an effective monotherapy for CTCL. PMID:26809303

  12. Formulation optimization of etoposide loaded PLGA nanoparticles by double factorial design and their evaluation.

    PubMed

    Yadav, Khushwant S; Sawant, Krutika K

    2010-01-01

    Etoposide is one of the most commonly used drugs in chemotherapy of acute lymphocytic leukemia and acute myelogenous leukaemia. Etoposide has variable oral bioavailability ranging from 24-74% and has terminal half life of 1.5 hours by intravenous route. The conventional parenteral therapy causes inconvenience and pain to the patients as it has to be given through a continuous IV infusion over 24-34 h. The present investigation was aimed at developing etoposide loaded biodegradable nanoparticles which would be a sustained release formulation and replace the conventional therapy of continuous intravenous administration. Nanoparticles were prepared by emulsion solvent evaporation method using high pressure homogenization. The process parameters like homogenization cycles (four) and homogenization pressure (10000 psi) were first optimized using a 3(2) factorial design based on response Y1(mean particle size of 98+/-1nm). Then a 32 factorial design was carried out to study the effect of two independent variables, ratio of drug and polymer (X1) and surfactant concentration (X2) on the two responses to obtain their optimized values, percentage entrapment efficiency (Y2, 83.12+/-8.3%) and mean particle size (Y3, 105+/-5.4 nm) for Etoposide loaded PLGA Nanoparticles. Contour plots and response surface plots showed visual representation of relationship between the experimental responses and the set of input variables. The adequacy of the regression model was verified by a check point analysis. The zeta potential values ranged between -23.0 to -34.2 mV, indicating stability. Sucrose was used as cryoprotectant during lyophilization. DSC and XRD studies indicated that etoposide was present in the amorphous phase and may have been homogeneously dispersed in the PLGA matrix. The electron micrographs showed spherical, discrete and homogenous particles. Drug release study showed that etoposide loaded PLGA nanoparticles sustained release up to 72h. The release from the nanoparticles

  13. Sensitization of pancreatic cancer stem cells to gemcitabine by Chk1 inhibition.

    PubMed

    Venkatesha, Venkatasubbaiah A; Parsels, Leslie A; Parsels, Joshua D; Zhao, Lili; Zabludoff, Sonya D; Simeone, Diane M; Maybaum, Jonathan; Lawrence, Theodore S; Morgan, Meredith A

    2012-06-01

    Checkpoint kinase 1 (Chk1) inhibition sensitizes pancreatic cancer cells and tumors to gemcitabine. We hypothesized that Chk1 inhibition would sensitize pancreatic cancer stem cells to gemcitabine. We tested this hypothesis by using two patient-derived xenograft models (designated J and F) and the pancreatic cancer stem cell markers CD24, CD44, and ESA. We determined the percentage of marker-positive cells and their tumor-initiating capacity (by limiting dilution assays) after treatment with gemcitabine and the Chk1 inhibitor, AZD7762. We found that marker-positive cells were significantly reduced by the combination of gemcitabine and AZD7762. In addition, secondary tumor initiation was significantly delayed in response to primary tumor treatment with gemcitabine + AZD7762 compared with control, gemcitabine, or AZD7762 alone. Furthermore, for the same number of stem cells implanted from gemcitabine- versus gemcitabine + AZD7762-treated primary tumors, secondary tumor initiation at 10 weeks was 83% versus 43%, respectively. We also found that pS345 Chk1, which is a measure of DNA damage, was induced in marker-positive cells but not in the marker-negative cells. These data demonstrate that Chk1 inhibition in combination with gemcitabine reduces both the percentage and the tumor-initiating capacity of pancreatic cancer stem cells. Furthermore, the finding that the Chk1-mediated DNA damage response was greater in stem cells than in non-stem cells suggests that Chk1 inhibition may selectively sensitize pancreatic cancer stem cells to gemcitabine, thus making Chk1 a potential therapeutic target for improving pancreatic cancer therapy. PMID:22787433

  14. Increased nephrotoxicity of combination taxol and cisplatin chemotherapy in gynecologic cancers as compared to cisplatin alone.

    PubMed

    Merouani, A; Davidson, S A; Schrier, R W

    1997-01-01

    To investigate the increased nephrotoxicity of taxol and cisplatin combination chemotherapy in gynecologic cancers as compared to cisplatin alone, the medical records of 25 patients with gynecological cancers were reviewed for evaluation of nephrotoxicity after chemotherapy treatment. The data included age, serum creatinine, calculated creatinine clearance, initial and cumulative dose of cisplatin and taxol, primary site of the cancer, renal ultrasound and hydration protocols. Renal function was evaluated before, during and 6 months after chemotherapy. Renal dysfunction was defined as a greater than 25% decrease in creatinine clearance. Comparing 11 patients treated with taxol and cisplatin versus 14 treated with cisplatin alone, there was a significant difference in effect on renal function. Nine of 11 patients (81%) treated with the combination chemotherapy had a greater than 25% decrease in creatinine clearance while only 4 of the 14 patients (29%) treated with cisplatin alone had such a decrease in creatinine clearance (p < 0.004). The patients treated with the combination chemotherapy, however, received a higher dose of cisplatin (80.4 vs. 66.4 mg/m2, p < 0.02) and were treated longer (6.7 vs. 4.3 months, p < 0.002). Nevertheless, when the patients were matched for age, initial dose and cumulative dose of cisplatin, a higher frequency of nephrotoxicity persisted in patients treated with taxol and cisplatin as compared to cisplatin alone (72 as compared to 20%, p < 0.02). The patients in both groups were comparably hydrated; prerenal failure and urinary tract obstruction were excluded in all patients. Six months after completion of chemotherapy, a significantly lower creatinine clearance was still observed in patients treated with taxol and cisplatin combination therapy (46 vs. 76 ml/min, p < 0.01). In summary, a retrospective analysis of renal function in patients with gynecological cancers showed an increased nephrotoxicity in patients treated with taxol and

  15. Gemcitabine plus paclitaxel versus carboplatin plus either gemcitabine or paclitaxel in advanced non-small-cell lung cancer: a literature-based meta-analysis.

    PubMed

    Li, Chenguang; Sun, Yihua; Pan, Yunjian; Wang, Qifeng; Yang, Shu; Chen, Haiquan

    2010-10-01

    The combination of gemcitabine plus paclitaxel has been proposed as an alternative to the platinum-based combinations for treatment of advanced non-small-cell lung cancer (NSCLC). However, conflicting results have been reported. This meta-analysis was performed to compare the activity, efficacy, and toxicity of gemcitabine plus paclitaxel versus carboplatin plus either gemcitabine or paclitaxel in patients with untreated advanced NSCLC. Randomized phase II and phase III clinical trials comparing gemcitabine plus paclitaxel with carboplatin plus gemcitabine or paclitaxel were collected from electronic databases (Medline, EMBASE, and the Cochrane Central Register of Controlled Trials), relevant reference lists, and abstract books. The published languages and years were not limited. Pooled odds ratios (ORs) were calculated for the 1-year survival rate (1-year SR), the overall response rate (ORR), and grade 3 and grade 4 toxicities. Four randomized controlled trials (2186 patients) were identified from 2051 reports. They were all published as full-text articles. No significant heterogeneity was detected in these studies. A significant difference in ORR favoring gemcitabine plus paclitaxel over carboplatin-based doublets was observed [OR = 1.20; 95% confidence interval (95% CI) = 1.02-1.42; P = 0.03], whereas the trend toward an improved 1-year SR was not significant (OR = 1.07; 95% CI = 0.91-1.26; P = 0.41). An increased risk of grade 3-4 toxicities for patients receiving carboplatin-based chemotherapy was statistically demonstrated. The gemcitabine plus paclitaxel combination showed an improved ORR and a better toxicity profile but a similar 1-year SR compared to carboplatin-based doublets. For nonplatinum-based chemotherapy, gemcitabine plus paclitaxel is a useful alternative. PMID:20703493

  16. High concentrations of glucose suppress etoposide-induced cell death of B-cell lymphoma through BCL-6.

    PubMed

    Shao, Yan; Ling, Chang Chun; Liu, Xu Qing

    2014-07-18

    Glucose is potentially a factor in the resistance to chemotherapy of B-cell lymphomas. In this study we investigated the expression of the glucose induced transcription factor Bcl-6 and the underlying mechanism by which it suppresses B-cell lymphoma cell death. Glucose was found to prevent etoposide-induced tumor cell death. BCL-6 expression was induced by glucose but down-regulated by etoposide. BCL-6 expression was regulated by the interaction of VDUP1 and p53. The molecular mechanism by which glucose prevented etoposide-induced tumor cell death was shown to involve the BCL-6 mediated caspase pathway. Our data suggest that glucose-induced BCL-6 overexpression could abrogate the etoposide chemotherapy effect on tumor cell death. PMID:24878528

  17. Cytoreduction of lymphoid malignancies and mobilization of blood hematopoietic progenitor cells with high doses of cyclophosphamide and etoposide plus filgrastim.

    PubMed

    Damon, Lloyd; Rugo, Hope; Tolaney, Sara; Navarro, Willis; Martin, Thomas; Ries, Curt; Case, Delvyn; Ault, Kenneth; Linker, Charles

    2006-03-01

    We evaluated the efficiency of high doses of cyclophosphamide (6 g/m2) and etoposide (2 g/m2) plus filgrastim (granulocyte colony-stimulating factor; G-CSF) to mobilize autologous hematopoietic progenitor cells in patients with non-Hodgkin lymphoma, multiple myeloma, and Waldenström macroglobulinemia. We also evaluated the safety of this regimen and the engraftment kinetics after myeloablative chemotherapy. Seventy-nine patients with high-risk or relapsed/primary refractory non-Hodgkin lymphoma, multiple myeloma, or Waldenström macroglobulinemia were treated. The mobilizing regimen was as follows: cyclophosphamide 600 mg/m2 twice daily for 10 doses, etoposide 200 mg/m2 twice daily for 10 doses (continuous; n=57) or 2 g/m2 over 10 hours on day 5 of etoposide (bolus; n=22), and G-CSF 5 microg/kg/d beginning day 14. Fifty-nine percent of patients achieved the primary end point (a CD34 cell dose of 5 million per kilogram with a single leukapheresis). More bolus etoposide patients achieved the primary end point (86%) compared with continuous etoposide patients (47%; P<.0001). The CD34 cell dose collected was greater in bolus etoposide patients (44 million per kilogram) than in continuous etoposide patients (10.9 million per kilogram; P<.0001). Patients took 3 weeks to recover >500/microL neutrophils and >20000/microL platelets after cyclophosphamide and etoposide. The overall response rate was 69% for non-Hodgkin lymphoma patients and 71% for multiple myeloma/Waldenström macroglobulinemia patients. The treatment-related mortality was 2.5%. Sixteen percent of surviving patients experienced grade>or=3 nonhematologic toxicity. Patients receiving bolus etoposide had significantly less grade>or=2 oral mucositis, less use of total parenteral nutrition, and less need for red blood cell and platelet transfusions. Sixty-four patients (81%) underwent autologous hematopoietic progenitor cell transplantation, with prompt engraftment. Four patients (5%) did not undergo autologous

  18. Veliparib, Cisplatin, and Gemcitabine Hydrochloride in Treating Patients With Advanced Biliary, Pancreatic, Urothelial, or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-07-01

    Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Stage III Bladder Cancer; Stage III Pancreatic Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Bladder Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Pancreatic Cancer; Transitional Cell Carcinoma of the Bladder; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  19. Tumour resistance to cisplatin: a modelling approach

    NASA Astrophysics Data System (ADS)

    Marcu, L.; Bezak, E.; Olver, I.; van Doorn, T.

    2005-01-01

    Although chemotherapy has revolutionized the treatment of haematological tumours, in many common solid tumours the success has been limited. Some of the reasons for the limitations are: the timing of drug delivery, resistance to the drug, repopulation between cycles of chemotherapy and the lack of complete understanding of the pharmacokinetics and pharmacodynamics of a specific agent. Cisplatin is among the most effective cytotoxic agents used in head and neck cancer treatments. When modelling cisplatin as a single agent, the properties of cisplatin only have to be taken into account, reducing the number of assumptions that are considered in the generalized chemotherapy models. The aim of the present paper is to model the biological effect of cisplatin and to simulate the consequence of cisplatin resistance on tumour control. The 'treated' tumour is a squamous cell carcinoma of the head and neck, previously grown by computer-based Monte Carlo techniques. The model maintained the biological constitution of a tumour through the generation of stem cells, proliferating cells and non-proliferating cells. Cell kinetic parameters (mean cell cycle time, cell loss factor, thymidine labelling index) were also consistent with the literature. A sensitivity study on the contribution of various mechanisms leading to drug resistance is undertaken. To quantify the extent of drug resistance, the cisplatin resistance factor (CRF) is defined as the ratio between the number of surviving cells of the resistant population and the number of surviving cells of the sensitive population, determined after the same treatment time. It is shown that there is a supra-linear dependence of CRF on the percentage of cisplatin-DNA adducts formed, and a sigmoid-like dependence between CRF and the percentage of cells killed in resistant tumours. Drug resistance is shown to be a cumulative process which eventually can overcome tumour regression leading to treatment failure.

  20. Mutant p53 cooperates with ETS2 to promote etoposide resistance

    PubMed Central

    Do, Phi M.; Varanasi, Lakshman; Fan, Songqing; Li, Chunyang; Kubacka, Iwona; Newman, Virginia; Chauhan, Krishna; Daniels, Silvano Rakeem; Boccetta, Maurizio; Garrett, Michael R.; Li, Runzhao; Martinez, Luis A.

    2012-01-01

    Mutant p53 (mtp53) promotes chemotherapy resistance through multiple mechanisms, including disabling proapoptotic proteins and regulating gene expression. Comparison of genome wide analysis of mtp53 binding revealed that the ETS-binding site motif (EBS) is prevalent within predicted mtp53-binding sites. We demonstrate that mtp53 regulates gene expression through EBS in promoters and that ETS2 mediates the interaction with this motif. Importantly, we identified TDP2, a 5′-tyrosyl DNA phosphodiesterase involved in the repair of DNA damage caused by etoposide, as a transcriptional target of mtp53. We demonstrate that suppression of TDP2 sensitizes mtp53-expressing cells to etoposide and that mtp53 and TDP2 are frequently overexpressed in human lung cancer; thus, our analysis identifies a potentially “druggable” component of mtp53's gain-of-function activity. PMID:22508727

  1. Etoposide interferes with the process of chromatin condensation during alga Chara vulgaris spermiogenesis.

    PubMed

    Agnieszka, Wojtczak

    2014-10-01

    DNA topoisomerase II plays an essential role in animal spermiogenesis, where changes of chromatin structure are connected with appearance of transient DNA breaks. Such topo II activity can be curtailed by inhibitors such as etoposide and suramine. The aim of the present study was to investigate, for the first time, the effect of etoposide on spermatid chromatin remodeling in the green alga Chara vulgaris. This inhibitor prolonged the early spermiogenesis stages and blocked the formation of the phosphorylated form of histone H2AX at stages VI-VII. The lack of transient DSBs at these stages impairs the elimination of supercoils containing nucleosomes which lead to disturbances in nucleoprotein exchange and the pattern of spermatid chromatin fibrils at stages VI-VIII. Immunofluorescent and ultrastructural observations revealed that during C. vulgaris spermiogenesis topo II played an important role similar to that in mammals. Some corresponding features had been pointed out before, the present studies showed further similarities. PMID:25041830

  2. Mutant p53 cooperates with ETS2 to promote etoposide resistance.

    PubMed

    Do, Phi M; Varanasi, Lakshman; Fan, Songqing; Li, Chunyang; Kubacka, Iwona; Newman, Virginia; Chauhan, Krishna; Daniels, Silvano Rakeem; Boccetta, Maurizio; Garrett, Michael R; Li, Runzhao; Martinez, Luis A

    2012-04-15

    Mutant p53 (mtp53) promotes chemotherapy resistance through multiple mechanisms, including disabling proapoptotic proteins and regulating gene expression. Comparison of genome wide analysis of mtp53 binding revealed that the ETS-binding site motif (EBS) is prevalent within predicted mtp53-binding sites. We demonstrate that mtp53 regulates gene expression through EBS in promoters and that ETS2 mediates the interaction with this motif. Importantly, we identified TDP2, a 5'-tyrosyl DNA phosphodiesterase involved in the repair of DNA damage caused by etoposide, as a transcriptional target of mtp53. We demonstrate that suppression of TDP2 sensitizes mtp53-expressing cells to etoposide and that mtp53 and TDP2 are frequently overexpressed in human lung cancer; thus, our analysis identifies a potentially "druggable" component of mtp53's gain-of-function activity. PMID:22508727

  3. Dimethylaminoparthenolide and gemcitabine: a survival study using a genetically engineered mouse model of pancreatic cancer

    PubMed Central

    2013-01-01

    Background Pancreatic cancer remains one of the deadliest cancers due to lack of early detection and absence of effective treatments. Gemcitabine, the current standard-of-care chemotherapy for pancreatic cancer, has limited clinical benefit. Treatment of pancreatic cancer cells with gemcitabine has been shown to induce the activity of the transcription factor nuclear factor-kappaB (NF-κB) which regulates the expression of genes involved in the inflammatory response and tumorigenesis. It has therefore been proposed that gemcitabine-induced NF-κB activation may result in chemoresistance. We hypothesize that NF-κB suppression by the novel inhibitor dimethylaminoparthenolide (DMAPT) may enhance the effect of gemcitabine in pancreatic cancer. Methods The efficacy of DMAPT and gemcitabine was evaluated in a chemoprevention trial using the mutant Kras and p53-expressing LSL-KrasG12D/+; LSL-Trp53R172H; Pdx-1-Cre mouse model of pancreatic cancer. Mice were randomized to treatment groups (placebo, DMAPT [40 mg/kg/day], gemcitabine [50 mg/kg twice weekly], and the combination DMAPT/gemcitabine). Treatment was continued until mice showed signs of ill health at which time they were sacrificed. Plasma cytokine levels were determined using a Bio-Plex immunoassay. Statistical tests used included log-rank test, ANOVA with Dunnett’s post-test, Student’s t-test, and Fisher exact test. Results Gemcitabine or the combination DMAPT/gemcitabine significantly increased median survival and decreased the incidence and multiplicity of pancreatic adenocarcinomas. The DMAPT/gemcitabine combination also significantly decreased tumor size and the incidence of metastasis to the liver. No significant differences in the percentages of normal pancreatic ducts or premalignant pancreatic lesions were observed between the treatment groups. Pancreata in which no tumors formed were analyzed to determine the extent of pre-neoplasia; mostly normal ducts or low grade pancreatic lesions were

  4. Intraventricular etoposide safety and toxicity profile in children and young adults with refractory or recurrent malignant brain tumors.

    PubMed

    Pajtler, Kristian W; Tippelt, Stephan; Siegler, Nele; Reichling, Stefanie; Zimmermann, Martina; Mikasch, Ruth; Bode, Udo; Gnekow, Astrid; Pietsch, Torsten; Benesch, Martin; Rutkowski, Stefan; Fleischhack, Gudrun

    2016-07-01

    Systemic administration of etoposide is effective in treating metastatic, recurrent or refractory brain tumors, but penetration into the cerebrospinal fluid is extremely poor. This study was designed to determine the safety and toxicity profile of intraventricular etoposide administration and was affiliated with the prospective, multicenter, nonblinded, nonrandomized, multi-armed HIT-REZ-97 trial. The study enrolled 68 patients, aged 1.1-34.6 (median age 11 years). Adverse events that could possibly be related to intraventricular etoposide therapy were documented and analyzed. Intraventricular etoposide was simultaneously administered with either oral or intravenous chemotherapy in 426 courses according to three major schedules varying in dosing (0.25-1 mg), frequency of administration (bolus injection, every 12 or 24 h), course duration (5-10 days) and length of interval between courses (2-5 weeks). Potential treatment-related adverse effects included transient headache, seizures, infection of the reservoir, nausea and neuropsychological symptoms. Hematological side effects were not observed. One patient, with history of multiple prior therapies, who received long-term intraventricular and oral etoposide treatment developed acute myeloid leukemia as a secondary malignancy. Overall intraventricular etoposide is well tolerated. The results of this study have warranted a phase II trial to determine the effectiveness of this regimen in disease stages with very limited therapeutic options. PMID:27147083

  5. Stereotactic Body Radiotherapy and Gemcitabine for Locally Advanced Pancreatic Cancer

    SciTech Connect

    Mahadevan, Anand; Jain, Sanjay; Goldstein, Michael; Miksad, Rebecca; Pleskow, Douglas; Sawhney, Mandeep; Brennan, Darren M.D.; Callery, Mark; Vollmer, Charles

    2010-11-01

    Purpose: Patients with nonmetastatic locally advanced unresectable pancreatic cancer have a dismal prognosis. Conventional concurrent chemoradiotherapy requires 6 weeks of daily treatment and can be arduous. We explored the safety and effectiveness of a 3-day course of hypofractionated stereotactic body radiotherapy (SBRT) followed by gemcitabine in this population. Patients and Methods: A total of 36 patients with nonmetastatic, locally advanced, unresectable pancreatic cancer with {>=}12 months of follow-up were included. They received three fractions of 8, 10, or 12 Gy (total dose, 24-36 Gy) of SBRT according to the tumor location in relation to the stomach and duodenum, using fiducial-based respiratory motion tracking on a robotic radiosurgery system. The patients were then offered gemcitabine for 6 months or until tolerance or disease progression. Results: With an overall median follow-up of 24 months (range, 12-33), the local control rate was 78%, the median overall survival time was 14.3 months, the median carbohydrate antigen 19-9-determined progression-free survival time was 7.9 months, and the median computed tomography-determined progression-free survival time was 9.6 months. Of the 36 patients, 28 (78%) eventually developed distant metastases. Six patients (17%) were free of progression at the last follow-up visit (range, 13-30 months) as determined by normalized tumor markers with stable computed tomography findings. Nine Grade 2 (25%) and five Grade 3 (14%) toxicities attributable to SBRT occurred. Conclusion: Hypofractionated SBRT can be delivered quickly and effectively in patients with nonmetastatic, locally advanced, unresectable pancreatic cancer with acceptable side effects and minimal interference with gemcitabine chemotherapy.

  6. Mechanisms of resistance to combinations of vincristine, etoposide and doxorubicin in Chinese hamster ovary cells.

    PubMed Central

    Souès, S.; Laval, F.; Charcosset, J. Y.

    1995-01-01

    We have isolated from Chinese hamster ovary cells, 30 sublines resistant to vincristine, doxorubicin or etoposide and 43 sublines evading treatment with a pair of these drugs. Isolated in one step and under low selective pressure, sublines were 3- to 25-fold more resistant to their selecting drug(s) than the parental cells. Possible P-glycoprotein-associated multidrug resistance was investigated through pgp gene copy number and mRNA expression level. DNA topoisomerase II alteration was evaluated from the ability of nuclear extracts to form cleavable complexes. Vincristine (all sublines) and doxorubicin (6/7 sublines) preferentially selected for pgp gene amplification and mRNA overexpression, whereas selection with etoposide resulted in a decrease of cleavable complex formation in 11 out of 13 sublines. A common pgp gene-mediated resistance was found in the 13 doxorubicin plus vincristine-selected sublines, whereas all but one of the 12 etoposide plus vincristine-resistant sublines displayed both pgp mRNA overexpression and decreased ability to form cleavable complexes. Among the 18 doxorubicin plus etoposide selected sublines, five exhibited a decreased ability to form cleavable complexes only, six exhibited pgp mRNA overexpression only and six exhibited both alterations. Overall, drug resistance could not be attributed to either mechanism in three of the 73 sublines. We conclude that under low selective pressure it is possible to find a combination of drugs which require simultaneous selection of more than one resistance mechanism; such cells emerge with very low frequency. Images Figure 1 Figure 2 Figure 4 Figure 5 Figure 6 PMID:7880729

  7. Resistance to etoposide-induced apoptosis in a Burkitt's lymphoma cell line.

    PubMed

    Zhao, E G; Song, Q; Cross, S; Misko, I; Lees-Miller, S P; Lavin, M F

    1998-08-31

    Burkitt's lymphoma cells that vary in their phenotypic characteristics show significantly different degrees of susceptibility to radiation-induced apoptosis. Propensity to undergo apoptosis is reflected in the degradation of substrates such as DNA-dependent protein kinase but the status of bcl-2, c-myc and p53 has been uninformative. In this study, we have focused on 2 Epstein-Barr virus (EBV)-associated Burkitt's cell lines, one (WW2) susceptible and the other (BL29) resistant to etoposide-induced apoptosis. Differences in expression of BHRF1, an EBV gene that is homologous to the Bcl-2 proto-oncogene and known to inhibit apoptosis, or changes in apoptosis inhibitory proteins (IAPs), did not appear to account for the difference in susceptibility in the 2 cell lines. Cytoplasmic extracts from etoposide-treated WW2 cells caused apoptotic changes in nuclei isolated from either BL29 or WW2 cells, whereas extracts from BL29 cells failed to do so. In addition, extracts from etoposide-treated WW2 cells degraded the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), an important indicator of apoptosis, but this protein was resistant to degradation by BL29 extracts. It appears likely that caspase 3 (CPP32) is involved in this degradation since it was activated only in the apoptosis susceptible cells and the pattern of cleavage of DNA-PKcs was similar to that reported previously with recombinant caspase 3. As observed previously, addition of caspase 3 to nuclei failed to induce morphological changes indicative of apoptosis, but addition of caspase 3 to nuclei in the presence of extract from the resistant cells led to apoptotic changes. We conclude that resistance to apoptosis in BL29 cells is due to a failure of etoposide to activate upstream effectors of caspase activity. PMID:9688310

  8. The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo

    PubMed Central

    Vendetti, Frank P.; Lau, Alan; Schamus, Sandra; Conrads, Thomas P.; O'Connor, Mark J.; Bakkenist, Christopher J.

    2015-01-01

    ATR and ATM are DNA damage signaling kinases that phosphorylate several thousand substrates. ATR kinase activity is increased at damaged replication forks and resected DNA double-strand breaks (DSBs). ATM kinase activity is increased at DSBs. ATM has been widely studied since ataxia telangiectasia individuals who express no ATM protein are the most radiosensitive patients identified. Since ATM is not an essential protein, it is widely believed that ATM kinase inhibitors will be well-tolerated in the clinic. ATR has been widely studied, but advances have been complicated by the finding that ATR is an essential protein and it is widely believed that ATR kinase inhibitors will be toxic in the clinic. We describe AZD6738, an orally active and bioavailable ATR kinase inhibitor. AZD6738 induces cell death and senescence in non-small cell lung cancer (NSCLC) cell lines. AZD6738 potentiates the cytotoxicity of cisplatin and gemcitabine in NSCLC cell lines with intact ATM kinase signaling, and potently synergizes with cisplatin in ATM-deficient NSCLC cells. In contrast to expectations, daily administration of AZD6738 and ATR kinase inhibition for 14 consecutive days is tolerated in mice and enhances the therapeutic efficacy of cisplatin in xenograft models. Remarkably, the combination of cisplatin and AZD6738 resolves ATM-deficient lung cancer xenografts. PMID:26517239

  9. Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin.

    PubMed

    Chan, Pan F; Srikannathasan, Velupillai; Huang, Jianzhong; Cui, Haifeng; Fosberry, Andrew P; Gu, Minghua; Hann, Michael M; Hibbs, Martin; Homes, Paul; Ingraham, Karen; Pizzollo, Jason; Shen, Carol; Shillings, Anthony J; Spitzfaden, Claus E; Tanner, Robert; Theobald, Andrew J; Stavenger, Robert A; Bax, Benjamin D; Gwynn, Michael N

    2015-01-01

    New antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand DNA breaks. Here we report the first co-crystal structures of the antibacterial QPT-1 and the anticancer drug etoposide with Staphylococcus aureus DNA gyrase, showing binding at the same sites in the cleaved DNA as the fluoroquinolone moxifloxacin. Unlike moxifloxacin, QPT-1 and etoposide interact with conserved GyrB TOPRIM residues rationalizing why QPT-1 can overcome fluoroquinolone resistance. Our data show etoposide's antibacterial activity is due to DNA gyrase inhibition and suggests other anticancer agents act similarly. Analysis of multiple DNA gyrase co-crystal structures, including asymmetric cleavage complexes, led to a 'pair of swing-doors' hypothesis in which the movement of one DNA segment regulates cleavage and religation of the second DNA duplex. This mechanism can explain QPT-1's bacterial specificity. Structure-based strategies for developing topo2A antibacterials are suggested. PMID:26640131

  10. Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin

    PubMed Central

    Chan, Pan F.; Srikannathasan, Velupillai; Huang, Jianzhong; Cui, Haifeng; Fosberry, Andrew P.; Gu, Minghua; Hann, Michael M.; Hibbs, Martin; Homes, Paul; Ingraham, Karen; Pizzollo, Jason; Shen, Carol; Shillings, Anthony J.; Spitzfaden, Claus E.; Tanner, Robert; Theobald, Andrew J.; Stavenger, Robert A.; Bax, Benjamin D.; Gwynn, Michael N.

    2015-01-01

    New antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand DNA breaks. Here we report the first co-crystal structures of the antibacterial QPT-1 and the anticancer drug etoposide with Staphylococcus aureus DNA gyrase, showing binding at the same sites in the cleaved DNA as the fluoroquinolone moxifloxacin. Unlike moxifloxacin, QPT-1 and etoposide interact with conserved GyrB TOPRIM residues rationalizing why QPT-1 can overcome fluoroquinolone resistance. Our data show etoposide's antibacterial activity is due to DNA gyrase inhibition and suggests other anticancer agents act similarly. Analysis of multiple DNA gyrase co-crystal structures, including asymmetric cleavage complexes, led to a ‘pair of swing-doors' hypothesis in which the movement of one DNA segment regulates cleavage and religation of the second DNA duplex. This mechanism can explain QPT-1's bacterial specificity. Structure-based strategies for developing topo2A antibacterials are suggested. PMID:26640131

  11. Activity of cyclin B1 in HL-60 cells treated with etoposide.

    PubMed

    Żuryń, Agnieszka; Krajewski, Adrian; Szulc, Dawid; Litwiniec, Anna; Grzanka, Alina

    2016-06-01

    Cyclin B1 triggers G2/M phase transition phosphorylating with its catalytical partner - Cdc2 many of the molecular targets essential for cell cycle progression. Human leukemia cell line HL-60 were treated with increasing doses of etoposide (ETP) (0.5; 0.75; 1μM) to investigate how the drug affects cell morphology, viability, cell cycle distribution and expression of cyclin B1. To achieve this aim we applied light and transmission electron microscopy to observe morphological and ultra structural changes, image-based cytometry for apoptosis evaluation and cell cycle analysis, and then we conducted immunohistochemical and immunofluorescence staining to visualize cyclin localization and expression. Quantitive data about cyclin B1 expression were obtained from flow cytometry. Etoposide caused decrease in cell viability, induced apoptosis and G2/M arrest accompanied by enhanced expression of cyclin B1. Changes in expression and localization of cyclin B1 may constitute a part of the mechanism responsible for resistance of HL-60 cells to etoposide. Our results may reflect involvement of cyclin B1 in opposite processes - apoptosis induction and maintenance of cell viability in leukemia cells. We hypothesized possible roles and pathways by which cyclin B1 takes part in drug treatment response and chemosensitivity. PMID:27297620

  12. Effects on platelet function of combination etoposide and carboplatin chemotherapy in pediatric oncology patients.

    PubMed

    Pignatelli, P; Properzi, E; Pisani, M; Clerico, A; Schiavetti, A; Lenti, L; Pulcinelli, F M; Ferroni, P; Gazzaniga, P P

    1998-01-01

    The effects of a therapeutic course of the combination of carboplatin and etoposide on platelet function have been evaluated in 10 pediatric patients with brain tumors. Platelet count, in vitro aggregation tests, P-selectin expression and agonist-induced ATP release were evaluated before, and 7 and 15 days after one cycle of chemotherapy. The analysis of the results demonstrated the presence of an in vitro platelet aggregation defect in response to collagen and arachidonic acid in all patients 7 days after therapy. A concomitant decrease of collagen- and arachidonic acid-induced ATP release was also observed. Both platelet aggregation and ATP release returned to baseline values 15 days after chemotherapy administration. Conversely, in vitro platelet aggregation and secretion induced by ADP and epinephrine were unaltered by carboplatin and etoposide administration. Furthermore, P-selectin expression was negative at baseline and did not change after chemotherapy. These results support the hypothesis that combination etoposide and carboplatin chemotherapy in pediatric patients is responsible for possible disturbances in biochemical pathways required for platelet secretion and aggregation. PMID:16793755

  13. Transdermal Delivery of Etoposide Phosphate I: In Vitro and In Vivo Evaluation.

    PubMed

    Patel, Hiren; Joshi, Abhay; Joshi, Amit; Stagni, Grazia

    2016-07-01

    Cancer chemotherapy frequently requires long periods of multiple intravenous infusions that often results in patients opting out of treatment. The main purpose of this study was to investigate the feasibility of delivering one of these anticancer agents: etoposide phosphate (ETP) transdermally using iontophoresis and a combination of iontophoresis/microporation. The iontophoresis conditions for ETP were first optimized in vitro then tested in vivo in a rabbit model. Both ETP and its active form etoposide (VP) were quantified in dermis (via microdialysis sampling) and in plasma, with a specially developed high-performance liquid chromatography method. In vitro, the amount of total etoposide permeated and the steady state flux increased (p < 0.05) with increase in iontophoretic current densities (100-400 μA/cm(2)). At 300 μA/cm(2), microporation/iontophoresis further improved both parameters by 2- and 2.8-fold, respectively. In vivo, exposure increased proportionally to current density in plasma, whereas dermal concentration dropped significantly at the highest current density. Microporation led to a 50% increase in Cmax and AUClast values in both skin and plasma. In conclusion, a mild current density (300 μA/cm(2)) and a small surface area (10.1 cm(2)) achieved and maintained the minimum effective concentration for the entire duration of electrical current delivery; microporation further increased the plasma concentrations at the same current density. PMID:27233689

  14. Cisplatin Targeting of Bacterial Ribosomal RNA Hairpins

    PubMed Central

    Dedduwa-Mudalige, Gayani N. P.; Chow, Christine S.

    2015-01-01

    Cisplatin is a clinically important chemotherapeutic agent known to target purine bases in nucleic acids. In addition to major deoxyribonucleic acid (DNA) intrastrand cross-links, cisplatin also forms stable adducts with many types of ribonucleic acid (RNA) including siRNA, spliceosomal RNAs, tRNA, and rRNA. All of these RNAs play vital roles in the cell, such as catalysis of protein synthesis by rRNA, and therefore serve as potential drug targets. This work focused on platination of two highly conserved RNA hairpins from E. coli ribosomes, namely pseudouridine-modified helix 69 from 23S rRNA and the 790 loop of helix 24 from 16S rRNA. RNase T1 probing, MALDI mass spectrometry, and dimethyl sulfate mapping revealed platination at GpG sites. Chemical probing results also showed platination-induced RNA structural changes. These findings reveal solvent and structural accessibility of sites within bacterial RNA secondary structures that are functionally significant and therefore viable targets for cisplatin as well as other classes of small molecules. Identifying target preferences at the nucleotide level, as well as determining cisplatin-induced RNA conformational changes, is important for the design of more potent drug molecules. Furthermore, the knowledge gained through studies of RNA-targeting by cisplatin is applicable to a broad range of organisms from bacteria to human. PMID:26370969

  15. Cetuximab intensifies cisplatin-induced testicular toxicity.

    PubMed

    Levi, Mattan; Popovtzer, Aron; Tzabari, Moran; Mizrachi, Aviram; Savion, Naphtali; Stemmer, Salomon M; Shalgi, Ruth; Ben-Aharon, Irit

    2016-07-01

    Epidermal growth factor receptor (EGFR) has proliferative properties in the testis. Cetuximab, an anti-EGFR, is administered together with chemotherapy to patients with various types of cancer. This studies aim was to investigate the effect of cetuximab on testicular function. Adult male mice were injected with cetuximab (10 mg/kg), cisplatin (8 mg/kg) or a combination of both, and killed one week or one month later. The doses were chosen by human equivalent dose calculation. Testicular function was evaluated by epididymal-spermatozoa total motile count and sperm motility, weights of testes and epididymides, and the level of anti-Müllerian hormone (AMH) in the serum. Immunohistochemistry was performed to examine germ cell proliferation (Ki-67), apoptosis (Terminal transferase-mediated deoxyuridine 5-triphosphate nick-end labelling), reserve (DAZL-Deleted in azoospermia-like, Promyelocytic leukaemia zinc-finger), blood vessels (CD34) and Sertoli cells (GATA-4). Administration of cetuximab alone increased testicular apoptosis and decreased epididymal-spermatozoa total motile count over time. When added to cisplatin, cetuximab exacerbated most of the recorded testicular parameters, compared with the effect of cisplatin alone, including testis and epididymis weights, epididymal-spermatozoa total motile count, AMH concentration, meiosis and apoptosis. In conclusion, cetuximab has only a mild effect on testicular reserve, but when added to cisplatin, it exacerbates cisplatin-induced testicular toxicity. PMID:27184186

  16. Gemcitabine-Induced Pulmonary Toxicity: A Case Report of Pulmonary Veno-Occlusive Disease

    PubMed Central

    Turco, Célia; Jary, Marine; Kim, Stefano; Moltenis, Mélanie; Degano, Bruno; Manzoni, Philippe; Nguyen, Thierry; Genet, Bruno; Rabier, Marie-Blanche Valnet; Heyd, Bruno; Borg, Christophe

    2015-01-01

    INTRODUCTION Gemcitabine is a chemotherapeutic agent frequently used by for the treatment of several malignancies both in the adjuvant and metastatic setting. Although myelosuppression is the most adverse event of this therapy, gemcitabine might induce severe pulmonary toxicities. We describe a case of pulmonary veno-occlusive disease (PVOD) related to gemcitabine. CASE PRESENTATION The patient was an 83-year-old man with a metastatic pancreatic cancer who was treated by gemcitabine as first-line therapy. He was in good health and received no other chemotherapy. A dose of 1000 mg/m2 of gemcitabine was administered over a 30-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. After a period of 6 months, a complete response was observed. Nevertheless, the patient developed a severe dyspnea, with arterial hypoxemia and very low lung diffusion for carbon monoxide. A CT scan showed diffuse ground glass opacities with septal lines, bilateral pleural effusion, and lymph node enlargement. On echocardiography, there was a suspicion of pulmonary hypertension with elevated systolic pulmonary artery pressure and normal left ventricular pressures. Right heart catheterization confirmed pulmonary hypertension and normal pulmonary artery occlusion pressure. Diagnosis of PVOD was made, and a gemcitabine-induced toxicity was suspected. A symptomatic treatment was started. At last follow-up, patient was in functional class I with near-normal of CT scan, arterial blood gases, and echocardiography. A gemcitabine-induced PVOD is the more likely diagnosis. PMID:26380562

  17. Adenovirus type 5 E1A sensitizes hepatocellular carcinoma cells to gemcitabine.

    PubMed

    Lee, Wei-Ping; Tai, Dar-In; Tsai, Sun-Lung; Yeh, Chau-Ting; Chao, Yee; Lee, Shou-Dong; Hung, Mien-Chie

    2003-10-01

    Hepatocellular carcinoma (HCC) is resistant to conventional chemotherapy. A few clinical trials have shown that the cytidine analogue gemcitabine appears to have antitumor activity for HCC, but the overall survival times remain to be improved. In this study, we examined the synergistic effect of adenovirus type 5 E1A (E1A) and gemcitabine on HCC and found that E1A sensitized J5, J7, Huh7, and HepG2 HCC cells to gemcitabine. To further study the E1A-mediated chemosensitization, we established stable cell lines that expressed the E1A gene and then examined whether E1A could have proapoptotic activity while expressed in HCC cells. Our results clearly showed that E1A sensitized HCC cells to gemcitabine through induction of apoptosis. To study the underlying mechanism, we tested nuclear factor (NF)-kappaB activity and found that NF-kappaB was activated in HCC cells treated with gemcitabine but not in HCC cells that expressed E1A. Occurrence of apoptosis entails cleavage of poly (ADP-ribose) polymerase (PARP), a nuclear protein involved in DNA repair, genome stability, and maintenance of telomere length. Our study showed that gemcitabine enhanced PARP expression. However, E1A did not induce PARP cleavage but rather suppressed PARP expression at the transcriptional level. Further study showed that both NF-kappaB and PARP played protective roles in the prevention of E1A+gemcitabine-induced apoptosis. PMID:14559808

  18. Loading of Gemcitabine on chitosan magnetic nanoparticles increases the anti-cancer efficacy of the drug.

    PubMed

    Parsian, Maryam; Unsoy, Gozde; Mutlu, Pelin; Yalcin, Serap; Tezcaner, Aysen; Gunduz, Ufuk

    2016-08-01

    Targeted delivery of anti-cancer drugs increase the efficacy, while decreasing adverse effects. Among various delivery systems, chitosan coated iron oxide nanoparticles (CsMNPs) gained attention with their biocompatibility, biodegradability, low toxicity and targetability under magnetic field. This study aimed to increase the cellular uptake and efficacy of Gemcitabine. CsMNPs were synthesized by in situ co-precipitation and Gemcitabine was loaded onto the nanoparticles. Nanoparticle characterization was performed by TEM, FTIR, XPS, and zeta potential. Gemcitabine release and stability was analyzed. The cellular uptake was shown. Cytotoxicity of free-Gemcitabine and Gem-CsMNPs were examined on SKBR and MCF-7 breast cancer cells by XTT assay. Gemcitabine loading was optimized as 30µM by spectrophotometric analyses. Drug release was highest (65%) at pH 4.2, while it was 8% at pH 7.2. This is a desired release characteristic since pH of tumor-tissue and endosomes are acidic, while the blood-stream and healthy-tissues are neutral. Peaks reflecting the presence of Gemcitabine were observed in FTIR and XPS. At neutral pH, zeta potential increased after Gemcitabine loading. TEM images displayed, Gem-CsMNPs were 4nm with uniform size-distribution and have spherical shape. The cellular uptake and targetability of CsMNPs was studied on MCF-7 breast cancer cell lines. IC50 value of Gem-CsMNPs was 1.4 fold and 2.6 fold lower than free-Gem on SKBR-3 and MCF-7 cell lines respectively, indicating the increased efficacy of Gemcitabine when loaded onto nanoparticles. Targetability by magnetic field, stability, size distribution, cellular uptake and toxicity characteristics of CsMNPs in this study provides a useful targeted delivery system for Gemcitabine in cancer therapy. PMID:27181067

  19. Pharmacokinetic Study of Adjuvant Gemcitabine Therapy for Biliary Tract Cancer following Major Hepatectomy (KHBO1101)

    PubMed Central

    Fujiwara, Yutaka; Kobayashi, Shogo; Nagano, Hiroaki; Kanai, Masashi; Hatano, Etsuo; Toyoda, Masanori; Ajiki, Tetsuo; Takashima, Yuki; Yoshimura, Kenichi; Hamada, Akinobu; Minami, Hironobu; Ioka, Tatsuya

    2015-01-01

    Background Biliary tract cancer (BTC) patients who have undergone surgical resection with major hepatectomy cannot tolerate the standard gemcitabine regimen (1,000 mg/m2 on days 1, 8, and 15 every 4 weeks) due to severe toxicities such as myelosuppression. Our dose-finding study of adjuvant gemcitabine therapy for biliary tract cancer following major hepatectomy determined that the recommended dose is 1,000 mg/m2 on days 1 and 15 every 4 weeks. Here, we evaluate the pharmacokinetics and pharmacodynamics of gemcitabine in these subjects. Methods We evaluated BTC patients scheduled to undergo surgical resection with major hepatectomy followed by gemcitabine therapy. A pharmacokinetic evaluation of gemcitabine and its main metabolite, 2′,2′-difluorodeoxyuridine (dFdU), was conducted at the initial administration of gemcitabine, which was given by intravenous infusion over 30 min at a dose of 800–1,000 mg/m2. Physical examination and adverse events were monitored for 12 weeks. Results Thirteen patients were enrolled from August 2011 to January 2013, with 12 ultimately completing the pharmacokinetic study. Eight patients had hilar cholangiocarcinoma, three had intrahepatic cholangiocarcinoma, and one had superficial spreading type cholangiocarcinoma. The median interval from surgery to first administration of gemcitabine was 65.5 days (range, 43–83 days). We observed the following toxicities: neutropenia (n = 11, 91.7%), leukopenia (n = 10, 83.3%), thrombocytopenia (n = 6, 50.0%), and infection (n = 5, 41.7%). Grade 3 or 4 neutropenia was observed in 25% (n = 3) of patients. There were differences in clearance of gemcitabine and dFdU between our subjects and the subjects who had not undergone hepatectomy. Conclusion Major hepatectomy did not affect the pharmacokinetics of gemcitabine or dFdU. Trial Registration UMIN-CTR in (JPRN) UMIN000005109 PMID:26633034

  20. Gemcitabine-related radiation recall in a patient with pancreatic cancer.

    PubMed

    Saif, M Wasif; Sellers, Sandra; Russo, Suzanne

    2006-01-01

    Radiation recall refers to inflammatory reactions triggered by chemotherapeutic agents and develops cutaneously in the previously irradiated areas. Such agents include anthracyclines, taxanes and capecitabine. Radiation recall related to gemcitabine has been reported in lung and breast cancer. Similar phenomenon associated with gemcitabine, the only FDA-approved drug for pancreatic cancer, is rarely reported. We report a patient with inoperable pancreatic cancer who developed gastrointestinal bleeding secondary to radiation-recall related to gemcitabine and review literature. A 57-year-old white male with unresectable pancreatic cancer received capecitabine in combination with radiation therapy followed by capecitabine alone given over approximately a 3-month time period. Computed tomography re-evaluation demonstrated a new liver lesion. The patient was then treated with gemcitabine and irinotecan. On day 15 of cycle 1, he reported progressive worsening of weakness and fatigue, and melena. Physical examination revealed hypotension (84/47 mmHg) and heme-positive stool on rectal examination. He denied aspirin or non-steroidal anti-inflammatory drug use. Chemotherapy was held. Hematocrit was 20% (previously 33%). He was transfused with 3 units of packed red blood cells. An esophago-gastro-duodenal examination was performed which showed antritis and duodenitis consistent with radiation therapy. A single site of oozing was injected with epinephrine. The diffuse gastritis was aggressively treated with proton pump inhibitors. The patient's hematocrit eventually stabilized and was 30% at discharge. Gemcitabine was not resumed. Radiation recall from gemcitabine is rare, but can potentially arise in any site that has been previously irradiated. Gemcitabine should be added to the list of drugs known to cause radiation recall. Treating physicians must be aware of this potential toxicity from gemcitabine either given concomitantly or followed by radiation. We suggest

  1. Correlation of EGFR-expression with safety and efficacy outcomes in SQUIRE: a randomized, multicenter, open-label, phase III study of gemcitabine–cisplatin plus necitumumab versus gemcitabine–cisplatin alone in the first-line treatment of patients with stage IV squamous non-small-cell lung cancer

    PubMed Central

    Paz-Ares, L.; Socinski, M. A.; Shahidi, J.; Hozak, R. R.; Soldatenkova, V.; Kurek, R.; Varella-Garcia, M.; Thatcher, N.; Hirsch, F. R.

    2016-01-01

    Background SQUIRE demonstrated addition of necitumumab to gemcitabine and cisplatin significantly improved survival in patients with stage IV sq-NSCLC. Here, we report additional outcomes for the subpopulation of patients with tumor epidermal growth factor receptor (EGFR) protein expression. Patients and methods Patients with pathologically confirmed stage IV sq-NSCLC were randomized 1:1 to receive a maximum of six 3-week cycles of gemcitabine (1250 mg/m2 i.v., days 1 and 8) and cisplatin (75 mg/m2 i.v., day 1) chemotherapy with or without necitumumab (800 mg i.v., days 1 and 8). Patients in the chemotherapy plus necitumumab group with no progression continued on necitumumab alone until disease progression or intolerable toxicity. SQUIRE included mandatory tissue collection. EGFR protein expression was detected by immunohistochemistry (IHC) in a central laboratory. Exploratory analyses were pre-specified for patients with EGFR protein expressing (EGFR > 0) and non-expressing (EGFR = 0) tumors. Results A total of 982 patients [90% of intention-to-treat (ITT)] had evaluable IHC results. The large majority of these patients (95%) had tumor samples expressing EGFR protein; only 5% had tumors without detectable EGFR protein. Overall survival (OS) for EGFR > 0 patients was significantly longer in the necitumumab plus gemcitabine–cisplatin group than in the gemcitabine–cisplatin group {stratified hazard ratio (HR) 0.79 [95% confidence interval (CI) 0.69, 0.92; P = 0.002]; median 11.7 months (95% CI 10.7, 12.9) versus 10.0 months (8.9, 11.4)}. Additionally, an OS benefit was seen in all pre-specified subgroups in EGFR > 0 patients. However, OS HR for EGFR = 0 was 1.52. Adverse events of interest with the largest difference between treatment groups in EGFR > 0 patients (Grade ≥3) were hypomagnesemia (10% versus <1%) and skin rash (6% versus <1%). Conclusions In line with SQUIRE ITT, addition of necitumumab to gemcitabine–cisplatin significantly prolonged OS and was

  2. [Preparation and in vitro and in vivo evaluation of etoposide submicro-emulsion for intravenous injection].

    PubMed

    Tian, Ling-Ling; Tang, Xing; He, Hai-Bing; Wang, Jing

    2007-08-01

    The aim of this thesis is to prepare etoposide submicro-emulsion (ESE) for intravenous injection and investigate its characteristics in vitro and in vivo. High-pressure homogenization was used to prepare ESE, using 10% (w/w) soybean oil and 10% (w/w) medium-chain triglyceride as mixed oil phase, and 1.8% (w/w) fabaceous lecithin as emulsifier. The pH was adjusted to 5.5 with 0.1 mol x L(-1) NaOH to keep the most stability of ESE. The particle size distribution and zeta potential were measured using photon correlation spectroscopy. Ultrafiltration was used to estimate the relative percentages of etoposide in each phase. Long-term storage test and accelerated isothermal test-Weibull distribution method were used to estimate the physical and chemical stability of ESE. Plasma pharmacokinetics in rats was monitored by high performance liquid chromatography by comparison with etoposide nonaqueous solution at the same time. The mean particle size, zeta potential and entrapment efficiency of ESE were (189.9 +/- 54.6) nm, - 32.6 mV and 91.7%, respectively. The emulsion was stable during 9 month storage at 4 degrees C. The shelf life (T0.9) of etoposide in lipid emulsion was estimated to be about 665 days at 4 degrees C. The drug concentration-time curves of ESE and solution were similar and could be described by two compartment model. The area under the curve of concentration versus time from zero to the last time point and the mean residence time of ESE and solution were (18.30 +/- 8.74) and (19.32 +/- 6.45) microg x h x mL(-1), and (1.46 +/- 0.32) and (1.71 +/- 0.52) h, respectively. Etoposide was incorporated in submicro-emulsion to improve its physical and chemical stability without addition of organic solvents with insignificant different characteristics in vivo when compared with solution. PMID:17944242

  3. Recognition of cisplatin adducts by cellular proteins.

    PubMed

    Kartalou, M; Essigmann, J M

    2001-07-01

    Cisplatin is a widely used chemotherapeutic agent. It reacts with nucleophilic bases in DNA and forms 1,2-d(ApG), 1,2-d(GpG) and 1,3-d(GpTpG) intrastrand crosslinks, interstrand crosslinks and monofunctional adducts. The presence of these adducts in DNA is through to be responsible for the therapeutic efficacy of cisplatin. The exact signal transduction pathway that leads to cell cycle arrest and cell death following treatment with the drug is not known but cell death is believed to be mediated by the recognition of the adducts by cellular proteins. Here we describe the structural information available for cisplatin and related platinum adducts, the interactions of the adducts with cellular proteins and the implications of these interactions for cell survival. PMID:11406166

  4. Modulation of the ribonucleotide reductase M1-gemcitabine interaction in vivo by N-ethylmaleimide

    SciTech Connect

    Chen, Zhengming; Zhou, Jun; Zhang, Yingtao; Bepler, Gerold

    2011-09-23

    Highlights: {yields} Gemcitabine induces a RRM1 conformational change in tumor cell lines and xenografts. {yields} The 110 kDa RRM1 is unique to gemcitabine interaction among 12 cytotoxic agents. {yields} The 110 kDa RRM1 can be stabilized by the thiol alkylator N-ethylmaleimide. {yields} C218A, C429A, and E431A mutations in RRM1 abolished the conformational change. {yields} The 110 kDa RRM1 may be a specific biomarker of gemcitabine's therapeutic efficacy. -- Abstract: Ribonucleotide reductase M1 (RRM1) is the regulatory subunit of the holoenzyme that catalyzes the conversion of ribonucleotides to 2'-deoxyribonucleotides. Its function is indispensible in cell proliferation and DNA repair. It also serves as a biomarker of therapeutic efficacy of the antimetabolite drug gemcitabine (2',2'-difluoro-2'-deoxycytidine) in various malignancies. However, a mechanistic explanation remains to be determined. This study investigated how the alkylating agent N-ethylmaleimide (NEM) interacts with the inhibitory activity of gemcitabine on its target protein RRM1 in vivo. We found, when cells were treated with gemcitabine in the presence of NEM, a novel 110 kDa band, along with the 90 kDa native RRM1 band, appeared in immunoblots. This 110 kDa band was identified as RRM1 by mass spectrometry (LC-MS/MS) and represented a conformational change resulting from covalent labeling by gemcitabine. It is specific to gemcitabine/NEM, among 11 other chemotherapy drugs tested. It was also detectable in human tumor xenografts in mice treated with gemcitabine. Among mutations of seven residues essential for RRM1 function, C218A, C429A, and E431A abolished the conformational change, while N427A, C787A, and C790A diminished it. C444A was unique since it was able to alter the conformation even in absence of gemcitabine treatment. We conclude that the thiol alkylator NEM can stabilize the gemcitabine-induced conformational change of RRM1, and this stabilized RRM1 conformation has the potential to

  5. Gemcitabine: metabolism and molecular mechanisms of action, sensitivity and chemoresistance in pancreatic cancer.

    PubMed

    de Sousa Cavalcante, Lucas; Monteiro, Gisele

    2014-10-15

    Gemcitabine is the first-line treatment for pancreatic adenocarcinoma, but is increasingly used to treat breast, bladder, and non-small cell lung cancers. Despite such broad use, intrinsic and acquired chemoresistance is common. In general, the underlying mechanisms of chemoresistance are poorly understood. Here, current knowledge of gemcitabine metabolism, mechanisms of action, sensitivity and chemoresistance reported over the past two decades are reviewed; and we also offer new perspectives to improve gemcitabine efficacy with particular reference to the treatment of pancreatic cancer. PMID:25084222

  6. Simultaneous determination of etoposide and its catechol metabolite in the plasma of pediatric patients by liquid chromatography/tandem mass spectrometry.

    PubMed

    Pang, S; Zheng, N; Felix, C A; Scavuzzo, J; Boston, R; Blair, I A

    2001-07-01

    The anticancer drug etoposide is associated with leukemias with MLL gene translocations and other translocations as a treatment complication. The genotype of cytochrome P450 3A4 (CYP3A4), which converts etoposide to its catechol metabolite, influences the risk. In order to perform pharmacokinetic studies aimed at further elucidation of the translocation mechanism, we have developed and validated a liquid chromatography/electrospray/tandem mass spectrometry assay for the simultaneous analysis of etoposide and its catechol metabolite in human plasma. The etoposide analog teniposide was used as the internal standard. Liquid chromatography was performed on a YMC ODS-AQ column. Simultaneous determination of etoposide and its catechol metabolite was achieved using a small volume of plasma, so that the method is suitable for pediatric patients. The limits of detection were 200 ng ml(-1) etoposide and 10 ng ml(-1) catechol metabolite in human plasma and 25 ng ml(-1) etoposide and 2.5 ng ml(-1) catechol metabolite in protein-free plasma, respectively. Acceptable precision and accuracy were obtained for concentrations in the calibration curve ranges 0.2--100 microg ml(-1) etoposide and 10--5000 ng ml(-1) catechol metabolite in human plasma. Acceptable precision and accuracy for protein-free human plasma in the range 25--15 000 ng ml(-1) etoposide and 2.5--1500 ng ml(-1) etoposide catechol were also achieved. This method was selective and sensitive enough for the simultaneous quantitation of etoposide and its catechol as a total and protein-free fraction in small plasma volumes from pediatric cancer patients receiving etoposide chemotherapy. A pharmacokinetic model has been developed for future studies in large populations. PMID:11473400

  7. Variability of gemcitabine accumulation and its relationship to expression of nucleoside transporters in peripheral blood mononuclear cells.

    PubMed

    Choi, Min-Koo

    2012-05-01

    The concentrative nucleoside transporter CNT1 and equilibrated nucleoside transporter ENT1 mediate the cellular uptake of naturally occurring pyrimidine and purine nucleosides and many structurally diverse anticancer and antiviral nucleoside analogs, thereby regulating drug responses or toxicity at the target site. The objectives of this study were to analyze interindividual variations in the cellular accumulation of gemcitabine and to examine the correlation between the uptake of gemcitabine and expression levels of CNT1 and ENT1 transporters. Gemcitabine was a substrate for both CNT1 and ENT1 with higher affinity to CNT1 than to ENT1. The difference in gemcitabine uptake was 4.8-fold in peripheral blood mononuclear cells (PBMCs) from 10 subjects. Among these, the CNT1- and ENT1-mediated uptake of gemcitabine was 14.3- and 16.5-folds, respectively. CNT1-mediated gemcitabine uptake showed a higher correlation with the CNT1 expression level than did ENT1-mediated uptake with ENT1 expression level. In conclusion, CNT1 seemed to be a major contributing factor to gemcitabine uptake in PBMCs and showed 14.3-fold inter-individual variations. However, ENT1-mediated uptake of gemcitabine might compensate for the total uptake of gemcitabine; therefore, the variation in the apparent accumulation of gemcitabine was smaller than that of the individual transporters. PMID:22644860

  8. The development of orally administrable gemcitabine prodrugs with D-enantiomer amino acids: Enhanced membrane permeability and enzymatic stability

    PubMed Central

    Tsume, Yasuhiro; Incecayir, Tuba; Song, Xueqin; Hilfinger, John M.; Amidon, Gordon L.

    2014-01-01

    Gemcitabine prodrugs with D- and L-configuration amino acids were synthesized and their chemical stability in buffers, resistance to glycosidic bond metabolism, enzymatic activation, permeability in Caco-2 cells and mouse intestinal membrane, anti-proliferation activity in cancer cell were determined and compared to that of parent drug, gemcitabine. Prodrugs containing D-configuration amino acids were enzymatically more stable than ones with L-configuration amino acids. The activation of all gemcitabine prodrugs was 1.3–17.6-fold faster in cancer cell homogenate than their hydrolysis in buffer, suggesting enzymatic action. The enzymatic activation of amino acid monoester prodrugs containing D-configuration amino acids in cell homogenates was 2.2–10.9-fold slower than one of amino acid monoester prodrugs with L-configuration amino acids. All prodrugs exhibited enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase compared to parent gemcitabine. Gemcitabine prodrugs showed superior the effective permeability in mouse jejunum to gemcitabine. More importantly, the high plasma concentration of D-amino acid gemcitabine prodrugs was observed more than one of L-amino acid gem-citabine prodrugs. In general, the 5′-mono-amino acid monoester gemcitabine prodrugs exhibited higher permeability and uptake than their parent drug, gemcitabine. Cell proliferation assays in AsPC-1 pancreatic ductal cell line indicated that gemcitabine prodrugs were more potent than their parent drug, gemcitabine. The transport and enzymatic profiles of 5′-D-valyl-gemcitabine and 5′-D-phenylalanyl-gem-citabine suggest their potential for increased oral uptake and delayed enzymatic bioconversion as well as enhanced uptake and cytotoxic activity in cancer cells, would facilitate the development of oral dosage form for anti-cancer agents and, hence, improve the quality of life for the cancer patients. PMID:24361461

  9. Etoposide in combination with cyclophosphamide and total body irradiation or busulfan as conditioning for marrow transplantation in adults and children

    SciTech Connect

    Spitzer, T.R.; Ortlieb, M.; Tefft, M.C.; Torrisi, J.; Cahill, R.; Deeg, H.J. ); Peters, C.; Gadner, H. ); Urban, C. )

    1994-04-30

    In an attempt to intensify conditioning therapy for bone marrow transplantation of hematologic malignancies, a retrospective three center evaluation of escalating doses of etoposide added to cyclophosphamide and either total body irradiation or busulfan was undertaken. Seventy-six patients who received etoposide (25-65 mg/kg) added to cyclophosphamide (60-120 mg/kg) and either total body irradiation (12.0-13.2 Gy) or busulfan (12-16 mg/kg) were evaluable for toxicity. Fifty-one of the evaluable patients received allogeneic transplants, while twenty-six received autologous transplants. A comparative analysis of toxicities according to conditioning regimen, donor source and etoposide dose was made. Similar toxicities were observed among the treatment groups with the exception of more frequent skin (p = 0.03) and life threatening hepatic toxicities (p = 0.01) in the busulfan treated patients. Life threatening or fatal toxicities were not influenced by donor source, either when analyzed by treatment group or etoposide dose. Etoposide at a dose of 60-65 mg/kg in combination with TBI and cyclophosphamide was associated with a significantly increased incidence of life threatening or fatal toxicities compared with a combination using a dose of 25-50 mg/kg (15 of 24 vs. 5 of 20; p = 0.013). The maximally tolerated dose of etoposide in combination with busulfan and cyclophosphamide cannot be definitively established in this analysis in part due to the heterogeneity of the patient population and treatment schemes. Although toxicities with bone marrow transplant preparative regimens containing etoposide in combination with cyclophosphamide and total body irradiation or busulfan were frequently severe, treatment related mortality risk was believed to be acceptably low. 27 refs., 3 tabs.

  10. Strong adsorption of Al-doped carbon nanotubes toward cisplatin

    NASA Astrophysics Data System (ADS)

    Li, Wei; Li, Guo-Qing; Lu, Xiao-Min; Ma, Juan-Juan; Zeng, Peng-Yu; He, Qin-Yu; Wang, Yin-Zhen

    2016-08-01

    The adsorption of cisplatin molecule on Al-doped CNTs is investigated using density functional theory. The obtained results indicate that Al-doped carbon nanotubes can strongly absorb cisplatin. After absorbing cisplatin, the symmetry of CNTs has some changes. We innovatively defined a parameter of symmetry variation which relates to the adsorption. By analyzing the electronic structure, it can be concluded that under the circumstance that cisplatin was absorbed by Al-doped CNTs through aluminum atom of Al-doped CNTs. In conclusion, Al-doped CNTs is a kind of potential delivery carrier with high quality for anticancer drug cisplatin.

  11. Concurrent gemcitabine and radiotherapy with and without neoadjuvant gemcitabine for locally advanced unresectable or resected pancreatic cancer: A phase I-II study

    SciTech Connect

    Brade, Anthony . E-mail: anthony.brade@rmp.uhn.on.ca; Brierley, James; Oza, Amit; Gallinger, Steven; Cummings, Bernard; MacLean, Martha; Pond, Gregory R.; Hedley, David; Wong Shun; Townsley, Carol; Brezden-Masley, Christine; Moore, Malcolm

    2007-03-15

    Purpose: To determine the safety, efficacy, and tolerability of biweekly gemcitabine with concurrent radiotherapy (RT) for resected and locally advanced (LA) pancreatic cancer. Methods and Materials: Eligible patients had either LA or resected pancreatic cancer. Between March 1999 and July 2001, 63 patients (31 with LA and 32 with resected disease) were treated. Of the 63 patients, 28 were enrolled in a Phase I study of increasing radiation doses (35 Gy [n = 7], 43.75 Gy [n = 11], and 52.5 Gy [n = 10] given within 4, 5, or 6 weeks, respectively, in 1.75-Gy fractions) concurrently with 40 mg/m{sup 2} gemcitabine biweekly. Subsequently, 35 were enrolled in a Phase II study with the addition of induction gemcitabine 1000 mg/m{sup 2} within 7 or 8 weeks to concurrent biweekly gemcitabine (40 mg/m{sup 2}) and 52.5 Gy RT within 6 weeks. Results: In the LA population, the best response observed was a complete response in 1, partial response in 3, stable disease in 10, and progressive disease in 17. In the phase II trial, gemcitabine plus RT was not delivered to 8 patients because of progression with induction gemcitabine alone (n = 5) or by patient request (n = 3). On intent-to-treat analysis, the median survival in the LA patients was 13.9 months and the 2-year survival rate was 16.1%. In the resected population, the median progression-free survival was 8.3 months, the median survival was 18.4 months, and the 2- and 5-year survival rate was 36% and 19.4%, respectively. The treatment was well tolerated; the median gemcitabine dose intensity was 96% of the planned dose in the neoadjuvant and concurrent portions of the Phase II study. No treatment-related deaths occurred. Conclusion: Biweekly gemcitabine (40 mg/m{sup 2}) concurrently with RT (52.5 Gy in 30 fractions of 1.75 Gy) with or without induction gemcitabine is safe and tolerable and shows efficacy in patients with LA and resected pancreatic cancer.

  12. Proteasome Inhibitor YSY01A Enhances Cisplatin Cytotoxicity in Cisplatin-Resistant Human Ovarian Cancer Cells

    PubMed Central

    Huang, Wei; Zhou, Quan; Yuan, Xia; Ge, Ze-mei; Ran, Fu-xiang; Yang, Hua-yu; Qiang, Guang-liang; Li, Run-tao; Cui, Jing-rong

    2016-01-01

    Cisplatin is one of the most common drugs used for treatment of solid tumors such as ovarian cancer. Unfortunately, the development of resistance against this cytotoxic agent limits its clinical use. Here we report that YSY01A, a novel proteasome inhibitor, is capable of suppressing survival of cisplatin-resistant ovarian cancer cells by inducing apoptosis. And YSY01A treatment enhances the cytotoxicity of cisplatin in drug-resistant ovarian cancer cells. Specifically, YSY01A abrogates regulatory proteins important for cell proliferation and anti-apoptosis including NF-κB p65 and STAT3, resulting in down-regulation of Bcl-2. A dramatic increase in cisplatin uptake was also observed by inductively coupled plasma-mass spectrometry following exposure to YSY01A. Taken together, YSY01A serves as a potential candidate for further development as anticancer therapeutics targeting the proteasome. PMID:27326257

  13. Maspin mediates the gemcitabine sensitivity of hormone-independent prostate cancer.

    PubMed

    Huang, Chien-Yu; Chang, Yu-Jia; Luo, Sheng-Dean; Uyanga, Batzorig; Lin, Feng-Yen; Tai, Cheng-Jeng; Huang, Ming-Te

    2016-03-01

    Androgen deprivation therapy has constituted the main treatment for prostate cancer; however, tumors ultimately progress to hormone-independent prostate cancer (HIPC), and suitable therapeutic strategies for HIPC are not available. Maspin, which is also known as mammary serine protease inhibitor, has been suggested to be a valuable focus for targeted cancer therapy. Specifically, maspin has been shown to be upregulated after androgen ablation therapy. Gemcitabine is used as a first-line therapy for metastatic castration-resistant prostate cancer, but its disease control rate is low. Furthermore, the role of maspin in the therapeutic efficacy of gemcitabine for HIPC remains unclear. The expression levels of maspin in PC-3 and DU145 cells were determined by real-time PCR and Western blotting. Furthermore, the expression of maspin was silenced using shRNA technology to generate maspin-KD cells. The cytotoxicity of gemcitabine to prostate cancer cells was assessed using 3-[4,5-dimethylthiazol-2-yl]-3,5-diphenyl tetrazolium bromide (MTT) assays, whereas flow cytometry analyses and annexin V-propidium iodide (PI) apoptosis assays were used to assess the ability of gemcitabine to induce apoptosis in maspin-KD and control cells. Additionally, the expression patterns of anti-apoptosis proteins (myeloid cell leukemia 1 (Mcl-1) and B cell lymphoma 2 (Bcl-2)) and pro-apoptosis proteins (Bcl-2-associated death promoter (Bad) and Bcl-2-associated X protein (Bax)) were determined by Western blotting. In this study, PC-3 cells were more resistant to gemcitabine administration than DU145 cells, which correlated with the higher expression levels of maspin observed in PC-3 cells. Furthermore, maspin knockdown enhanced gemcitabine-induced cell death, as evidenced by the increased number of apoptotic cells. Gemcitabine treatment upregulated the levels of anti-apoptosis proteins (Mcl-2 and Bcl-2) in both scrambled control and maspin-KD cells; however, the fold changes in Mcl-1 and Bcl-2

  14. Magnetoresponsive squalenoyl gemcitabine composite nanoparticles for cancer active targeting.

    PubMed

    Arias, José L; Reddy, L Harivardhan; Couvreur, Patrick

    2008-07-15

    Gemcitabine is widely used against a variety of solid tumors; however, it possesses some important drawbacks such as rapid deamination leading to short biological half-life and induction of tumor resistance. We have shown previously that the covalent coupling of squalene (a precursor of cholesterol in sterol biosynthesis) to gemcitabine resulted in a potent nanomedicine, squalenoyl gemcitabine (SQdFdC), which displayed appreciable anticancer activity. Now, the present study describes the concept of magnetic responsiveness of SQdFdC nanoparticles obtained by the nanoprecipitation of SQdFdC around magnetite nanoparticles. To investigate these new core/shell nanoparticles, we have compared their structure, chemical composition and surface properties with those of either the magnetic core alone or of the SQdFdC coating material. X-ray diffraction and infrared spectroscopy studies have shown that the composite core/shell particles displayed an intermediate behavior between that of pure magnetite and of pure SQdFdC nanoparticles, whereas dark-field, high-resolution transmission electron microscopy allowed clear demonstration of the core/shell structure. Electrophoresis measurements as a function of both pH and ionic strength, as well as thermodynamic consideration, showed similar behavior of core/shell and pure SQdFdC nanoparticles, suggesting again the coating of the magnetite core by the SQdFdC prodrug. The two important parameters to be controlled in the efficient adsorption of SQdFdC onto magnetite nanocores were the magnetite/SQdFdC weight ratio and the pluronic F-68 concentration. Pluronic F-68 was found to play a key role as a surfactant in the generation of stable composite core/shell nanoparticle suspensions. Finally, the characterization of the magnetic properties of these core/shell nanoparticles revealed that if the squalenoyl shell reduced the magnetic responsiveness of the particles, it kept unchanged their soft ferrimagnetic character. Thus, the

  15. SL-01, an oral derivative of gemcitabine, inhibited human breast cancer growth through induction of apoptosis

    SciTech Connect

    Li, Yuan-Yuan; Qin, Yi-Zhuo; Wang, Rui-Qi; Li, Wen-Bao; Qu, Xian-Jun

    2013-08-23

    Highlights: •SL-01 is an oral derivative of gemcitabine. •SL-01 possessed activity against human breast cancer growth via apoptotic induction. •SL-01’s activity was more potently than that of gemcitabine. •SL-01 inhibited cancer growth without toxicity to mice. -- Abstract: SL-01 is an oral derivative of gemcitabine that was synthesized by introducing the moiety of 3-(dodecyloxycarbonyl) pyrazine-2-carbonyl at N4-position on cytidine ring of gemcitabine. We aimed to evaluate the efficacy of SL-01 on human breast cancer growth. SL-01 significantly inhibited MCF-7 proliferation as estimated by colorimetric assay. Flow cytometry assay indicated the apoptotic induction and cell cycle arrest in G1 phase. SL-01 modulated the expressions of p-ATM, p53 and p21 and decrease of cyclin D1 in MCF-7 cells. Further experiments were performed in a MCF-7 xenografts mouse model. SL-01 by oral administration strongly inhibited MCF-7 xenografts growth. This effect of SL-01 might arise from its roles in the induction of apoptosis. Immunohistochemistry assay showed the increase of TUNEL staining cells. Western blotting indicated the modulation of apoptotic proteins in SL-01-treated xenografts. During the course of study, there was no evidence of toxicity to mice. In contrast, the decrease of neutrophil cells in peripheral and increase of AST and ALT levels in serum were observed in the gemcitabine-treated mice. Conclusion: SL-01 possessed similar activity against human breast cancer growth with gemcitabine, whereas, with lower toxicity to gemcitabine. SL-01 is a potent oral agent that may supplant the use of gemcitabine.

  16. Phase I trial combining gemcitabine and treosulfan in advanced cutaneous and uveal melanoma patients

    PubMed Central

    Corrie, P G; Shaw, J; Spanswick, V J; Sehmbi, R; Jonson, A; Mayer, A; Bulusu, R; Hartley, J A; Cree, I A

    2005-01-01

    Gemcitabine and treosulfan are DNA-damaging agents. Preclinical studies suggest that synergism exists when melanoma cells are exposed to both drugs concurrently. We conducted a phase I trial in advanced melanoma patients to determine the optimal dose of gemcitabine to be combined with treosulfan. Cohorts of three patients received increasing doses of gemcitabine, commencing at 0.5 g m−2, followed by a fixed dose of 5.0 g m−2 treosulfan on day one of a 21-day cycle. Patients alternately received a first cycle of single-agent gemcitabine or treosulfan before subsequent cycles of both drugs. Peripheral blood lymphocytes were collected in cycles 1 and 2 at various time points until 48 h post-treatment. The single-cell gel electrophoresis (Comet) assay was used to measure chemotherapy-induced DNA damage. A total of 27 patients were enrolled, no objective responses were observed, but two uveal melanoma patients had minor responses. Dose-limiting myelosuppression was reached at 3.0 g m−2 gemcitabine. DNA single-strand breaks were detected 4 h post-gemcitabine, repaired by 24 h. DNA interstrand crosslinks were detected 4 h post-treosulfan, fully removed by 48 h. Following combination chemotherapy, treosulfan-induced DNA crosslinks persisted, still being detectable 48 h post-treatment, supporting the hypothesis that gemcitabine potentiates treosulfan-induced cytotoxicity. The recommended regimen for further study is 2.5 g m−2 gemcitabine combined with 5.0 g m−2 treosulfan. PMID:15886706

  17. A Potent Chemotherapeutic Strategy with Eg5 Inhibitor against Gemcitabine Resistant Bladder Cancer

    PubMed Central

    Sun, Liang; Lu, Jiaju; Niu, Zhihong; Ding, Kejia; Bi, Dongbin; Liu, Shuai; Li, Jiamei; Wu, Fei; Zhang, Hui; Zhao, Zuohui; Ding, Sentai

    2015-01-01

    Development of resistance to gemcitabine is a major concern in bladder cancer therapy, and the mechanism remains unclear. Eg5 has been recently identified as an attractive target in cancer chemotherapy, so novel targeted chemotherapy with Eg5 inhibitor is expected to improve the anticancer effect in gemcitabine-resistant bladder cancer. In this research, RT112-Gr cells were 350-fold less sensitive to gemcitabine than the parental cell lines, while KU7-Gr cells were 15-fold less sensitive to gemcitabine than the parental cell lines. Human OneArray Microarray analysis was performed to obtain broad spectrum information about the genes differentially expressed in RT112 and RT112-Gr cells. The anti-proliferative activity of S(MeO)TLC, an Eg5 inhibitor, was analyzed in RT112-Gr cell lines using a cell viability assay. Furthermore, the inhibitory effect was evaluated in vivo using subcutaneous xenograft tumor model. According to the result of Human OneArray® GeneChip, RRM1 and RRM2 were up-regulated, while there was no significant change in Eg5. Trypan blue staining confirmed that in S(MeO)TLC and Gemcitabine combining S(MeO)TLC group cell viability were significantly decreased in RT112-Gr cells as compared with other groups. S(MeO)TLC and S(MeO)TLC+gemcitabine groups prominently suppressed tumor growth in comparison with other groups’ in vivo. There were no significant differences in S(MeO)TLC and gemcitabine+S(MeO)TLC group in the effect of inhibition of bladder cancer in vivo and in vitro. Our data collectively demonstrated that S(MeO)TLC represents a novel strategy for the treatment of gemcitabine resistant bladder cancer. PMID:26658059

  18. Synthesis, crystallization, and biological evaluation of an orally active prodrug of gemcitabine.

    PubMed

    Bender, David M; Bao, Jingqi; Dantzig, Anne H; Diseroad, William D; Law, Kevin L; Magnus, Nicholas A; Peterson, Jeffrey A; Perkins, Everett J; Pu, Yangwei J; Reutzel-Edens, Susan M; Remick, David M; Starling, James J; Stephenson, Gregory A; Vaid, Radhe K; Zhang, Deyi; McCarthy, James R

    2009-11-26

    The design, synthesis, and biological characterization of an orally active prodrug (3) of gemcitabine are described. Additionally, the identification of a novel co-crystal solid form of the compound is presented. Valproate amide 3 is orally bioavailable and releases gemcitabine into the systemic circulation after passing through the intestinal mucosa. The compound has entered clinical trials and is being evaluated as a potential new anticancer agent. PMID:19860433

  19. Secreted protein acidic and rich in cysteine enhances the chemosensitivity of pancreatic cancer cells to gemcitabine.

    PubMed

    Fan, Xin; Mao, Zhengfa; Ma, Xiaoyan; Cui, Lei; Qu, Jianguo; Lv, Lihui; Dang, ShengChun; Wang, Xuqing; Zhang, Jianxin

    2016-02-01

    It has been previously shown that the simultaneous exposure of colon cancer cells MIP to irinotecan and secreted protein acidic and rich in cysteine (SPARC) enhances anticancer activity. However, whether there is same effect of SPARC in pancreatic cancer remains largely unknown. Therefore in this study, we aimed to investigate the role of SPARC played in the sensitivity of pancreatic cancer to gemcitabine. We first treated MIAPaCa2 and MIAPaCa2/SPARC69 cells with different concentrations of gemcitabine (2, 5, 10, and 20 μM) for 24, 48, and 72 h and selected the appropriated concentration for further study. Then we analyzed cell viability, cell cycle, and apoptosis and the levels of apoptosis-related proteins by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, fluorescence-activated cell sorting and Western blot were used, respectively. In this study, we found that gemcitabine inhibited the proliferation of pancreatic cancer cells in a time- and dose-dependent manner. Overexpression of SPARC increased the inhibiting effect of gemcitabine on pancreatic cancer cells. The colony size of MIAPaCa2/SPARC69 was much smaller than that of MIAPaCa2/V. There was a G0/G1 arrest with significant increase of apoptosis after gemcitabine treatment in MIAPaCa2/SPARC69 cells. Furthermore, our results demonstrated that overexpression of SPARC markedly increased the levels of pro-apoptotic proteins in gemcitabine-treated pancreatic cancer cells. The SPARC can enhance the chemosensitivity of pancreatic cancer cells to gemcitabine via regulating the expression of apoptosis-related proteins. These results have shown that the SPARC/ gemcitabine combination treatment may be a potentially useful therapeutic option for individuals diagnosed with pancreatic cancer. PMID:26358255

  20. Antitumor gemcitabine conjugated micelles from amphiphilic comb-like random copolymers.

    PubMed

    Wang, Jianfeng; Zhang, Xiaomin; Cen, Yixin; Lin, Xianfu; Wu, Qi

    2016-10-01

    Gemcitabine is an important pyrimidine antimetabolite that inhibits cellular DNA synthesis. However, the therapeutic efficacy and clinical benefit of gemcitabine are severely compromised due to its rapid plasma metabolism and low selectivity towards tumor tissues. To overcome these limitations, we prepared novel PEGylated gemcitabine-contained comb-like copolymers poly(monomethoxyl PEG350 methylacrylate -co- 5'-O-vinyladipyl- gemcitabine) (poly(mPEG350MA-co-VAG) and (poly(mPEG1000MA-co-VAG), which could self-assemble into micelles and displayed enhanced antitumor activity. The copolymers and the formed micelles were well characterized for their structure, critical aggregation concentration (CAC), morphology, cellular uptake, cell cytotoxicity, and controlled drug release. Cellular uptake and in vitro cytotoxicity assays against human lung cancerous cells (A549) demonstrated that these micelles could be effectively internalized and induced cell apoptosis. These micelles efficiently inhibited tumor growth when injected intravenously into A549 cell derived xenograft tumor bearing Balb/C nude mice using a dose of 10mg/kg in terms of reduced tumor volume compared to free gemcitabine. In conclusion, PEGylated micelles could protect gemcitabine from rapid plasma metabolism, provided a sustained release and showed enhanced antitumor activity, thus have the potential to be used as novel anticancer drug delivery vehicle. PMID:27434158

  1. Preparation, physicochemical characterization and cytotoxicity in vitro of gemcitabine-loaded PEG-PDLLA nanovesicles

    PubMed Central

    Jia, Lin; Zheng, Jian-Jun; Jiang, Shu-Man; Huang, Kai-Hong

    2010-01-01

    AIM: To investigate the preparation, physicochemical characterization and cytotoxicity in vitro of Gemcitabine-loaded poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-PDLLA) nanovesicles. METHODS: The nanovesicle carriers were prepared from the amphiphilic block copolymer of PEG-PDLLA by a double emulsion technique, and gemcitabine was used as the model drug. The morphology of the nanovesicles was determined by scanning and transmission electron microscopy, and the drug content, drug entrapment and drug-release curve in vitro were detected by UV-Vis-NIR spectrophotometry. Cytotoxicity in the human pancreatic cancer cell line SW1990 was tested by 3-(4,5-dimethyl) ethiazole (MTT) assay. RESULTS: The gemcitabine-loaded nanovesicles were hollow nanospheres with a mean size of 200.6 nm, drug loading of 4.14% and drug embedding ratio of 20.54%. The nanovesicles showed excellent controlled release that was characterized by a fast initial release during the first 72 h, followed by a slower and continuous release. The MTT assay demonstrated that gemcitabine-loaded nanovesicles exhibited dose-dependent and time-delayed cytotoxicity in the human pancreatic cancer cell line SW1990. CONCLUSION: Gemcitabine-loaded PEG-PDLLA nanovesicles prepared by a double emulsion technique exhibited good performance for controlled drug release, and had similar cytotoxic activity to free gemcitabine. PMID:20180242

  2. Concurrent Chemo-Radiation With or Without Induction Gemcitabine, Carboplatin, and Paclitaxel: A Randomized, Phase 2/3 Trial in Locally Advanced Nasopharyngeal Carcinoma

    SciTech Connect

    Tan, Terence; Lim, Wan-Teck; Fong, Kam-Weng; Cheah, Shie-Lee; Soong, Yoke-Lim; Ang, Mei-Kim; Ng, Quan-Sing; Tan, Daniel; Ong, Whee-Sze; Tan, Sze-Huey; Yip, Connie; Quah, Daniel; Soo, Khee-Chee; Wee, Joseph

    2015-04-01

    Purpose: To compare survival, tumor control, toxicities, and quality of life of patients with locally advanced nasopharyngeal carcinoma (NPC) treated with induction chemotherapy and concurrent chemo-radiation (CCRT), against CCRT alone. Patients and Methods: Patients were stratified by N stage and randomized to induction GCP (3 cycles of gemcitabine 1000 mg/m{sup 2}, carboplatin area under the concentration-time-curve 2.5, and paclitaxel 70 mg/m{sup 2} given days 1 and 8 every 21 days) followed by CCRT (radiation therapy 69.96 Gy with weekly cisplatin 40 mg/m{sup 2}), or CCRT alone. The accrual of 172 was planned to detect a 15% difference in 5-year overall survival (OS) with a 5% significance level and 80% power. Results: Between September 2004 and August 2012, 180 patients were accrued, and 172 (GCP 86, control 86) were analyzed by intention to treat. There was no significant difference in OS (3-year OS 94.3% [GCP] vs 92.3% [control]; hazard ratio 1.05; 1-sided P=.494]), disease-free survival (hazard ratio 0.77, 95% confidence interval 0.44-1.35, P=.362), and distant metastases–free survival (hazard ratio 0.80, 95% confidence interval 0.38-1.67, P=.547) between the 2 arms. Treatment compliance in the induction phase was good, but the relative dose intensity for concurrent cisplatin was significantly lower in the GCP arm. Overall, the GCP arm had higher rates of grades 3 and 4 leukopenia (52% vs 37%) and neutropenia (24% vs 12%), but grade 3 and 4 acute radiation toxicities were not statistically different between the 2 arms. The global quality of life scores were comparable in both arms. Conclusion: Induction chemotherapy with GCP before concurrent chemo-irradiation did not improve survival in locally advanced NPC.

  3. A phase I clinical trial of continual alternating etoposide and topotecan in refractory solid tumours.

    PubMed

    Penson, R T; Seiden, M V; Matulonis, U A; Appleman, L J; Fuller, A F; Goodman, A; Campos, S M; Clark, J W; Roche, M; Eder, J P

    2005-07-11

    The goal of this phase I study was to develop a novel schedule using oral etoposide and infusional topotecan as a continually alternating schedule with potentially optimal reciprocal induction of the nontarget topoisomerase. The initial etoposide dose was 15 mg m(-2) b.i.d. days (D)1-5 weeks 1,3,5,7,9 and 11, escalated 5 mg per dose per dose level (DL). Topotecan in weeks 2,4,6,8,10 and 12 was administered by 96 h infusion at an initial dose of 0.2 mg m(-2) day(-1) with a dose escalation of 0.1, then at 0.05 mg m(-2) day(-1). Eligibility criteria required no organ dysfunction. Two dose reductions or delays were allowed. A total of 36 patients with a median age of 57 (22-78) years, received a median 8 (2-19) weeks of chemotherapy. At DL 6, dose-limiting toxicities consisted of grade 3 nausea, vomiting and intolerable fatigue. Three patients developed a line-related thrombosis or infection and one subsequently developed AML. There was no febrile neutropenia. There were six radiologically confirmed responses (18%) and 56% of patients demonstrated a response or stable disease, typically with only modest toxicity. Oral etoposide 35 mg m(-2) b.i.d. D1-5 and 1.8 mg m(-2) 96 h (total dose) infusional topotecan D8-11 can be administered on an alternating continual weekly schedule for at least 12 weeks, with promising clinical activity. PMID:15986034

  4. [Therapy-Related Acute Myeloid Leukemia Following Etoposide Based Chemotherapy in Germ Cell Tumor].

    PubMed

    Okumura, Yoshinaga; Oae, Masashi; Shiraishi, Yusuke; Soda, Takeshi; Kanamaru, Hiroshi; Arima, Nobuyoshi

    2016-05-01

    A 27-year-old man visited our hospital with painless swelling of the left scrotum. Hematologic studies showed the following levels of lactate dehydrogenase, 3,171 IU/l ; alpha-fetoprotein, 2.2 ng/ml ; and β- human chorionic gonadotropin, 0.4 ng/ml, and abdominal computed tomography revealed a mass of 10×8 ×4 cm in the left testis, and that of 3.5×3.0×5.0 cm in the left renal hilar lymph node, without any other metastasis. Left high inguinal orchiectomy was performed, and histopathological examination revealed mixed form with seminoma and teratoma. He was diagnosed to have a left germ cell tumor with left renal hilar lymph node metastases, pT1, N3, M0, stage II C, indicating poor prognosis with IGCCC. The patient received four cycles of chemotherapy, COMPE regimen (CDDP, VCR, MTX, PEP, VP-16 [etoposide]). After lactate dehydrogenase, alpha-fetoprotein, and β -human chorionic gonadotropin all normalized, retroperitoneal lymph node dissection was performed. Histopathological examination revealed only a mature teratoma. Two and half years later, hematologic studies showed blast transformation. Bone marrow biopsy revealed acute myeloblastic lymphoma (M2). The patient received one cycle of AraC and daunorubicin, one cycle of high dose AraC, and three cycles of AraC and mitoxantrone. After chemotherapy, he has maintained a disease-free status for 11 years. In this case, etoposide, a topoisomerase II inhibitor, was the presumed cause of therapy-related acute myeloid leukemia. After administering chemotherapeutic agents especially etoposide, it is important to check blood count periodically for a long time. PMID:27320120

  5. Etoposide loaded solid lipid nanoparticles for curtailing B16F10 melanoma colonization in lung.

    PubMed

    Athawale, Rajani B; Jain, Darshana S; Singh, Kamlinder K; Gude, Rajiv P

    2014-03-01

    Poor solubility of etoposide and associated poor bioavailability of the drug was circumvented by developing solid lipid nanocarrier system. The objective of the research work was to prepare etoposide loaded solid lipid nanoparticles (SLN) for improved efficacy and therapy of metastasized cancers. Entrapment of drug into nanoparticulate system modifies the pharmacokinetic and biodistribution profile of the drug with improved therapeutic efficacy. Solid lipid nanoparticles of various triglycerides were prepared using hot homogenization technique. Further, the process and formulation parameters viz. homogenization cycle and pressure, type of lipid were optimized. Developed nanoparticles were characterised for particle size, in vitro dissolution studies, DSC thermogram, surface morphology and cytotoxicity assay. Pharmacokinetic and biodistribution study were performed to assess the distribution of the drug in vivo. Modulation of the therapeutic activity of the drug was studied by performing antimetastatic activity on a B16F10 melanoma mouse model. The obtained results exhibited suitability of trimysristin for fabrication of nanoparticles. Characterisation of nanoparticles depicted formation of homogenous, spherical particles entrapping approximately 50% of the drug. The results for the performed MTT assay suggested that the developed nanoparticles exhibited cytotoxicity in a time- and concentration-dependent fashion. These findings concord with the results of the in vitro dissolution profile. Pharmacokinetic parameters demonstrated increase in area under curve (AUC), t1/2 and mean residence time (MRT) for drug in plasma. Further there is enhancement in the ratio of the drug that reaches to the highly perfused organs (upon encapsulation into solid lipid nanoparticles). Generally, cancer cells metastasized through the blood or lymphatic system. Accumulation of the drug in the highly perfused organ suggests suitability of the developed nanoparticles for targeting

  6. OPEC chemotherapy (vincristine, prednisolone, etoposide and chlorambucil) for refractory and recurrent Hodgkin's disease.

    PubMed

    Barnett, M J; Man, A M; Richards, M A; Waxman, J H; Wrigley, P F; Lister, T A

    1987-01-01

    Fifteen adults with refractory or recurrent Hodgkin's disease were treated with a combination of: vincristine, prednisolone, etoposide and chlorambucil (OPEC). All had previously received mustine, vinblastine, procarbazine and prednisolone (MVPP) and seven had subsequently been treated with alternative regimens. Responses were achieved in four, but complete remission in only one. Toxicity was considerable and five died of treatment related complications. Only two are alive (one in complete remission) more than three years after therapy. The toxicity of the OPEC regimen outweighed its benefit in this group of poor prognosis patients. PMID:3596472

  7. Therapeutic potential of thalidomide for gemcitabine-resistant bladder cancer.

    PubMed

    Huang, Yen Ta; Cheng, Chuan Chu; Chiu, Ted H; Lai, Pei Chun

    2015-11-01

    Controversial effects of thalidomide for solid malignancies have been reported. In the present study, we evaluate the effects of thalidomide for transitional cell carcinoma (TCC), the most common type of bladder cancer. Thalidomide precipitates were observed when its DMSO solution was added to the culture medium. No precipitation was found when thalidomide was dissolved in 45% γ-cyclodextrin, and this concentration of γ-cyclodextrin elicited slight cytotoxicity on TCC BFTC905 and primary human urothelial cells. Thalidomide-γ-cyclodextrin complex exerted a concentration-dependent cytotoxicity in TCC cells, but was relatively less cytotoxic (with IC50 of 200 µM) in BFTC905 cells than the other 3 TCC cell lines, possibly due to upregulation of Bcl-xL and HIF-1α mediated carbonic anhydrase IX, and promotion of quiescence. Gemcitabine-resistant BFTC905 cells were chosen for additional experiments. Thalidomide induced apoptosis through downregulation of survivin and securin. The secretion of VEGF and TNF-α was ameliorated by thalidomide, but they did not affect cell proliferation. Immune-modulating lenalidomide and pomalidomide did not elicit cytotoxicity. In addition, cereblon did not play a role in the thalidomide effect. Oxidative DNA damage was triggered by thalidomide, and anti-oxidants reversed the effect. Thalidomide also inhibited TNF-α induced invasion through inhibition of NF-κB, and downregulation of effectors, ICAM-1 and MMP-9. Thalidomide inhibited the growth of BFTC905 xenograft tumors in SCID mice via induction of DNA damage and suppression of angiogenesis. Higher average body weight, indicating less chachexia, was observed in thalidomide treated group. Sedative effect was observed within one-week of treatment. These pre-clinical results suggest therapeutic potential of thalidomide for gemcitabine-resistant bladder cancer. PMID:26398114

  8. Protective effects of ethyl pyruvate in cisplatin-induced nephrotoxicity

    PubMed Central

    Kelle, Ilker; Akkoc, Hasan; Tunik, Selcuk; Nergiz, Yusuf; Erdinc, Meral; Erdinc, Levent

    2014-01-01

    This study was performed to investigate the effect of ethyl pyruvate on changes in renal functions and oxidative stress related renal injury caused by cisplatin (cis-dichlorodiammine platinum-II; CDDP). Male Wistar albino rats were divided into four groups (n = 8): (1) control group (1 ml Ringer's lactate solution i.p.); (2) ethyl pyruvate (EP) group (50 mg/kg Ringer's EP solution (REPS) i.p.); (3) cisplatin group (a single dose of cisplatin (5 mg/kg, i.p.); and (4) cisplatin + EP group (a single dose of cisplatin (5 mg/kg, i.p.) + REPS 50 mg/kg/day, i.p.) for five days. At the sixth day, kidneys of rats were mounted to a Langendorff apparatus. Renal perfusion pressures were recorded. Blood samples were taken for serum urea, creatinine, total oxidant status (TOS), total antioxidant status (TAS) and oxidative stres index (OSI) evaluations. Kidney tissues were obtained for malondialdehyde (MDA) analyses and histopathological examination. Perfusion pressures, serum urea, creatinine, TOS, OSI and tissue MDA levels were found significantly higher, whereas TAS was notably lower in cisplatin group. Histopathological examination showed apparent renal paranchymal injury in cisplatin group. In cisplatin + REPS group, perfusion pressures, serum urea, creatinine and tissue MDA levels were decreased. Moreover, EP co-administration provided less inflammatory cell infiltration, tubular dilatation, whereas TOS, TAS and OSI improved significantly versus cisplatin group. These findings show that EP has protective effects against cisplatin nephrotoxicity. PMID:26019553

  9. LY2109761 enhances cisplatin antitumor activity in ovarian cancer cells

    PubMed Central

    Gao, Yuxiu; Shan, Ning; Zhao, Cheng; Wang, Yunhai; Xu, Fuliang; Li, Jiacun; Yu, Xiaoqian; Gao, Lifeng; Yi, Zhengjun

    2015-01-01

    Background and Objective: Ovarian cancer is among the most lethal of all malignancies in women. While chemotherapy is the preferred treatment modality, chemoresistance severely limits treatment success. Because transforming growth factor-beta (TGF-β) could increase survival of ovarian cancer cells in the presence of cisplatin, we conducted a preclinical study of the antitumor effects of the TGF-β type I (TβRI) and type II (TβRII) kinase inhibitor LY2109761 in combination with cisplatin. Methods: SKOV3, OV-90 and SKOV3DDP cells were treated with LY2109761, and/or cisplatin, and cell viability, apoptosis mRNA and protein expression levels were then evaluated. Furthermore, the efficacy of LY2109761 combined with cisplatin was further examined in established xenograft models. Results: LY2109761 was sufficient to induce spontaneous apoptosis of ovarian cancer cells. Combination with LY2109761 significantly augmented the cytotoxicity of cisplatin in both parental and cisplatin resistant ovarian cancer cells. LY2109761 significantly increased apoptotic cell death in cisplatin-resistant cells. Combination treatment of LY2109761 and cisplatin showed antiproliferative effects and induced a greater rate of apoptosis than the sum of the single-treatment rates and promoted tumor regression in established parental and cisplatin resistant ovarian cancer xenograft models. Conclusions: Chemotherapeutic approaches using LY2109761 might enhance the treatment benefit of the cisplatin in the treatment of ovarian cancer patients. PMID:26191185

  10. Cisplatin loaded albumin mesospheres for lung cancer treatment

    PubMed Central

    Lee, Hung-Yen; Mohammed, Kamal A; Goldberg, Eugene P; Kaye, Frederic; Nasreen, Najmunnisa

    2015-01-01

    The low solubility of cisplatin in aqueous solution limits the treatment effectiveness and the application of cisplatin in various kinds of drug-eluting devices. Although cisplatin has a high solubility in Dimethyl sulfoxide (DMSO), the toxicity of cisplatin can be greatly reduced while dissolved in DMSO. In this study, the solid powder of cisplatin-loaded albumin mesospheres (CDDP/DMSO-AMS), in a size range of 1 to 10 µm, were post-loaded with cisplatin and showed high cisplatin content (16% w/w) and effective cytotoxicity to lung cancer cells. Cisplatin were efficiently absorbed into the albumin mesospheres (AMS) in DMSO and, most importantly, the toxicity of cisplatin was remained at 100% after the loading process. This CDDP/DMSO-AMS was designed for the intratumoral injection through the bronchoscopic catheter or dry powder inhalation (DPI) due to its high stability in air or in solution. This CDDP/DMSO-AMS showed a fast cisplatin release within 24 hours. In the in vitro study, CDDP/DMSO-AMS showed high effectiveness on killing the lung cancer cells including the non-small cell lung cancer (NCL-H23 and A549), malignant mesothelioma (CRL-2081) and the mouse lung carcinoma (Lewis lung carcinoma) cell lines. The albumin based mesospheres provide an ideal loading matrix for cisplatin and other metal-based drugs due to the high swelling degree and fast uptake rate in the organic solvents with high polarity. In addition, to investigate the effects of polysaccharides, such as chitosan and chondroitin, on enhancing loading efficiency and lasting cytotoxicity of cisplatin, the polysaccharide-modified albumin mesospheres were synthesized and loaded with cisplatin in this study. PMID:25973300

  11. Cisplatin loaded albumin mesospheres for lung cancer treatment.

    PubMed

    Lee, Hung-Yen; Mohammed, Kamal A; Goldberg, Eugene P; Kaye, Frederic; Nasreen, Najmunnisa

    2015-01-01

    The low solubility of cisplatin in aqueous solution limits the treatment effectiveness and the application of cisplatin in various kinds of drug-eluting devices. Although cisplatin has a high solubility in Dimethyl sulfoxide (DMSO), the toxicity of cisplatin can be greatly reduced while dissolved in DMSO. In this study, the solid powder of cisplatin-loaded albumin mesospheres (CDDP/DMSO-AMS), in a size range of 1 to 10 µm, were post-loaded with cisplatin and showed high cisplatin content (16% w/w) and effective cytotoxicity to lung cancer cells. Cisplatin were efficiently absorbed into the albumin mesospheres (AMS) in DMSO and, most importantly, the toxicity of cisplatin was remained at 100% after the loading process. This CDDP/DMSO-AMS was designed for the intratumoral injection through the bronchoscopic catheter or dry powder inhalation (DPI) due to its high stability in air or in solution. This CDDP/DMSO-AMS showed a fast cisplatin release within 24 hours. In the in vitro study, CDDP/DMSO-AMS showed high effectiveness on killing the lung cancer cells including the non-small cell lung cancer (NCL-H23 and A549), malignant mesothelioma (CRL-2081) and the mouse lung carcinoma (Lewis lung carcinoma) cell lines. The albumin based mesospheres provide an ideal loading matrix for cisplatin and other metal-based drugs due to the high swelling degree and fast uptake rate in the organic solvents with high polarity. In addition, to investigate the effects of polysaccharides, such as chitosan and chondroitin, on enhancing loading efficiency and lasting cytotoxicity of cisplatin, the polysaccharide-modified albumin mesospheres were synthesized and loaded with cisplatin in this study. PMID:25973300

  12. Prostate cancer stem-like cells proliferate slowly and resist etoposide-induced cytotoxicity via enhancing DNA damage response

    SciTech Connect

    Yan, Judy; Tang, Damu

    2014-10-15

    Despite the development of chemoresistance as a major concern in prostate cancer therapy, the underlying mechanisms remain elusive. In this report, we demonstrate that DU145-derived prostate cancer stem cells (PCSCs) progress slowly with more cells accumulating in the G1 phase in comparison to DU145 non-PCSCs. Consistent with the important role of the AKT pathway in promoting G1 progression, DU145 PCSCs were less sensitive to growth factor-induced activation of AKT in comparison to non-PCSCs. In response to etoposide (one of the most commonly used chemotherapeutic drugs), DU145 PCSCs survived significantly better than non-PCSCs. In addition to etoposide, PCSCs demonstrated increased resistance to docetaxel, a taxane drug that is commonly used to treat castration-resistant prostate cancer. Etoposide produced elevated levels of γH2AX and triggered a robust G2/M arrest along with a coordinated reduction of the G1 population in PCSCs compared to non-PCSCs, suggesting that elevated γH2AX plays a role in the resistance of PCSCs to etoposide-induced cytotoxicity. We have generated xenograft tumors from DU145 PCSCs and non-PCSCs. Consistent with the knowledge that PCSCs produce xenograft tumors with more advanced features, we were able to demonstrate that PCSC-derived xenograft tumors displayed higher levels of γH2AX and p-CHK1 compared to non-PCSC-produced xenograft tumors. Collectively, our research suggests that the elevation of DNA damage response contributes to PCSC-associated resistance to genotoxic reagents. - Highlights: • Increased survival in DU145 PCSCs following etoposide-induced cytotoxicity. • PCSCs exhibit increased sensitivity to etoposide-induced DDR. • Resistance to cytotoxicity may be due to slower proliferation in PCSCs. • Reduced kinetics to growth factor induced activation of AKT in PCSCs.

  13. PTEN enhances G2/M arrest in etoposide-treated MCF‑7 cells through activation of the ATM pathway.

    PubMed

    Zhang, Ruopeng; Zhu, Li; Zhang, Lirong; Xu, Anli; Li, Zhengwei; Xu, Yijuan; He, Pei; Wu, Maoqing; Wei, Fengxiang; Wang, Chenhong

    2016-05-01

    As an effective tumor suppressor, phosphatase and tensin homolog (PTEN) has attracted the increased attention of scientists. Recent studies have shown that PTEN plays unique roles in the DNA damage response (DDR) and can interact with the Chk1 pathway. However, little is known about how PTEN contributes to DDR through the ATM-Chk2 pathway. It is well-known that etoposide induces G2/M arrest in a variety of cell lines, including MCF-7 cells. The DNA damage-induced G2/M arrest results from the activation of protein kinase ataxia telangiectasia mutated (ATM), followed by the activation of Chk2 that subsequently inactivates CDC25C, resulting in G2/M arrest. In the present study, we assessed the contribution of PTEN to the etoposide-induced G2/M cell cycle arrest. PTEN was knocked down in MCF-7 cells by specific shRNA, and the effects of PTEN on the ATM-Chk2 pathway were investigated through various approaches. The results showed that knockdown of PTEN strongly antagonized ATM activation in response to etoposide treatment, and thereby reduced the phosphorylation level of ATM substrates, including H2AX, P53 and Chk2. Furthermore, depletion of PTEN reduced the etoposide-induced phosphorylation of CDC25C and strikingly compromised etoposide-induced G2/M arrest in the MCF-7 cells. Altogether, we demonstrated that PTEN plays a unique role in etoposide-induced G2/M arrest by facilitating the activation of the ATM pathway, and PTEN was required for the proper activation of checkpoints in response to DNA damage in MCF-7 cells. PMID:26986476

  14. Flavonoids, the emerging dietary supplement against cisplatin-induced nephrotoxicity.

    PubMed

    Athira, K V; Madhana, Rajaram Mohanrao; Lahkar, Mangala

    2016-03-25

    The letter illustrates the emerging potential of flavonoids as dietary supplement to ameliorate cisplatin-induced nephrotoxicity and refers to the recent article on ''Anti-apoptotic and anti-inflammatory effects of naringin on cisplatin-induced renal injury in the rat'' by Chtourou et al. They demonstrated that supplementation of naringin, a flavanone glycoside, found in grape and citrus fruit species, can attenuate cisplatin-induced renal dysfunction via restoration of redox balance and suppression of inflammation, NF-κB activation and apoptosis. The chemotherapeutic efficacy of cisplatin has always compelled the researchers to find solution to ameliorate its side effects. In recent years, numerous candidates have been evaluated for their protective potential against cisplatin-induced nephrotoxicity and flavonoids have come up with promising results. The future prospects might be promising with a proper refinement and collective integration of the preclinical and clinical research in the field of flavonoid supplementation to cisplatin therapy. PMID:26876905

  15. Phase II Clinical Trial of Neoadjuvant Alternating Doublet Chemotherapy With Ifosfamide/Doxorubicin and Etoposide/Cisplatin in Small-Cell Urothelial Cancer

    PubMed Central

    Siefker-Radtke, Arlene O.; Kamat, Ashish M.; Grossman, H. Barton; Williams, Dallas L.; Qiao, Wei; Thall, Peter F.; Dinney, Colin P.; Millikan, Randall E.

    2009-01-01

    Purpose Currently, treatment recommendations for small-cell urothelial cancer (SCUC) are based on anecdotal case reports and small retrospective series. We now report results from the first phase II clinical trial developed exclusively for SCUC, to our knowledge. Patients and Methods From 2001 to 2006, 30 patients with SCUC provided consent and were treated with alternating doublet chemotherapy. Patients with surgically resectable disease (≤ cT4aN0M0) received a total of four cycles of neoadjuvant chemotherapy, whereas those with unresectable disease (≥ cT4b, N+, or M+) received two cycles beyond maximal response. Results Eighteen patients with surgically resectable SCUC received neoadjuvant treatment with a median overall survival (OS) of 58 months; 13 of these patients remain alive and cancer free. For patients with cT2N0M0 SCUC, the 5-year OS rate is 80%; only one of four patients with cT3b-4aN0M0 remains alive (median OS, 37.8 months). For 12 patients with unresectable or metastatic SCUC, the median OS was 13.3 months. Chemotherapy was well tolerated, with transfusion, neutropenic fever, and infection remaining the most frequent grade 3 and 4 toxicities. There was only one postsurgical death. Brain metastases were strongly associated with more advanced-stage disease, developing in eight of 16 patients with either bulky tumors (≥ cT3b) or metastatic disease (P = .004). Conclusion These clinical trial results are consistent with previously reported retrospective data demonstrating long-term survival with four cycles of neoadjuvant chemotherapy for surgically resectable SCUC. Once metastases develop, the prognosis remains poor. The strong positive association between disease stage and brain metastases highlights a patient subset that may potentially benefit from prophylactic cranial irradiation. PMID:19414678

  16. Paclitaxel and Carboplatin or Bleomycin Sulfate, Etoposide Phosphate, and Cisplatin in Treating Patients With Advanced or Recurrent Sex Cord-Ovarian Stromal Tumors

    ClinicalTrials.gov

    2016-03-16

    Ovarian Granulosa Cell Tumor; Ovarian Gynandroblastoma; Ovarian Sertoli-Leydig Cell Tumor; Ovarian Sex Cord Tumor With Annular Tubules; Ovarian Sex Cord-Stromal Tumor; Ovarian Sex Cord-Stromal Tumor of Mixed or Unclassified Cell Types; Ovarian Steroid Cell Tumor

  17. Cisplatin and Etoposide With or Without Veliparib in Treating Patients With Extensive Stage Small Cell Lung Cancer or Metastatic Large Cell Neuroendocrine Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2016-06-01

    Carcinoma of Unknown Primary Origin; Extensive Stage Small Cell Lung Carcinoma; Large Cell Lung Carcinoma; Neuroendocrine Carcinoma; Newly Diagnosed Carcinoma of Unknown Primary Origin; Stage IV Non-Small Cell Lung Cancer

  18. Aerosol Gemcitabine: Preclinical Safety and In Vivo Antitumor Activity in Osteosarcoma-Bearing Dogs

    PubMed Central

    Crabbs, Torrie A.; Wilson, Dennis W.; Cannan, Virginia A.; Skorupski, Katherine A.; Gordon, Nancy; Koshkina, Nadya; Kleinerman, Eugenie; Anderson, Peter M.

    2010-01-01

    Abstract Background Osteosarcoma is the most common skeletal malignancy in the dog and in young humans. Although chemotherapy improves survival time, death continues to be attributed to metastases. Aerosol delivery can provide a strategy with which to improve the lung drug delivery while reducing systemic toxicity. The purpose of this study is to assess the safety of a regional aerosol approach to chemotherapy delivery in osteosarcoma-bearing dogs, and second, to evaluate the effect of gemcitabine on Fas expression in the pulmonary metastasis. Methods We examined the systemic and local effects of aerosol gemcitabine on lung and pulmonary metastasis in this relevant large-animal tumor model using serial laboratory and arterial blood gas analysis and histopathology and immunohistochemistry, respectively. Results and Conclusions Six hundred seventy-two 1-h doses of aerosol gemcitabine were delivered. The treatment was well tolerated by these subjects with osteosarcoma (n = 20). Aerosol-treated subjects had metastatic foci that demonstrated extensive, predominately central, intratumoral necrosis. Fas expression was decreased in pulmonary metastases compared to the primary tumor (p = 0.008). After aerosol gemcitabine Fas expression in the metastatic foci was increased compared to lung metastases before treatment (p = 0.0075), and even was higher than the primary tumor (p = 0.025). Increased apoptosis (TUNEL) staining was also detected in aerosol gemcitabine treated metastasis compared to untreated controls (p = 0.028). The results from this pivotal translational study support the concept that aerosol gemcitabine may be useful against pulmonary metastases of osteosarcoma. Additional studies that evaluate the aerosol route of administration of gemcitabine in humans should be safe and are warranted. PMID:19803732

  19. Pharmacogenomic characterization of gemcitabine response – a framework for data integration to enable personalized medicine

    PubMed Central

    Harris, Michael; Bhuvaneshwar, Krithika; Natarajan, Thanemozhi; Sheahan, Laura; Wang, Difei; Tadesse, Mahlet G.; Shoulson, Ira; Filice, Ross; Steadman, Kenneth; Pishvaian, Michael J.; Deeken, John

    2014-01-01

    Objectives Response to the oncology drug gemcitabine may be variable in part due to genetic differences in the enzymes and transporters responsible for its metabolism and disposition. The aim of our in-silico study was to identify gene variants significantly associated with gemcitabine response that may help to personalize treatment in the clinic. Methods We analyzed two independent data sets: (a) genotype data from NCI-60 cell lines using the Affymetrix DMET 1.0 platform combined with gemcitabine cytotoxicity data in those cell lines, and (b) genome-wide association studies (GWAS) data from 351 pancreatic cancer patients treated on an NCI-sponsored phase III clinical trial. We also performed a subset analysis on the GWAS data set for 135 patients who were given gemcitabine+placebo. Statistical and systems biology analyses were performed on each individual data set to identify biomarkers significantly associated with gemcitabine response. Results Genetic variants in the ABC transporters (ABCC1, ABCC4) and the CYP4 family members CYP4F8 and CYP4F12, CHST3, and PPARD were found to be significant in both the NCI-60 and GWAS data sets. We report significant association between drug response and variants within members of the chondroitin sulfotransferase family (CHST) whose role in gemcitabine response is yet to be delineated. Conclusion Biomarkers identified in this integrative analysis may contribute insights into gemcitabine response variability. As genotype data become more readily available, similar studies can be conducted to gain insights into drug response mechanisms and to facilitate clinical trial design and regulatory reviews. PMID:24401833

  20. Crystal Structures of Cisplatin Bound to a Human Copper Chaperone

    SciTech Connect

    Boal, Amie K.; Rosenzweig, Amy C.

    2010-08-16

    Copper trafficking proteins, including the chaperone Atox1 and the P{sub 1B}-type ATPase ATP7B, have been implicated in cellular resistance to the anticancer drug cisplatin. We have determined two crystal structures of cisplatin-Atox1 adducts that reveal platinum coordination by the conserved CXXC copper-binding motif. Direct interaction of cisplatin with this functionally relevant site has significant implications for understanding the molecular basis for resistance mediated by copper transport pathways.

  1. A kinome screen identifies checkpoint kinase 1 (CHK1) as a sensitizer for RRM1-dependent gemcitabine efficacy.

    PubMed

    Zhou, Jun; Chen, Zhengming; Malysa, Agnes; Li, Xin; Oliveira, Paula; Zhang, Yingtao; Bepler, Gerold

    2013-01-01

    Gemcitabine is among the most efficacious and widely used antimetabolite agents. Its molecular targets are ribonucleotide reductase M1 (RRM1) and elongating DNA. Acquired and de novo resistance as a result of RRM1 overexpression are major obstacles to therapeutic efficacy. We deployed a synthetic lethality screen to investigate if knockdown of 87 selected protein kinases by siRNA could overcome RRM1-dependent gemcitabine resistance in high and low RRM1-expressing model systems. The models included genetically RRM1-modified lung and breast cancer cell lines, cell lines with gemcitabine-induced RRM1 overexpression, and a series of naturally gemcitabine-resistant cell lines. Lead molecular targets were validated by determination of differential gemcitabine activity using cell lines with and without target knock down, and by assessing synergistic activity between gemcitabine and an inhibitor of the lead target. CHK1 was identified has the kinase with the most significant and robust interaction, and it was validated using AZD7762, a small-molecule ATP-competitive inhibitor of CHK1 activation. Synergism between CHK1 inhibition and RRM1-dependent gemcitabine efficacy was observed in cells with high RRM1 levels, while antagonism was observed in cells with low RRM1 levels. In addition, four cell lines with natural gemcitabine resistance demonstrated improved gemcitabine efficacy after CHK1 inhibition. In tumor specimens from 187 patients with non-small-cell lung cancer, total CHK1 and RRM1 in situ protein levels were significantly (p = 0.003) and inversely correlated. We conclude that inhibition of CHK1 may have its greatest clinical utility in malignancies where gemcitabine resistance is a result of elevated RRM1 levels. We also conclude that CHK1 inhibition in tumors with low RRM1 levels may be detrimental to gemcitabine efficacy. PMID:23483975

  2. Etoposide Injection

    MedlinePlus

    ... cancer (cancer that begins in the female reproductive organs where eggs are formed), another type of lung ... This branded product is no longer on the market. Generic alternatives may be available.

  3. Association of ABCC2 polymorphisms with cisplatin disposition and efficacy

    PubMed Central

    Sprowl, JA; Gregorc, V; Lazzari, C; Mathijssen, RH; Loos, WJ; Sparreboom, A

    2012-01-01

    ABCC2 (MRP2; cMOAT) expression has been implicated in cisplatin resistance in vitro. In mice, cisplatin disposition and toxicity were unaffected by Abcc2 knockout. Moreover, in cancer patients (n=237), cisplatin pharmacokinetics (P>0.12) and efficacy (P>0.41) were not associated with 7 SNPs in ABCC2. These SNPs were also not correlated with ABCC2 expression in the NCI60 panel (P>0.26) or cisplatin-induced cytotoxicity (P=0.21). These findings highlight the importance of verifying drug-transporter interactions from in vitro tests in humans. PMID:22534871

  4. Walnut consumption protects rats against cisplatin-induced neurotoxicity.

    PubMed

    Shabani, Mohammad; Nazeri, Masoud; Parsania, Shahrnaz; Razavinasab, Moazamehosadat; Zangiabadi, Nasser; Esmaeilpour, Khadije; Abareghi, Fatemeh

    2012-10-01

    Walnut is extensively used in traditional medicine for treatment of various ailments. It is described as an anticancer, anti-inflammatory, blood purifier and antioxidant agent. In this study, we investigated whether or not Walnut could protect neurons against cisplatin-induced neurotoxicity in rats. Dietary walnut (6%) was assessed for its neuroprotective effects through the alteration in performance of hippocampus- and cerebellum-related behaviors following chronic cisplatin treatment (5 mg/kg/week for 5 consecutive weeks) in male rats. We also evaluated the effect of cisplatin and walnut administration on nociception. We showed that exposure of adolescent rats to cisplatin resulted in significant decrease in explorative behaviors and memory retention. Walnut consumption improved memory and motor abilities in cisplatin treated rats, while walnut alone did not show any significant changes in these abilities compared to saline. Cisplatin increased latency of response to nociception, and walnut reversed this effect of cisplatin. We conclude that walnuts in the diet following anticancer drugs such as cisplatin might have a protective effect against cisplatin-induced disruptions in motor and cognitive function. However, further studies are needed to elucidate the exact mechanisms of this protective effect of walnut and to explore underlying mechanisms. PMID:22935099

  5. Molecular mechanisms of cisplatin resistance in cervical cancer

    PubMed Central

    Zhu, Haiyan; Luo, Hui; Zhang, Wenwen; Shen, Zhaojun; Hu, Xiaoli; Zhu, Xueqiong

    2016-01-01

    Patients with advanced or recurrent cervical cancer have poor prognosis, and their 1-year survival is only 10%–20%. Chemotherapy is considered as the standard treatment for patients with advanced or recurrent cervical cancer, and cisplatin appears to treat the disease effectively. However, resistance to cisplatin may develop, thus substantially compromising the efficacy of cisplatin to treat advanced or recurrent cervical cancer. In this article, we systematically review the recent literature and summarize the recent advances in our understanding of the molecular mechanisms underlying cisplatin resistance in cervical cancer. PMID:27354763

  6. Familial hearing loss and cisplatin therapy.

    PubMed

    Kennedy, B J; Torkelson, J L

    1998-01-01

    Familial high-tone hearing loss in males is a recessive trait often unrecognized. Cisplatin chemotherapy may be associated with hearing loss. A review was made of audiograms in 85 patients with testicular carcinoma prior to cisplatin chemotherapy to determine the extent of preexisting familial hearing loss. Clinical histories defined patients exposed to high noise levels and other common causes of hearing loss. Audiometric findings were classified according to normal hearing or mild, moderate, and severe hearing impairment. Pretreatment audiograms were normal in 51 patients and abnormal in 19 patients with histories of high-level noise exposure, and in 15 patients with high-frequency hearing loss there was no history of noise exposure, ear infection, or other potential causes of hearing loss. These last 15 patients were judged to have recessive familial hearing loss. Awareness of familial hearing loss is important in male patients in whom cisplatin chemotherapy is planned. Pretreatment hearing assessment, including audiograms, is recommended for such male patients. PMID:9589029

  7. Potential Combinational Anti-Cancer Therapy in Non-Small Cell Lung Cancer with Traditional Chinese Medicine Sun-Bai-Pi Extract and Cisplatin

    PubMed Central

    Wang, Jhih-Syuan; Chung, Meng-Chi; Chang, Jing-Fen; Chao, Ming-Wei

    2016-01-01

    Traditional lung cancer treatments involve chemical or radiation therapies after surgical tumor removal; however, these procedures often kill normal cells as well. Recent studies indicate that chemotherapies, when combined with Traditional Chinese Medicines, may offer a new way to treat cancer. In vitro tests measuring the induction of autophagy and/or apoptosis were used to examine the cytotoxicity of SBPE, commonly used for lung inflammation on A549 cell line. The results indicated that intercellular levels of p62 and Atg12 were increased, LC3-I was cleaved into LC3-II, and autophagy was induced with SBPE only. After 24 hours, the apoptotic mechanism was induced. If the Cisplatin was added after cells reached the autophagy state, we observed synergistic effects of the two could achieve sufficient death of lung cancer cells. Therefore, the Cisplatin dosage used to induce apoptosis could be reduced by half, and the amount of time needed to achieve the inhibitory concentration of 50% was also half that of the original. In addition to inducing autophagy within a shortened period of time, the SBPE and chemotherapy drug combination therapy was able to achieve the objective of rapid low-dosage cancer cell elimination. Besides, SBPE was applied with Gemcitabine or Paclitaxel, and found that the combination treatment indeed achieve improved lung cancer cell killing effects. However, SBPE may also be less toxic to normal cells. PMID:27171432

  8. Potential Combinational Anti-Cancer Therapy in Non-Small Cell Lung Cancer with Traditional Chinese Medicine Sun-Bai-Pi Extract and Cisplatin.

    PubMed

    Tseng, Chia-Yi; Lin, Chin-Hung; Wu, Lung-Yuan; Wang, Jhih-Syuan; Chung, Meng-Chi; Chang, Jing-Fen; Chao, Ming-Wei

    2016-01-01

    Traditional lung cancer treatments involve chemical or radiation therapies after surgical tumor removal; however, these procedures often kill normal cells as well. Recent studies indicate that chemotherapies, when combined with Traditional Chinese Medicines, may offer a new way to treat cancer. In vitro tests measuring the induction of autophagy and/or apoptosis were used to examine the cytotoxicity of SBPE, commonly used for lung inflammation on A549 cell line. The results indicated that intercellular levels of p62 and Atg12 were increased, LC3-I was cleaved into LC3-II, and autophagy was induced with SBPE only. After 24 hours, the apoptotic mechanism was induced. If the Cisplatin was added after cells reached the autophagy state, we observed synergistic effects of the two could achieve sufficient death of lung cancer cells. Therefore, the Cisplatin dosage used to induce apoptosis could be reduced by half, and the amount of time needed to achieve the inhibitory concentration of 50% was also half that of the original. In addition to inducing autophagy within a shortened period of time, the SBPE and chemotherapy drug combination therapy was able to achieve the objective of rapid low-dosage cancer cell elimination. Besides, SBPE was applied with Gemcitabine or Paclitaxel, and found that the combination treatment indeed achieve improved lung cancer cell killing effects. However, SBPE may also be less toxic to normal cells. PMID:27171432

  9. Head-To-Head Comparison of Different Solubility-Enabling Formulations of Etoposide and Their Consequent Solubility-Permeability Interplay.

    PubMed

    Beig, Avital; Miller, Jonathan M; Lindley, David; Carr, Robert A; Zocharski, Philip; Agbaria, Riad; Dahan, Arik

    2015-09-01

    The purpose of this study was to conduct a head-to-head comparison of different solubility-enabling formulations, and their consequent solubility-permeability interplay. The low-solubility anticancer drug etoposide was formulated in several strengths of four solubility-enabling formulations: hydroxypropyl-β-cyclodextrin, the cosolvent polyethylene glycol 400 (PEG-400), the surfactant sodium lauryl sulfate, and an amorphous solid dispersion formulation. The ability of these formulations to increase the solubility of etoposide was investigated, followed by permeability studies using the parallel artificial membrane permeability assay (PAMPA) and examination of the consequent solubility-permeability interplay. All formulations significantly increased etoposide's apparent solubility. The cyclodextrin-, surfactant-, and cosolvent-based formulations resulted in a concomitant decreased permeability that could be modeled directly from the proportional increase in the apparent solubility. On the contrary, etoposide permeability remained constant when using the ASD formulation, irrespective of the increased apparent solubility provided by the formulation. In conclusion, supersaturation resulting from the amorphous form overcomes the solubility-permeability tradeoff associated with other formulation techniques. Accounting for the solubility-permeability interplay may allow to develop better solubility-enabling formulations, thereby maximizing the overall absorption of lipophilic orally administered drugs. PMID:25989509

  10. Durable Response of Leptomeningeal Metastasis of Breast Cancer to Salvage Intrathecal Etoposide After Methotrexate: A Case Report and Literature Review

    PubMed Central

    Park, Min Jae

    2015-01-01

    Patient: Female, 42 Final Diagnosis: Breast cancer with leptomeningeal metastasis Symptoms: Headache Medication: Etoposide Clinical Procedure: Intrathecal chemotherapy Specialty: Oncology Objective: Unusual setting of medical care Background: Leptomeningeal metastasis (LM) is recently on the rise as one of important clinical issues in the management of metastatic breast cancer (MBC). Clinical research on salvage intrathecal chemotherapy after failure of first-line treatment for MBC patients with LM has rarely been reported. Case Report: We report the case of a breast cancer patient with LM who showed durable response to salvage intrathecal etoposide subsequent to failure of methotrexate. Etoposide 1 mg was injected through an Ommaya reservoir every week. Corticosteroid was used for a prophylaxis of chemical arachnoiditis. The treatment was successful palliation of LM for 33 weeks without significant adverse effects. Time to neurologic progression was estimated to be about 230 days for the treatment and overall survival was 301 days from the diagnosis of LM. Conclusions: Intrathecal etoposide can be considered as an additional treatment option for LM in breast cancer. Further large clinical studies are necessary to investigate the effectiveness and safety of the treatment. PMID:26258900

  11. Integrated experimental and simulation study of the response to sequential treatment with erlotinib and gemcitabine in pancreatic cancer

    PubMed Central

    Ubezio, Paolo; Falcetta, Francesca; Carrassa, Laura; Lupi, Monica

    2016-01-01

    The combination of erlotinib with gemcitabine is one of the most promising therapies for advanced pancreatic cancer. Aiming at optimizing this combination, we analyzed in detail the response to sequential treatments with erlotinib → gemcitabine and gemcitabine → erlotinib with an 18 h interval, adopting a previously established experimental/computational approach to quantify the cytostatic and cytotoxic effects at G1, S and G2M checkpoints. This assessment was achieved by contemporary fits of flow cytometric and time-lapse experiments in two human pancreatic cancer cell lines (BxPC-3 and Capan-1) with a mathematical model reproducing the fluxes of cells through the cycle during and after treatment. The S-phase checkpoint contributes in the response to erlotinib, suggesting that the G1 arrest may hamper S-phase cytotoxicity. The response to gemcitabine was driven by the dynamics of the progressive resumption from the S-phase arrest after drug washout. The effects induced by single drugs were used to simulate combined treatments, introducing changes when required. Gemcitabine → erlotinib was more than additive in both cell lines, strengthening the cytostatic effects on cells recovering from the arrest induced by gemcitabine. The interval in the erlotinib → gemcitabine sequence enabled to overcome the antagonist effect of G1 block on gemcitabine efficacy and improved the outcome in Capan-1 cells. PMID:26909860

  12. High-intensity focused ultrasound therapy in combination with gemcitabine for unresectable pancreatic carcinoma

    PubMed Central

    Lv, Wei; Yan, Tao; Wang, Guojin; Zhao, Wei; Zhang, Tao; Zhou, Dinghua

    2016-01-01

    Objective To investigate the therapeutic effect and safety of high-intensity focused ultrasound (HIFU) therapy combined with gemcitabine in treating unresectable pancreatic carcinoma. Methods The 45 patients suffering from pancreatic carcinoma were randomized into two groups. The patients in the experimental group (n=23) received HIFU in combination with gemcitabine and those in the control group (n=22) received gemcitabine alone. The effect and clinical benefit rates in the two groups were compared. The median survival time and 6-month and 12-month survival rates were calculated by Kaplan–Meier method and log-rank test. Results The median survival time and 6-month survival rate were significantly higher in the experimental group than in the control group (8.91 months vs 5.53 months, 73.9% vs 40.9%, respectively P<0.05), but 12-month survival rate was not statistically different between the two groups (13.0% vs 4.5%, P>0.05). The clinical benefit rates in the experimental group and the control group were 69.6% and 36.3%, respectively (P<0.05). The pain remission rate in the experimental group was significantly higher than that in the control group (65.2% vs 31.8%, P<0.05). Conclusion HIFU in combination with gemcitabine is better than gemcitabine alone. This combinatorial therapy may become a better and effective treatment for unresectable pancreatic carcinoma. PMID:27194912

  13. Therapy of pancreatic cancer via an EphA2 receptor-targeted delivery of gemcitabine

    PubMed Central

    Barile, Elisa; Das, Swadesh K.; Emdad, Luni; Sarkar, Devanand; De, Surya K.; Kharagh, Susan Morvaridi; Stebbins, John L.; Pandol, Stephen J.; Fisher, Paul B.; Pellecchia, Maurizio

    2016-01-01

    First line treatment for pancreatic cancer consists of surgical resection, if possible, and a subsequent course of chemotherapy using the nucleoside analogue gemcitabine. In some patients, an active transport mechanism allows gemcitabine to enter efficiently into the tumor cells, resulting in a significant clinical benefit. However, in most patients, low expression of gemcitabine transporters limits the efficacy of the drug to marginal levels, and patients need frequent administration of the drug at high doses, significantly increasing systemic drug toxicity. In this article we focus on a novel targeted delivery approach for gemcitabine consisting of conjugating the drug with an EphA2 targeting agent. We show that the EphA2 receptor is highly expressed in pancreatic cancers, and accordingly, the drug-conjugate is more effective than gemcitabine alone in targeting pancreatic tumors. Our preliminary observations suggest that this approach may provide a general benefit to pancreatic cancer patients and offers a comprehensive strategy for enhancing delivery of diverse therapeutic agents to a wide range of cancers overexpressing EphA2, thereby potentially reducing toxicity while enhancing therapeutic efficacy. PMID:26959746

  14. Tailored Selection of First-Line Cisplatin-Based Chemotherapy in Patients with Metastatic Urothelial Carcinoma of Bladder

    PubMed Central

    Hsieh, Meng-Che; Huang, Cheng-Hua; Chiang, Po-Hui; Chen, Yen-Yang; Tang, Yeh; Su, Yu-Li

    2016-01-01

    Purpose: Methotrexate, vinblastine, doxorubicin plus cisplatin (MVAC) and gemcitabine plus cisplatin (GC) are both effective first-line chemotherapy. We explore the responsive variables of MVAC and GC for patients with metastatic urothelial carcinoma of bladder (mUCB). Materials and Methods: Patients who were initially diagnosed to have mUCB and received MVAC or GC as metastatic first-line chemotherapy between 2000 and 2014 at Kaohsiung Chang Gung Memorial Hospital were reviewed. Totally, 130 patients were enrolled into our study. Univariable Cox proportional hazard models were constructed for OS. Hazard ratio (HR) and 95% confidence intervals (CIs) was also presented. Results: There were 50 patients (38%) in the MVAC group and 80 patients (62%) in the GC group. The median OS was insignificantly different between MVAC and GC groups, accounting for 17.0 and 14.4 months (P = 0.214), respectively. OS of MVAC group was significantly longer with regard to age ≦ 60 years (HR: 0.38, 95% CI: 0.12-0.97, P = 0.036), pure urothelial carcinoma (HR: 0.56, 95% CI: 0.34-0.90, P = 0.015), > 1 metastatic sites (HR: 0.19, 95% CI: 0.08-0.44, P = < 0.001), and neutrophil to lymphocyte ratio > 3(HR: 0.45, 95% CI: 0.25-0.81, P = 0.006), while OS with GC group was significantly longer with regard to variant urothelial carcinoma (HR: 0.56, 95% CI: 0.34-0.90, P = 0.015). Conclusions: Our study disclosed the predictive factors of different regimen for mUCB. These results have clinical implication for physicians who treat patients with mUCB. PMID:27390610

  15. Challenges in management of patients with intracranial germ cell tumor and diabetes insipidus treated with cisplatin and/or ifosfamide based chemotherapy.

    PubMed

    Afzal, Samina; Wherrett, Diane; Bartels, Ute; Tabori, Uri; Huang, Annie; Stephens, Derek; Bouffet, Eric

    2010-05-01

    Patients with intracranial germ cell tumor (IGCT) often present with pituitary dysfunction, including diabetes insipidus (DI). Recent protocols have used pre-radiation chemotherapy with combinations of etoposide, carboplatin and/or cisplatin, and ifosfamide. Management of DI in these patients requires monitoring of electrolytes and fluids during chemotherapy and hyperhydration. All consecutive patients treated with chemotherapy for an IGCT during the period 1990-2007 at the Hospital for Sick Children, Toronto were reviewed. Out of 32 patients who received chemotherapy, 21 had DI. Only cycles containing cisplatin and/or ifosfamide and hyperhydration were considered. DI and non-DI patients were compared for each cycle of chemotherapy. Patients were studied for number of days in hospital per chemotherapy course, daily fluid input and output, changes in dose, schedule and route of administration of desmopressin (DDAVP) during chemotherapy, daily variations in sodium level, electrolyte monitoring requirements per day, and complications related to fluid and electrolyte disturbances. Fifty-four cycles of chemotherapy in DI patients were compared to 25 cycles in non DI patients. All 21 patients with DI required daily change in dosage and schedule of DDAVP. Marked variations in daily sodium level were observed in the DI group. Seventeen courses required prolonged admission in the DI group (one in non DI patients) and 6 patients experienced serious complications. In conclusion, DI is a risk factor for complications when cisplatin and/or ifosfamide based protocols are used. The role of these agents in the management of ICGT should be carefully evaluated and guidelines for management of DI established. PMID:19820898

  16. Predicting gemcitabine transport and toxicity in human pancreatic cancer cell lines with the positron emission tomography tracer 3'-deoxy-3'-fluorothymidine.

    PubMed

    Paproski, Robert J; Young, James D; Cass, Carol E

    2010-02-15

    The abundance of human equilibrative nucleoside transporter 1 (hENT1) has recently been shown to be a predictive marker of benefit from gemcitabine therapy in patients with pancreatic cancer. Since hENT1 is also important for the uptake of positron emission tomography (PET) tracer 3'-deoxy-3'-fluorothymidine (FLT) in various cultured human cell lines, this study was undertaken to determine if FLT uptake predicts gemcitabine uptake and/or toxicity in a panel of human pancreatic cancer cell lines (Capan-2, AsPC-1, BxPC-3, PL45, MIA PaCa-2, and PANC-1). Capan-2 cells displayed the lowest levels of (1) extracellular nitrobenzylmercaptopurine ribonucleoside (NBMPR) binding, which represents cell-surface hENT1, (2) FLT and gemcitabine uptake during short (1-45s) and prolonged (1h) periods, and (3) gemcitabine sensitivity. Exposure to NBMPR (inhibits only hENT1) or dilazep (inhibits hENT1 and hENT2) reduced FLT and gemcitabine uptake and gemcitabine sensitivity, with dilazep having greater effects than NBMPR. Gemcitabine permeation was almost completely mediated, primarily by hENT1 and to a lesser extent by hENT2, whereas FLT permeation included a substantial component of passive diffusion. In five of six cell lines, correlations were observed between (1) FLT and gemcitabine initial rates of uptake, (2) gemcitabine uptake and gemcitabine toxicity, (3) FLT uptake and gemcitabine toxicity, and (4) ribonucleotide reductase subunit M1 expression and gemcitabine toxicity. FLT and gemcitabine uptake were comparable for predicting gemcitabine toxicity in the tested pancreatic cancer cell lines suggesting that FLT PET may provide clinically useful information about tumor gemcitabine transport capacity and sensitivity. PMID:19788890

  17. Imexon enhances gemcitabine cytotoxicity by inhibition of ribonucleotide reductase

    PubMed Central

    Roman, Nicholas O.; Samulitis, Betty K.; Wisner, Lee; Landowski, Terry H.; Dorr, Robert T.

    2010-01-01

    Purpose Gemcitabine (GEM) is currently the standard first line treatment for pancreatic cancer; however, the overall survival of patients with this disease remains poor. Imexon is a pro-oxidant small molecule which produced a high response rate in combination with GEM in a phase I trial in pancreatic cancer. In this study, we investigate the combination of GEM with a novel redox-active agent, imexon, in vitro and in vivo. Methods Median effect analysis was used for in vitro combination cytotoxicity. The effect of imexon on GEM metabolism and uptake into cells and into DNA and effects on ribonucleotide reductase (RNR) were examined in vitro. The pharmacokinetics and antitumor efficacy of the imexon/GEM combination was evaluated in mouse models. Results In three human pancreatic cancer lines, there was additivity for the imexon/GEM combination. There was significantly greater efficacy for the drug combination in Panc-1 xenograft tumors. A pharmacokinetic study in mice showed a near doubling in the AUC of imexon when GEM was co-administered, with no effect of imexon on GEM's pharmacokinetic disposition. In vitro, imexon did not alter GEM's metabolism or uptake into DNA, but significantly inhibited RNR, and this effect was greater when combined with GEM. Conclusions These results suggest that the interaction between imexon and GEM may be due to complimentary inhibition of RNR plus an enhanced exposure to imexon when the GEM is administered in vivo. This combination is currently being tested in a randomized phase II trial in pancreatic cancer. PMID:20339847

  18. [Nab-Paclitaxel plus Gemcitabine for Metastatic Pancreatic Cancer].

    PubMed

    Katsura, Yoshiteru; Takeda, Yutaka; Ohmura, Yoshiaki; Motoyama, Yurina; Ishida, Tomo; Morimoto, Yoshihiro; Matsushita, Katsunori; Naito, Atsushi; Murakami, Kohei; Kagawa, Yoshinori; Okishiro, Masatsugu; Takeno, Atsushi; Egawa, Chiyomi; Kato, Takeshi; Tamura, Shigeyuki

    2015-11-01

    Pancreatic ductal carcinoma is a highly aggressive cancer, with one of the highest mortality rates among gastrointestinal cancers. Nab-paclitaxel plus gemcitabine (GEM) significantly improved overall survival, progression-free survival, and response rate in a phase Ⅲ trial in 151 community and academic centers in 11 countries. As a result, nab-paclitaxel plus GEM was approved for use in December 2014 in Japan. We report a case of a patient with pancreatic cancer who underwent this chemotherapy. A 47-year-old man was admitted to our hospital for evaluation of pancreatic lesions. Computed tomography revealed a hypoattenuating tumor in the body of the pancreas. After the patient underwent preoperative chemoradiotherapy under the diagnosis of cStage Ⅳa cancer, we planned to perform distal pancreatectomy. However, this case was inoperable because we found 3 liver metastases during surgery. On postoperative day 14, we treated the patient with nab-paclitaxel plus GEM. Grade 2 toxicities included neutropenia, diarrhea, and peripheral neuropathy, but serious adverse events did not occur. The progression-free survival was 5 months. He remained alive for 7 months after the chemotherapy. In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus GEM can be considered as the standard treatment. PMID:26805366

  19. N-acetyl-l-cysteine sensitizes pancreatic cancers to gemcitabine by targeting the NFκB pathway

    PubMed Central

    Qanungo, Suparna; Uys, Joachim D.; Manevich, Yefim; Distler, Anne M.; Shaner, Brooke; Hill, Elizabeth G.; Mieyal, John J.; Lemasters, John J.; Townsend, Danyelle M.; Nieminen, Anna-Liisa

    2015-01-01

    First-line therapy for pancreatic cancer is gemcitabine. Although tumors may initially respond to the gemcitabine treatment, soon tumor resistance develops leading to treatment failure. Previously, we demonstrated in human MIA PaCa-2 pancreatic cancer cells that N-acetyl-l-cysteine (NAC), a glutathione (GSH) precursor, prevents NFκB activation via S-glutathionylation of p65-NFκB, thereby blunting expression of survival genes. In this study, we documented the molecular sites of S-glutathionylation of p65, and we investigated whether NAC can suppress NFκB signaling and augment a therapeutic response to gemcitabine in vivo. Mass spectrometric analysis of S-glutathionylated p65-NFκB protein in vitro showed post-translational modifications of cysteines 38, 105, 120, 160 and 216 following oxidative and nitrosative stress. Circular dichroism revealed that S-glutathionylation of p65-NFκB did not change secondary structure of the protein, but increased tryptophan fluorescence revealed altered tertiary structure. Gemcitabine and NAC individually were not effective in decreasing MIA PaCa-2 tumor growth in vivo. However, combination treatment with NAC and gemcitabine decreased tumor growth by approximately 50%. NAC treatment also markedly enhanced tumor apoptosis in gemcitabine-treated mice. Compared to untreated tumors, gemcitabine treatment alone increased p65-NFκB nuclear translocation (3.7-fold) and DNA binding (2.5-fold), and these effects were blunted by NAC. In addition, NAC plus gemcitabine treatment decreased anti-apoptotic XIAP protein expression compared to gemcitabine alone. None of the treatments, however, affected extent of tumor hypoxia, as assessed by EF5 staining. Together, these results indicate that adjunct therapy with NAC prevents NFκB activation and improves gemcitabine chemotherapeutic efficacy. PMID:25257100

  20. N-acetyl-L-cysteine sensitizes pancreatic cancers to gemcitabine by targeting the NFκB pathway.

    PubMed

    Qanungo, Suparna; Uys, Joachim D; Manevich, Yefim; Distler, Anne M; Shaner, Brooke; Hill, Elizabeth G; Mieyal, John J; Lemasters, John J; Townsend, Danyelle M; Nieminen, Anna-Liisa

    2014-09-01

    First-line therapy for pancreatic cancer is gemcitabine. Although tumors may initially respond to the gemcitabine treatment, soon tumor resistance develops leading to treatment failure. Previously, we demonstrated in human MIA PaCa-2 pancreatic cancer cells that N-acetyl-l-cysteine (NAC), a glutathione (GSH) precursor, prevents NFκB activation via S-glutathionylation of p65-NFκB, thereby blunting expression of survival genes. In this study, we documented the molecular sites of S-glutathionylation of p65, and we investigated whether NAC can suppress NFκB signaling and augment a therapeutic response to gemcitabine in vivo. Mass spectrometric analysis of S-glutathionylated p65-NFκB protein in vitro showed post-translational modifications of cysteines 38, 105, 120, 160 and 216 following oxidative and nitrosative stress. Circular dichroism revealed that S-glutathionylation of p65-NFκB did not change secondary structure of the protein, but increased tryptophan fluorescence revealed altered tertiary structure. Gemcitabine and NAC individually were not effective in decreasing MIA PaCa-2 tumor growth in vivo. However, combination treatment with NAC and gemcitabine decreased tumor growth by approximately 50%. NAC treatment also markedly enhanced tumor apoptosis in gemcitabine-treated mice. Compared to untreated tumors, gemcitabine treatment alone increased p65-NFκB nuclear translocation (3.7-fold) and DNA binding (2.5-fold), and these effects were blunted by NAC. In addition, NAC plus gemcitabine treatment decreased anti-apoptotic XIAP protein expression compared to gemcitabine alone. None of the treatments, however, affected extent of tumor hypoxia, as assessed by EF5 staining. Together, these results indicate that adjunct therapy with NAC prevents NFκB activation and improves gemcitabine chemotherapeutic efficacy. PMID:25257100

  1. Molecular dynamics properties of varying amounts of the anticancer drug gemcitabine inside an open-ended single-walled carbon nanotube

    NASA Astrophysics Data System (ADS)

    Rungnim, Chompoonut; Arsawang, Uthumporn; Rungrotmongkol, Thanyada; Hannongbua, Supot

    2012-10-01

    To investigate the loading of multiple drugs inside single-walled carbon nanotubes (SWCNTs), molecular dynamics simulations were applied to the gemcitabine-SWCNT system with from one to six drug molecules being confined inside the SWCNT cavity. At low drug concentrations (1-4 gemcitabines inside each SWCNT), the π-π stacking of two cytosine rings of adjacent gemcitabine molecules caused them to orientate towards each other and move together inside the SWCNT. In contrast, at high drug concentrations (encapsulated gemcitabines ⩾5), the close contact of gemcitabines promoted electrostatic interactions through hydrogen bonding rather than the π-π stacking interaction from their cytosine rings.

  2. Beyond pancreatic cancer: irinotecan and gemcitabine in solid tumors and hematologic malignancies.

    PubMed

    Rocha Lima, C M; Urbanic, J J; Lal, A; Kneuper-Hall, R; Brunson, C Y; Green, M R

    2001-06-01

    Non-platinum combinations including gemcitabine and irinotecan (Gemzar; Eli Lilly and Company, Indianapolis, IN) for the management of a variety of malignancies have started to emerge. Gemcitabine and irinotecan are well-tolerated single agents, each with a broad spectrum of antitumor activity. Preclinical data suggests synergy for the two drugs when used in combination. A phase I trial has defined a well-tolerated combination regimen using both drugs on a day-1, -8 schedule every 3 weeks. Phase II data suggest activity for the combination in pancreatic cancer, and a phase III trial of the two-drug combination versus gemcitabine alone is underway in previously untreated pancreatic cancer patients. Other phase II trials evaluating the impact of this combination on a variety of other tumors, such as non-small cell lung, small cell lung, breast, colorectal, and non-Hodgkin's lymphoma, are either forthcoming or in progress. Semin Oncol 28 (suppl 10):34-43. PMID:11510032

  3. Development of gemcitabine-adsorbed magnetic gelatin nanoparticles for targeted drug delivery in lung cancer.

    PubMed

    Hamarat Sanlıer, Senay; Yasa, Merve; Cihnioglu, Aslı Ozge; Abdulhayoglu, Merve; Yılmaz, Habibe; Ak, Güliz

    2016-05-01

    Magnetic iron oxide nanoparticles (IONPs) were coated with gelatin type B by means of the two-step desolvation method. Drug loading by adsorption was studied under various conditions such as different temperature, contact time, pH, and initial gemcitabine concentration. Further, Langmuir isotherm curves were constracted and constants were calculated. According to the Langmuir isotherm, the Gibbs free energy of the adsorption process at 25°C was - 4.74 kJ/mol. On the other hand, this value at 37°C was - 7.86 kJ/mol. In vitro drug release was performed at pH levels of 5 and 7.4, with gemcitabine-loaded magnetic gelatin nanoparticles and free gemcitabine, and both the results were subsequently compared. PMID:25615875

  4. Immuno-modulating properties of saliphenylhalamide, SNS-032, obatoclax, and gemcitabine.

    PubMed

    Söderholm, Sandra; Anastasina, Maria; Islam, Mohammad Majharul; Tynell, Janne; Poranen, Minna M; Bamford, Dennis H; Stenman, Jakob; Julkunen, Ilkka; Šaulienė, Ingrida; De Brabander, Jef K; Matikainen, Sampsa; Nyman, Tuula A; Saelens, Xavier; Kainov, Denis

    2016-02-01

    Influenza A viruses (IAVs) impact the public health and global economy by causing yearly epidemics and occasional pandemics. Several anti-IAV drugs are available and many are in development. However, the question remains which of these antiviral agents may allow activation of immune responses and protect patients against co- and re-infections. To answer to this question, we analysed immuno-modulating properties of the antivirals saliphenylhalamide (SaliPhe), SNS-032, obatoclax, and gemcitabine, and found that only gemcitabine did not impair immune responses in infected cells. It also allowed activation of innate immune responses in lipopolysaccharide (LPS)- and interferon alpha (IFNα)-stimulated macrophages. Moreover, immuno-mediators produced by gemcitabine-treated IAV-infected macrophages were able to prime immune responses in non-infected cells. Thus, we identified an antiviral agent which might be beneficial for treatment of patients with severe viral infections. PMID:26738783

  5. Targeting etoposide to acute myelogenous leukaemia cells using nanostructured lipid carriers coated with transferrin

    NASA Astrophysics Data System (ADS)

    Khajavinia, Amir; Varshosaz, Jaleh; Jafarian Dehkordi, Abbas

    2012-10-01

    The aim of the present study was to evaluate the diverse properties of transferrin (Tf)-conjugated nanostructured lipid carriers (NLCs) prepared using three different fatty amines, including stearylamine (SA), dodecylamine (DA) and spermine (SP), and two different methods for Tf coupling. Etoposide-loaded NLCs were prepared by an emulsion-solvent evaporation method followed by probe sonication. Chemical coupling of NLCs with Tf was mediated by an amide linkage between the surface-exposed amino group of the fatty amine and the carboxyl group of the protein. The physical coating was performed in a Ringer-Hepes buffer medium. NLCs were characterized by their particle size, zeta potential, polydispersity index, drug entrapment percentage, drug release profiles and Tf-coupling efficiency. The cytotoxicity of NLCs on K562 acute myelogenous leukaemia cells was studied by MTT assay, and their cellular uptake was studied by a flow cytometry method. SA-containing NLCs showed the lowest particle size, the highest zeta potential and the largest coupling efficiency values. The drug entrapment percentage and the zeta potential decreased after Tf coupling, but the average particle size increased. SP-containing formulations released their drug contents comparatively slower than SA- or DA-containing NLCs. Unconjugated NLCs released moderately more drug than Tf-NLCs. Flow cytometry studies revealed enhanced cellular uptake of Tf-NLCs compared to unconjugated ones. Blocking Tf receptors resulted in a significantly higher cell survival rate for Tf-NLCs. The highest cytotoxic activity was observed in the chemically coupled SA-containing nanoparticles, with an IC50 value of 15-fold lower than free etoposide.

  6. Novel orally active epoxyeicosatrienoic acid (EET) analogs attenuate cisplatin nephrotoxicity.

    PubMed

    Khan, Md Abdul Hye; Liu, Jing; Kumar, Ganesh; Skapek, Stephen X; Falck, John R; Imig, John D

    2013-08-01

    Nephrotoxicity severely limits the use of the anticancer drug cisplatin. Oxidative stress, inflammation, and endoplasmic reticulum (ER) stress contribute to cisplatin-induced nephrotoxicity. We developed novel orally active epoxyeicosatrienoic acid (EET) analogs and investigated their prophylactic effect in cisplatin-induced nephrotoxicity in rats. Cisplatin-induced nephrotoxicity was manifested by increases in blood urea nitrogen, plasma creatinine, urinary N-acetyl-β-(d)-glucosaminidase activity, kidney injury molecule 1, and histopathology. EET analogs (10 mg/kg/d) attenuated cisplatin-induced nephrotoxicity by reducing these renal injury markers by 40-80% along with a 50-70% reduction in renal tubular cast formation. This attenuated renal injury is associated with reduced oxidative stress, inflammation, and ER stress evident from reduction in related biomarkers and in the renal expression of genes involved in these pathways. Moreover, we demonstrated that the attenuated nephrotoxicity correlated with decreased apoptosis that is associated with 50-90% reduction in Bcl-2 protein family mediated proapoptotic signaling, reduced renal caspase-12 expression, and a 50% reduction in renal caspase-3 activity. We further demonstrated in vitro that the protective activity of EET analogs does not compromise the anticancer effects of cisplatin. Collectively, our data provide evidence that EET analogs attenuate cisplatin-induced nephrotoxicity by reducing oxidative stress, inflammation, ER stress, and apoptosis without affecting the chemotherapeutic effects of cisplatin. PMID:23603837

  7. Rationally engineered polymeric cisplatin nanoparticles for improved antitumor efficacy

    NASA Astrophysics Data System (ADS)

    Paraskar, Abhimanyu; Soni, Shivani; Basu, Sudipta; Amarasiriwardena, Chitra J.; Lupoli, Nicola; Srivats, Shyam; Sinha Roy, Rituparna; Sengupta, Shiladitya

    2011-07-01

    The use of cisplatin, a first line chemotherapy for most cancers, is dose-limited due to nephrotoxicity. While this toxicity can be addressed through nanotechnology, previous attempts at engineering cisplatin nanoparticles have been limited by the impact on the potency of cisplatin. Here we report the rational engineering of a novel cisplatin nanoparticle by harnessing a novel polyethylene glycol-functionalized poly-isobutylene-maleic acid (PEG-PIMA) copolymer, which can complex with cis-platinum (II) through a monocarboxylato and a coordinate bond. We show that this complex self-assembles into a nanoparticle, and exhibits an IC50 = 0.77 ± 0.11 µM comparable to that of free cisplatin (IC50 = 0.44 ± 0.09 µM). The nanoparticles are internalized into the endolysosomal compartment of cancer cells, and release cisplatin in a pH-dependent manner. Furthermore, the nanoparticles exhibit significantly improved antitumor efficacy in a 4T1 breast cancer model in vivo, with limited nephrotoxicity, which can be explained by preferential biodistribution in the tumor with reduced kidney concentrations. Our results suggest that the PEG-PIMA-cisplatin nanoparticle can emerge as an attractive solution to the challenges in cisplatin chemotherapy.

  8. Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer

    PubMed Central

    Koay, Eugene J.; Baio, Flavio E.; Ondari, Alexander; Truty, Mark J.; Cristini, Vittorio; Thomas, Ryan M.; Chen, Rong; Chatterjee, Deyali; Kang, Ya’an; Zhang, Joy; Court, Laurence; Bhosale, Priya R.; Tamm, Eric P.; Qayyum, Aliya; Crane, Christopher H.; Javle, Milind; Katz, Matthew H.; Gottumukkala, Vijaya N.; Rozner, Marc A.; Shen, Haifa; Lee, Jeffrey E.; Wang, Huamin; Chen, Yuling; Plunkett, William; Abbruzzese, James L.; Wolff, Robert A.; Maitra, Anirban; Ferrari, Mauro; Varadhachary, Gauri R.; Fleming, Jason B.

    2014-01-01

    There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of

  9. Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer

    NASA Astrophysics Data System (ADS)

    Koay, Eugene J.; Baio, Flavio E.; Ondari, Alexander; Truty, Mark J.; Cristini, Vittorio; Thomas, Ryan M.; Chen, Rong; Chatterjee, Deyali; Kang, Ya'an; Zhang, Joy; Court, Laurence; Bhosale, Priya R.; Tamm, Eric P.; Qayyum, Aliya; Crane, Christopher H.; Javle, Milind; Katz, Matthew H.; Gottumukkala, Vijaya N.; Rozner, Marc A.; Shen, Haifa; Lee, Jeffrey E.; Wang, Huamin; Chen, Yuling; Plunkett, William; Abbruzzese, James L.; Wolff, Robert A.; Maitra, Anirban; Ferrari, Mauro; Varadhachary, Gauri R.; Fleming, Jason B.

    2014-12-01

    There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of

  10. Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer.

    PubMed

    Koay, Eugene J; Baio, Flavio E; Ondari, Alexander; Truty, Mark J; Cristini, Vittorio; Thomas, Ryan M; Chen, Rong; Chatterjee, Deyali; Kang, Ya'an; Zhang, Joy; Court, Laurence; Bhosale, Priya R; Tamm, Eric P; Qayyum, Aliya; Crane, Christopher H; Javle, Milind; Katz, Matthew H; Gottumukkala, Vijaya N; Rozner, Marc A; Shen, Haifa; Lee, Jeffrey E; Wang, Huamin; Chen, Yuling; Plunkett, William; Abbruzzese, James L; Wolff, Robert A; Maitra, Anirban; Ferrari, Mauro; Varadhachary, Gauri R; Fleming, Jason B

    2014-01-01

    There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of

  11. Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug.

    PubMed

    Guillermet-Guibert, Julie; Davenne, Lise; Pchejetski, Dimitri; Saint-Laurent, Nathalie; Brizuela, Leyre; Guilbeau-Frugier, Céline; Delisle, Marie-Bernadette; Cuvillier, Olivier; Susini, Christiane; Bousquet, Corinne

    2009-04-01

    Defeating pancreatic cancer resistance to the chemotherapeutic drug gemcitabine remains a challenge to treat this deadly cancer. Targeting the sphingolipid metabolism for improving tumor chemosensitivity has recently emerged as a promising strategy. The fine balance between intracellular levels of the prosurvival sphingosine-1-phosphate (S1P) and the proapoptotic ceramide sphingolipids determines cell fate. Among enzymes that control this metabolism, sphingosine kinase-1 (SphK1), a tumor-associated protein overexpressed in many cancers, favors survival through S1P production, and inhibitors of SphK1 are used in ongoing clinical trials to sensitize epithelial ovarian and prostate cancer cells to various chemotherapeutic drugs. We here report that the cellular ceramide/S1P ratio is a critical biosensor for predicting pancreatic cancer cell sensitivity to gemcitabine. A low level of the ceramide/S1P ratio, associated with a high SphK1 activity, correlates with a robust intrinsic pancreatic cancer cell chemoresistance toward gemcitabine. Strikingly, increasing the ceramide/S1P ratio, by using pharmacologic (SphK1 inhibitor or ceramide analogue) or small interfering RNA-based approaches to up-regulate intracellular ceramide levels or reduce SphK1 activity, sensitized pancreatic cancer cells to gemcitabine. Conversely, decreasing the ceramide/S1P ratio, by up-regulating SphK1 activity, promoted gemcitabine resistance in these cells. Development of novel pharmacologic strategies targeting the sphingolipid metabolism might therefore represent an interesting promising approach, when combined with gemcitabine, to defeat pancreatic cancer chemoresistance to this drug. PMID:19372554

  12. Frondoside A enhances the antiproliferative effects of gemcitabine in pancreatic cancer.

    PubMed

    Al Shemaili, J; Mensah-Brown, E; Parekh, K; Thomas, S A; Attoub, S; Hellman, B; Nyberg, F; Adem, A; Collin, P; Adrian, T E

    2014-05-01

    Pancreatic cancer has a very poor prognosis. While gemcitabine is the mainstay of therapy and improves quality of life, it has little impact on survival. More effective treatments are desperately needed for this disease. Frondoside A is a triterpenoid glycoside isolated from the Atlantic sea cucumber, Cucumaria frondosa. Frondoside A potently inhibits pancreatic cancer cell growth and induces apoptosis in vitro and in vivo. The aim of the present study was to investigate whether frondoside A could enhance the anti-cancer effects of gemcitabine. Effects of frondoside A and gemcitabine alone and in combination on proliferation were investigated in two human pancreatic cancer cell lines, AsPC-1 and S2013. To investigate possible synergistic effects, combinations of low concentrations of the two drugs were used for a 72 h treatment period in vitro. Growth inhibition was significantly greater with the drug combinations than their additive effects. Combinations of frondoside A and gemcitabine were tested in vivo using the athymic mouse model. Xenografts of AsPC-1 and S2013 cells were allowed to form tumours prior to treatment with the drugs alone or in combination for 30 days. Tumours grew rapidly in placebo-treated animals. Tumour growth was significantly reduced in all treatment groups. At the lowest dose tested, gemcitabine (4 mg/kg/dose), combined with frondoside A (100 μg/kg/day) was significantly more effective than with either drug alone. To conclude: The present data suggest that combinations of frondoside A and gemcitabine may provide clinical benefit for patients with pancreatic cancer. PMID:24462376

  13. Genomic signatures for paclitaxel and gemcitabine resistance in breast cancer derived by machine learning.

    PubMed

    Dorman, Stephanie N; Baranova, Katherina; Knoll, Joan H M; Urquhart, Brad L; Mariani, Gabriella; Carcangiu, Maria Luisa; Rogan, Peter K

    2016-01-01

    Increasingly, the effectiveness of adjuvant chemotherapy agents for breast cancer has been related to changes in the genomic profile of tumors. We investigated correspondence between growth inhibitory concentrations of paclitaxel and gemcitabine (GI50) and gene copy number, mutation, and expression first in breast cancer cell lines and then in patients. Genes encoding direct targets of these drugs, metabolizing enzymes, transporters, and those previously associated with chemoresistance to paclitaxel (n = 31 genes) or gemcitabine (n = 18) were analyzed. A multi-factorial, principal component analysis (MFA) indicated expression was the strongest indicator of sensitivity for paclitaxel, and copy number and expression were informative for gemcitabine. The factors were combined using support vector machines (SVM). Expression of 15 genes (ABCC10, BCL2, BCL2L1, BIRC5, BMF, FGF2, FN1, MAP4, MAPT, NFKB2, SLCO1B3, TLR6, TMEM243, TWIST1, and CSAG2) predicted cell line sensitivity to paclitaxel with 82% accuracy. Copy number profiles of 3 genes (ABCC10, NT5C, TYMS) together with expression of 7 genes (ABCB1, ABCC10, CMPK1, DCTD, NME1, RRM1, RRM2B), predicted gemcitabine response with 85% accuracy. Expression and copy number studies of two independent sets of patients with known responses were then analyzed with these models. These included tumor blocks from 21 patients that were treated with both paclitaxel and gemcitabine, and 319 patients on paclitaxel and anthracycline therapy. A new paclitaxel SVM was derived from an 11-gene subset since data for 4 of the original genes was unavailable. The accuracy of this SVM was similar in cell lines and tumor blocks (70-71%). The gemcitabine SVM exhibited 62% prediction accuracy for the tumor blocks due to the presence of samples with poor nucleic acid integrity. Nevertheless, the paclitaxel SVM predicted sensitivity in 84% of patients with no or minimal residual disease. PMID:26372358

  14. Tempol protects human lymphocytes from genotoxicity induced by cisplatin.

    PubMed

    Khabour, Omar F; Alzoubi, Karem H; Mfady, Doa'a S; Alasseiri, Mohammed; Hasheesh, Taghrid F

    2014-01-01

    The use of cisplatin in treatments of human malignancies is limited by its side effects that include DNA damage and the subsequent risk of developing secondary cancer. In this study, we examined the possible protective effect of Tempol against DNA damage induced by cisplatin in human lymphocytes using chromosomal aberrations (CAs) and sister chromatid exchanges (SCEs) assays. Cisplatin induced significant elevation in the frequencies of CAs and SCEs in cultured human lymphocytes (P < 0.01). Treatment of lymphocytes with Tempol significantly lowered CAs and SCEs induced by cisplatin. Tempol alone did not affect spontaneous levels of SCEs and CAs observed in the control group (P > 0.05). In conclusion, Tempol protects human lymphocytes against genotoxicity induced by the anticancer drug cisplatin. PMID:24955171

  15. Reduction of cisplatin-induced nephrotoxicity in vivo by selenomethionine: the effect on cisplatin-DNA adducts.

    PubMed

    García Sar, Daniel; Montes-Bayón, Maria; Blanco González, Elisa; Sierra Zapico, Luisa M; Sanz-Medel, Alfredo

    2011-06-20

    Cisplatin is one of the most effective chemotherapeutic agents, although its clinical use is limited by severe renal toxicity. This toxicity seems to be related to the accumulation of the drug in kidney tissues, leading to renal failure. For this reason, several compounds have been evaluated to ameliorate the nephrotoxicity induced by cisplatin. In the present investigation, we report the effect of the oral administration of selenomethionine before intraperitoneal cisplatin treatment. The preadministration of this Se species has been shown to have an important effect in reducing renal damage induced by cisplatin by increasing the excreted urea and improving creatinine clearance. Quantification of the level of DNA--cisplatin adducts in kidney and liver tissues was carried out by postcolumn isotope dilution analysis using liquid chromatography-inductively coupled plasma (LC-ICP-MS) as speciation set up. The level of DNA--cisplatin adducts in rats given Se-methionine in the drinking water before cisplatin administration was considerably lower in kidney tissues with respect to the animals drinking only water. Such effects were not observed in liver tissue. Initial speciation studies of Pt and Se conducted in kidney tissues of exposed animals by HPLC-ICP-MS have revealed the presence of cisplatin as part of a complex with Se-methionine, which can be eventually excreted into urine. This Pt--Se complex could explain the observed reduction of the kidney damage in Se-methionine-treated animals. PMID:21491944

  16. Dendrimers bind antioxidant polyphenols and cisplatin drug.

    PubMed

    Abderrezak, Amine; Bourassa, Philippe; Mandeville, Jean-Sebastian; Sedaghat-Herati, Reza; Tajmir-Riahi, Heidar-Ali

    2012-01-01

    Synthetic polymers of a specific shape and size play major role in drug delivery systems. Dendrimers are unique synthetic macromolecules of nanometer dimensions with a highly branched structure and globular shape with potential applications in gene and drug delivery. We examine the interaction of several dendrimers of different compositions mPEG-PAMAM (G3), mPEG-PAMAM (G4) and PAMAM (G4) with hydrophilic and hydrophobic drugs cisplatin, resveratrol, genistein and curcumin at physiological conditions. FTIR and UV-visible spectroscopic methods as well as molecular modeling were used to analyse drug binding mode, the binding constant and the effects of drug complexation on dendrimer stability and conformation. Structural analysis showed that cisplatin binds dendrimers in hydrophilic mode via Pt cation and polymer terminal NH(2) groups, while curcumin, genistein and resveratrol are located mainly in the cavities binding through both hydrophobic and hydrophilic contacts. The overall binding constants of durg-dendrimers are ranging from 10(2) M(-1) to 10(3) M(-1). The affinity of dendrimer binding was PAMAM-G4>mPEG-PAMAM-G4>mPEG-PAMAM-G3, while the order of drug-polymer stability was curcumin>cisplatin>genistein>resveratrol. Molecular modeling showed larger stability for genisten-PAMAM-G4 (ΔG = -4.75 kcal/mol) than curcumin-PAMAM-G4 ((ΔG = -4.53 kcal/mol) and resveratrol-PAMAM-G4 ((ΔG = -4.39 kcal/mol). Dendrimers might act as carriers to transport hydrophobic and hydrophilic drugs. PMID:22427960

  17. Calcitriol enhances gemcitabine antitumor activity in vitro and in vivo by promoting apoptosis in a human pancreatic carcinoma model system

    PubMed Central

    Yu, Wei-Dong; Ma, Yingyu; Flynn, Geraldine; Muindi, Josephia R; Kong, Rui-Xian; Trump, Donald L

    2010-01-01

    Gemcitabine is the standard care chemotherapeutic agent to treat pancreatic cancer. Previously we demonstrated that calcitriol (1, 25-dihydroxycholecalciferol) has significant anti-proliferative effects in vitro and in vivo in multiple tumor models and enhances the activity of a variety of chemotherapeutic agents. We therefore investigated whether calcitriol could potentiate the cytotoxic activity of gemcitabine in the human pancreatic cancer Capan-1 model system. Isobologram analysis revealed that calcitriol and gemcitabine had synergistic antiproliferative effect over a wide range of drug concentrations. Calcitriol did not reduce the cytidine deaminase activity in Capan-1 tumors nor in the livers of Capan-1 tumor bearing mice. Calcitriol and gemcitabine combination promoted apoptosis in Capan-1 cells compared with either agent alone. The combination treatment also increased the activation of caspases-8, -9, -6 and -3 in Capan-1 cells. This result was confirmed by substrate-based caspase activity assay. Akt phosphorylation was reduced by calcitriol and gemcitabine combination treatment compared to single agent treatment. However, ERK1/2 phosphorylation was not modulated by either agent alone or by the combination. Tumor regrowth delay studies showed that calcitriol in combination with gemcitabine resulted in a significant reduction of Capan-1 tumor volume compared to single agent treatment. Our study suggests that calcitriol and gemcitabine in combination promotes caspase-dependent apoptosis, which may contribute to increased anti-tumor activity compared to either agent alone. PMID:20699664

  18. Novel Etoposide Analogue Modulates Expression of Angiogenesis Associated microRNAs and Regulates Cell Proliferation by Targeting STAT3 in Breast Cancer

    PubMed Central

    Srinivas, Chatla; Ramaiah, M. Janaki; Lavanya, A.; Yerramsetty, Suresh; Kavi Kishor, P. B; Basha, Shaik Anver; Kamal, Ahmed; Bhadra, Utpal; Bhadra, Manika-Pal

    2015-01-01

    Tumor microenvironment play role in angiogenesis and carcinogenesis. Etoposide, a known topoisomerase II inhibitor induces DNA damage resulting in cell cycle arrest. We developed a novel Etoposide analogue, Quinazolino-4β-amidopodophyllotoxin (C-10) that show better efficacy in regulating cell proliferation and angiogenesis. We evaluated its role on expression of microRNAs-15, 16, 17 and 221 and its targets Bcl-2, STAT3 and VEGF that dictate cell proliferation and angiogenesis. Docking studies clearly demonstrated the binding of Etoposide and C-10 to STAT3. We conclude that combination of Etoposide or C-10 with miR-15, 16, 17 and 221 as a new approach to induce apoptosis and control angiogenesis in breast cancer. PMID:26551008

  19. Changes in DNA methylation and transgenerational mobilization of a transposable element (mPing) by the Topoisomerase II inhibitor, Etoposide, in rice

    PubMed Central

    2012-01-01

    Background Etoposide (epipodophyllotoxin) is a chemical commonly used as an anti-cancer drug which inhibits DNA synthesis by blocking topoisomerase II activity. Previous studies in animal cells have demonstrated that etoposide constitutes a genotoxic stress which may induce genomic instability including mobilization of normally quiescent transposable elements (TEs). However, it remained unknown whether similar genetically mutagenic effects could be imposed by etoposide in plant cells. Also, no information is available with regard to whether the drug may cause a perturbation of epigenetic stability in any organism. Results To investigate whether etoposide could generate genetic and/or epigenetic instability in plant cells, we applied etoposide to germinating seeds of six cultivated rice (Oryza sativa L.) genotypes including both subspecies, japonica and indica. Based on the methylation-sensitive gel-blotting results, epigenetic changes in DNA methylation of three TEs (Tos17, Osr23 and Osr36) and two protein-encoding genes (Homeobox and CDPK-related genes) were detected in the etoposide-treated plants (S0 generation) in four of the six studied japonica cultivars, Nipponbare, RZ1, RZ2, and RZ35, but not in the rest japonica cultivar (Matsumae) and the indica cultivar (93-11). DNA methylation changes in the etoposide-treated S0 rice plants were validated by bisulfite sequencing at both of two analyzed loci (Tos17 and Osr36). Transpositional activity was tested for eight TEs endogenous to the rice genome in both the S0 plants and their selfed progenies (S1 and S2) of one of the cultivars, RZ1, which manifested heritable phenotypic variations. Results indicated that no transposition occurred in the etoposide-treated S0 plants for any of the TEs. Nonetheless, a MITE transposon, mPing, showed rampant mobilization in the S1 and S2 progenies descended from the drug-treated S0 plants. Conclusions Our results demonstrate that etoposide imposes a similar genotoxic stress on

  20. Optimal dose of gemcitabine for the treatment of biliary tract or pancreatic cancer in patients with liver dysfunction.

    PubMed

    Shibata, Takashi; Ebata, Tomoki; Fujita, Ken-ichi; Shimokata, Tomoya; Maeda, Osamu; Mitsuma, Ayako; Sasaki, Yasutsuna; Nagino, Masato; Ando, Yuichi

    2016-02-01

    A clear consensus does not exist about whether the initial dose of gemcitabine, an essential anticancer antimetabolite, should be reduced in patients with liver dysfunction. Adult patients with biliary tract or pancreatic cancer were divided into three groups according to whether they had mild, moderate, or severe liver dysfunction, evaluated on the basis of serum bilirubin and liver transaminase levels at baseline. As anticancer treatment, gemcitabine at a dose of 800 or 1000 mg/m(2) was given as an i.v. infusion once weekly for 3 weeks of a 4-week cycle. The patients were prospectively evaluated for adverse events during the first cycle, and the pharmacokinetics of gemcitabine and its inactive metabolite, difluorodeoxyuridine, were studied to determine the optimal initial dose of gemcitabine as monotherapy according to the severity of liver dysfunction. A total of 15 patients were studied. Liver dysfunction was mild in one patient, moderate in six, and severe in eight. All 15 patients had been undergoing biliary drainage for obstructive jaundice when they received gemcitabine. Grade 3 cholangitis developed in one patient with moderate liver dysfunction who received gemcitabine at the dose level of 1000 mg/m(2). No other patients had severe treatment-related adverse events resulting in the omission or discontinuation of gemcitabine treatment. The plasma concentrations of gemcitabine and difluorodeoxyuridine were similar among the groups. An initial dose reduction of gemcitabine as monotherapy for the treatment of biliary tract or pancreatic cancers is not necessary for patients with hyperbilirubinemia, provided that obstructive jaundice is well managed. (Clinical trial registration no. UMIN000005363.) PMID:26595259

  1. Berbamine enhances the antineoplastic activity of gemcitabine in pancreatic cancer cells by activating transforming growth factor-β/Smad signaling.

    PubMed

    Jin, Xiaoli; Wu, Yulian

    2014-05-01

    Drug-resistance to gemcitabine chemotherapy in pancreatic cancer is still an unsolved problem. Combinations of other chemotherapy drugs with gemcitabine have been shown to increase the efficacy of gemcitabine-based treatment. In this study, the effect of berbamine on the antitumor activity of gemcitabine was evaluated in human pancreatic cancer cell lines Bxpc-3 and Panc-1, and the underlying mechanisms were explored. Our results demonstrated that berbamine exhibited a time- and dose-dependent inhibitory effect in the pancreatic cancer cell lines. Berbamine enhanced gemcitabine-induced cell growth inhibition and apoptosis in these cells. Combined treatment of berbamine and gemcitabine resulted in down-regulation of anti-apoptotic proteins (Bcl-2, Bcl-xL) and up-regulation of pro-apoptotic proteins (Bax, Bid). More importantly, berbamine treatment in combination with gemcitabine activated the transforming growth factor-β/Smad (TGF-β/Smad) signaling pathway, as a result of a decrease in Smad7 and an increase in transforming growth factor-β receptor II (TβRII) expression. Changes in downstream targets of Smad7, such as up-regulation of p21 and down-regulation of c-Myc and Cyclin D1 were also observed. Therefore, berbamine could enhance the antitumor activity of gemcitabine by inhibiting cell growth and inducing apoptosis, possibly through the regulation of the expression of apoptosis-related proteins and the activation of TGF-β/Smad signaling pathway. Our study indicates that berbamine may be a promising candidate to be used in combination with gemcitabine for pancreatic cancer treatment. PMID:24619961

  2. Long-term maintenance combination chemotherapy with OPEC/MPEC (vincristine or methotrexate, prednisolone, etoposide and cyclophosphamide) or with daily oral etoposide and prednisolone can improve survival and quality of life in adult T-cell leukemia/lymphoma.

    PubMed

    Matsushita, K; Matsumoto, T; Ohtsubo, H; Fujiwara, H; Imamura, N; Hidaka, S; Kukita, T; Tei, C; Matsumoto, M; Arima, N

    1999-12-01

    Acute leukemia and lymphoma varieties of adult T-cell leukemia/lymphoma (ATL) usually carry a poor prognosis. While etoposide is generally useful for treating ATL, especially as a daily oral maintenance regimen, etoposide has not proven effective in severe types of ATL efficient in some patients. Of 87 ATL patients whom we have treated, 51 had acute leukemia, 22 lymphoma and 14 progressive chronic leukemia. Seventy-nine patients were treated with a long term maintenance combination protocol, OPEC/MPEC (weekly doses of vincristine, 0.7 mg/m2 or methotrexate, 14 mg/m2; prednisolone, 20 mg/m2; etoposide, 70 mg/m2 and cyclophosphamide, 200 mg/m2). The other 8 patients, 3 with acute leukemia, 2 with lymphoma and 3 with progressive chronic leukemia, were treated with daily oral administration of 25 mg of etoposide and 10 mg of prednisolone (DOEP). The dose administered was modified in individual cases to maintain the granulocyte count and reduce the number of ATL cells. Considering both protocols, a complete response and a partial response were achieved in 31.0% and 58.6% patients, respectively. Median survival times (MST) of all patients and, acute leukemia, lymphoma and progressive chronic leukemia types were 7.5, 6.7, 9.6 and 12.4 months, respectively. Respective MST of patients treated with OPEC/MPEC or DOEP protocols were 7.1 and 18.0 months. Relatively normal WBC counts, lower lactate dehydrogenase concentration and normal calcium concentration, limited numbers of anatomic sites involved, good performance status and good response to chemotherapy were significantly associated with long survival time. Drug toxicity was not apparent, and about half of patients were treated in an outpatient setting. PMID:10613451

  3. Evaluation of nanoparticle delivered cisplatin in beagles

    NASA Astrophysics Data System (ADS)

    Feldhaeusser, Brittany; Platt, Simon R.; Marrache, Sean; Kolishetti, Nagesh; Pathak, Rakesh K.; Montgomery, David J.; Reno, Lisa R.; Howerth, Elizabeth; Dhar, Shanta

    2015-08-01

    Intracranial neoplasia is a significant cause of morbidity and mortality in both human and veterinary patients, and is difficult to treat with traditional therapeutic methods. Cisplatin is a platinum (Pt)-containing chemotherapeutic agent approved by the Food and Drug Administration; however, substantial limitations exist for its application in canine brain tumor treatment due to the difficulty in crossing the blood-brain barrier (BBB), development of resistance, and toxicity. A modified Pt(iv)-prodrug of cisplatin, Platin-M, was recently shown to be deliverable to the brain via a biocompatible mitochondria-targeted lipophilic polymeric nanoparticle (NP) that carries the drug across the BBB and to the mitochondria. NP mediated controlled release of Platin-M and subsequent reduction of this prodrug to cisplatin allowed cross-links to be formed with the mitochondrial DNA, which have no nucleotide excision repair system, forcing the overactive cancer cells to undergo apoptosis. Here, we report in vitro effects of targeted Platin-M NPs (T-Platin-M-NPs) in canine glioma and glioblastoma cell lines with results indicating that this targeted NP formulation is more effective than cisplatin. In both the cell lines, T-Platin-M-NP was significantly more efficacious compared to carboplatin, another Pt-based chemotherapy, which is used in the settings of recurrent high-grade glioblastoma. Mitochondrial stress analysis indicated that T-Platin-M-NP is more effective in disrupting the mitochondrial bioenergetics in both the cell types. A 14-day distribution study in healthy adult beagles using a single intravenous injection at 0.5 mg kg-1 (with respect to Platin-M) of T-Platin-M-NPs showed high levels of Pt accumulation in the brain, with negligible amounts in the other analyzed organs. Safety studies in the beagles monitoring physical, hematological, and serum chemistry evaluations were within the normal limits on days 1, 7, and 14 after injection of either 0.5 mg kg-1 or 2 mg kg

  4. Evaluation of nanoparticle delivered cisplatin in beagles

    NASA Astrophysics Data System (ADS)

    Feldhaeusser, Brittany; Platt, Simon R.; Marrache, Sean; Kolishetti, Nagesh; Pathak, Rakesh K.; Montgomery, David J.; Reno, Lisa R.; Howerth, Elizabeth; Dhar, Shanta

    2015-08-01

    Intracranial neoplasia is a significant cause of morbidity and mortality in both human and veterinary patients, and is difficult to treat with traditional therapeutic methods. Cisplatin is a platinum (Pt)-containing chemotherapeutic agent approved by the Food and Drug Administration; however, substantial limitations exist for its application in canine brain tumor treatment due to the difficulty in crossing the blood-brain barrier (BBB), development of resistance, and toxicity. A modified Pt(iv)-prodrug of cisplatin, Platin-M, was recently shown to be deliverable to the brain via a biocompatible mitochondria-targeted lipophilic polymeric nanoparticle (NP) that carries the drug across the BBB and to the mitochondria. NP mediated controlled release of Platin-M and subsequent reduction of this prodrug to cisplatin allowed cross-links to be formed with the mitochondrial DNA, which have no nucleotide excision repair system, forcing the overactive cancer cells to undergo apoptosis. Here, we report in vitro effects of targeted Platin-M NPs (T-Platin-M-NPs) in canine glioma and glioblastoma cell lines with results indicating that this targeted NP formulation is more effective than cisplatin. In both the cell lines, T-Platin-M-NP was significantly more efficacious compared to carboplatin, another Pt-based chemotherapy, which is used in the settings of recurrent high-grade glioblastoma. Mitochondrial stress analysis indicated that T-Platin-M-NP is more effective in disrupting the mitochondrial bioenergetics in both the cell types. A 14-day distribution study in healthy adult beagles using a single intravenous injection at 0.5 mg kg-1 (with respect to Platin-M) of T-Platin-M-NPs showed high levels of Pt accumulation in the brain, with negligible amounts in the other analyzed organs. Safety studies in the beagles monitoring physical, hematological, and serum chemistry evaluations were within the normal limits on days 1, 7, and 14 after injection of either 0.5 mg kg-1 or 2 mg kg

  5. Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity.

    PubMed

    Zhu, Jing; Carozzi, Valentina Alda; Reed, Nicole; Mi, Ruifa; Marmiroli, Paola; Cavaletti, Guido; Hoke, Ahmet

    2016-01-01

    Ethoxyquin was recently identified as a neuroprotective compound against toxic neuropathies and efficacy was demonstrated against paclitaxel-induced neurotoxicity in vivo. In this study we examined the efficacy of ethoxyquin in preventing neurotoxicity of cisplatin in rodent models of chemotherapy-induced peripheral neuropathy and explored its mechanism of action. Ethoxyquin prevented neurotoxicity of cisplatin in vitro in a sensory neuronal cell line and primary rat dorsal root ganglion neurons. In vivo, chronic co-administration of ethoxyquin partially abrogated cisplatin-induced behavioral, electrophysiological and morphological abnormalities. Furthermore, ethoxyquin did not interfere with cisplatin's ability to induce tumor cell death in ovarian cancer cell line in vitro and in vivo. Finally, ethoxyquin reduced the levels of two client proteins (SF3B2 and ataxin-2) of a chaperone protein, heat shock protein 90 (Hsp90) when co-administered with cisplatin in vitro. These results implied that the neuroprotective effect of ethoxyquin is mediated through these two client proteins of Hsp90. In fact, reducing levels of SF3B2 in tissue-cultured neurons was effective against neurotoxicity of cisplatin. These findings suggest that ethoxyquin or other compounds that inhibit chaperone activity of Hsp90 and reduce levels of its client protein, SF3B2 may be developed as an adjuvant therapy to prevent neurotoxicity in cisplatin-based chemotherapy protocols. PMID:27350330

  6. PREVENTION OF CISPLATIN-INDUCED NEPHROTOXICITY BY METHIMAZOLE.

    PubMed

    Osman; El-Sayed; El-Demerdash; Al-Hyder; El-Didi; Attia; Hamada

    2000-01-01

    Nephrotoxicity is a dose-limiting factor in the use of cisplatin against solid tumours. Methimazole, an antithyroid drug containing a free SH group, has a nephroprotective potential against chemically-induced nephrotoxicity. We tried to explore the nephrotoxic effect of the experimentally therapeutic dose of cisplatin (7 mg kg(-1), i.p.), particularly on the nuclear level of kidney cells in male albino rats, as well as the possible protective effect of methimazole. Furthermore, the drug interaction regarding the oncolytic effect of cisplatin was examined in Ehrlich ascites carcinoma (EAC)-bearing mice. A single dose of cisplatin caused kidney damage, 6 days after injection, manifested by 219% increase in serum creatinine, 384% increase in blood urea nitrogen and 170% increase in kidney content of lipid peroxides. Kidney DNA showed clear fragmentations detected by gel electrophoresis. However, kidney reduced glutathione was unchanged at that time period. Histological examination of kidney confirmed the toxic effect of cisplatin. Methimazole (40 mg kg(-1), i.p., 30 min before cisplatin injection) significantly protected the kidney from the nephrotoxic effect of cisplatin as judged from the biochemical parameters investigated as well as the histopathological examination. On the other hand, the survival data in EAC-bearing mice treated with both drugs indicated the persistence of an effective cytotoxic action. This study points to a promising use of this combination and necessitates further experimental and clinical studies. 2000 Academic Press@p$hr Copyright 2000 Academic Press. PMID:10712836

  7. Prevention of cisplatin-induced nephrotoxicity by methimazole.

    PubMed

    Osman, A M; El-Sayed, E M; El-Demerdash, E; Al-Hyder, A; El-Didi, M; Attia, A S; Hamada, F M

    2000-01-01

    Nephrotoxicity is a dose-limiting factor in the use of cisplatin against solid tumours. Methimazole, an antithyroid drug containing a free SH group, has a nephroprotective potential against chemically-induced nephrotoxicity. We tried to explore the nephrotoxic effect of the experimentally therapeutic dose of cisplatin (7 mg kg(-1), i.p.), particularly on the nuclear level of kidney cells in male albino rats, as well as the possible protective effect of methimazole. Furthermore, the drug interaction regarding the oncolytic effect of cisplatin was examined in Ehrlich ascites carcinoma (EAC)-bearing mice. A single dose of cisplatin caused kidney damage, 6 days after injection, manifested by 219% increase in serum creatinine, 384% increase in blood urea nitrogen and 170% increase in kidney content of lipid peroxides. Kidney DNA showed clear fragmentations detected by gel electrophoresis. However, kidney reduced glutathione was unchanged at that time period. Histological examination of kidney confirmed the toxic effect of cisplatin. Methimazole (40 mg kg(-1), i.p., 30 min before cisplatin injection) significantly protected the kidney from the nephrotoxic effect of cisplatin as judged from the biochemical parameters investigated as well as the histopathological examination. On the other hand, the survival data in EAC-bearing mice treated with both drugs indicated the persistence of an effective cytotoxic action. This study points to a promising use of this combination and necessitates further experimental and clinical studies. PMID:10600279

  8. New Therapeutic Concept of NAD Redox Balance for Cisplatin Nephrotoxicity

    PubMed Central

    Oh, Gi-Su; Kim, Hyung-Jin; Shen, AiHua; Lee, Su-Bin; Yang, Sei-Hoon; Shim, Hyeok; Cho, Eun-Young; Kwon, Kang-Beom; Kwak, Tae Hwan; So, Hong-Seob

    2016-01-01

    Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors. In addition to its antitumor activity, cisplatin affects normal cells and may induce adverse effects such as ototoxicity, nephrotoxicity, and peripheral neuropathy. Various mechanisms such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and inflammatory responses are closely associated with cisplatin-induced nephrotoxicity; however, the precise mechanism remains unclear. The cofactor nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of cellular energy metabolism and homeostasis. Recent studies have demonstrated associations between disturbance in intracellular NAD+ levels and clinical progression of various diseases through the production of reactive oxygen species and inflammation. Furthermore, we demonstrated that reduction of the intracellular NAD+/NADH ratio is critically involved in cisplatin-induced kidney damage through inflammation and oxidative stress and that increase of the cellular NAD+/NADH ratio suppresses cisplatin-induced kidney damage by modulation of potential damage mediators such as oxidative stress and inflammatory responses. In this review, we describe the role of NAD+ metabolism in cisplatin-induced nephrotoxicity and discuss a potential strategy for the prevention or treatment of cisplatin-induced adverse effects with a particular focus on NAD+-dependent cellular pathways. PMID:26881219

  9. Probe DNA-Cisplatin Interaction with Solid-State Nanopores

    NASA Astrophysics Data System (ADS)

    Zhou, Zhi; Hu, Ying; Li, Wei; Xu, Zhi; Wang, Pengye; Bai, Xuedong; Shan, Xinyan; Lu, Xinghua; Nanopore Collaboration

    2014-03-01

    Understanding the mechanism of DNA-cisplatin interaction is essential for clinical application and novel drug design. As an emerging single-molecule technology, solid-state nanopore has been employed in biomolecule detection and probing DNA-molecule interactions. Herein, we reported a real-time monitoring of DNA-cisplatin interaction by employing solid-state SiN nanopores. The DNA-cisplatin interacting process is clearly classified into three stages by measuring the capture rate of DNA-cisplatin adducts. In the first stage, the negative charged DNA molecules were partially discharged due to the bonding of positive charged cisplatin and forming of mono-adducts. In the second stage, forming of DNA-cisplatin di-adducts with the adjacent bases results in DNA bending and softening. The capture rate increases since the softened bi-adducts experience a lower barrier to thread into the nanopores. In the third stage, complex structures, such as micro-loop, are formed and the DNA-cisplatin adducts are aggregated. The capture rate decreases to zero as the aggregated adduct grows to the size of the pore. The characteristic time of this stage was found to be linear with the diameter of the nanopore and this dynamic process can be described with a second-order reaction model. We are grateful to Laboratory of Microfabrication, Dr. Y. Yao, and Prof. R.C. Yu (Institute of Physics, Chinese Academy of Sciences) for technical assistance.

  10. Pathophysiology of cisplatin-induced acute kidney injury.

    PubMed

    Ozkok, Abdullah; Edelstein, Charles L

    2014-01-01

    Cisplatin and other platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors. A known complication of cisplatin administration is acute kidney injury (AKI). The nephrotoxic effect of cisplatin is cumulative and dose-dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI may result in chronic kidney disease. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, oxidative stress, inflammation, and vascular injury in the kidney. There is predominantly acute tubular necrosis and also apoptosis in the proximal tubules. There is activation of multiple proinflammatory cytokines and infiltration of inflammatory cells in the kidney. Inhibition of the proinflammatory cytokines TNF-α or IL-33 or depletion of CD4+ T cells or mast cells protects against cisplatin-induced AKI. Cisplatin also causes endothelial cell injury. An understanding of the pathogenesis of cisplatin-induced AKI is important for the development of adjunctive therapies to prevent AKI, to lessen the need for dose decrease or drug withdrawal, and to lessen patient morbidity and mortality. PMID:25165721

  11. Failure of Elevating Calcium Induces Oxidative Stress Tolerance and Imparts Cisplatin Resistance in Ovarian Cancer Cells

    PubMed Central

    Ma, Liwei; Wang, Hongjun; Wang, Chunyan; Su, Jing; Xie, Qi; Xu, Lu; Yu, Yang; Liu, Shibing; Li, Songyan; Xu, Ye; Li, Zhixin

    2016-01-01

    Cisplatin is a commonly used chemotherapeutic drug, used for the treatment of malignant ovarian cancer, but acquired resistance limits its application. There is therefore an overwhelming need to understand the mechanism of cisplatin resistance in ovarian cancer, that is, ovarian cancer cells are insensitive to cisplatin treatment. Here, we show that failure of elevating calcium and oxidative stress tolerance play key roles in cisplatin resistance in ovarian cancer cell lines. Cisplatin induces an increase in oxidative stress and alters intracellular Ca2+ concentration, including cytosolic and mitochondrial Ca2+ in cisplatin-sensitive SKOV3 cells, but not in cisplatin-resistant SKOV3/DDP cells. Cisplatin induces mitochondrial damage and triggers the mitochondrial apoptotic pathway in cisplatin-sensitive SKOV3 cells, but rarely in cisplatin-resistant SKOV3/DDP cells. Inhibition of calcium signaling attenuates cisplatin-induced oxidative stress and intracellular Ca2+ overload in cisplatin-sensitive SKOV3 cells. Moreover, in vivo xenograft models of nude mouse, cisplatin significantly reduced the growth rates of tumors originating from SKOV3 cells, but not that of SKOV3/DDP cells. Collectively, our data indicate that failure of calcium up-regulation mediates cisplatin resistance by alleviating oxidative stress in ovarian cancer cells. Our results highlight potential therapeutic strategies to improve cisplatin resistance. PMID:27330840

  12. Systems biology of cisplatin resistance: past, present and future

    PubMed Central

    Galluzzi, L; Vitale, I; Michels, J; Brenner, C; Szabadkai, G; Harel-Bellan, A; Castedo, M; Kroemer, G

    2014-01-01

    The platinum derivative cis-diamminedichloroplatinum(II), best known as cisplatin, is currently employed for the clinical management of patients affected by testicular, ovarian, head and neck, colorectal, bladder and lung cancers. For a long time, the antineoplastic effects of cisplatin have been fully ascribed to its ability to generate unrepairable DNA lesions, hence inducing either a permanent proliferative arrest known as cellular senescence or the mitochondrial pathway of apoptosis. Accumulating evidence now suggests that the cytostatic and cytotoxic activity of cisplatin involves both a nuclear and a cytoplasmic component. Despite the unresolved issues regarding its mechanism of action, the administration of cisplatin is generally associated with high rates of clinical responses. However, in the vast majority of cases, malignant cells exposed to cisplatin activate a multipronged adaptive response that renders them less susceptible to the antiproliferative and cytotoxic effects of the drug, and eventually resume proliferation. Thus, a large fraction of cisplatin-treated patients is destined to experience therapeutic failure and tumor recurrence. Throughout the last four decades great efforts have been devoted to the characterization of the molecular mechanisms whereby neoplastic cells progressively lose their sensitivity to cisplatin. The advent of high-content and high-throughput screening technologies has accelerated the discovery of cell-intrinsic and cell-extrinsic pathways that may be targeted to prevent or reverse cisplatin resistance in cancer patients. Still, the multifactorial and redundant nature of this phenomenon poses a significant barrier against the identification of effective chemosensitization strategies. Here, we discuss recent systems biology studies aimed at deconvoluting the complex circuitries that underpin cisplatin resistance, and how their findings might drive the development of rational approaches to tackle this clinically relevant

  13. Novel orally active epoxyeicosatrienoic acid (EET) analogs attenuate cisplatin nephrotoxicity

    PubMed Central

    Khan, Md. Abdul Hye; Liu, Jing; Kumar, Ganesh; Skapek, Stephen X.; Falck, John R.; Imig, John D.

    2013-01-01

    Nephrotoxicity severely limits the use of the anticancer drug cisplatin. Oxidative stress, inflammation, and endoplasmic reticulum (ER) stress contribute to cisplatin-induced nephrotoxicity. We developed novel orally active epoxyeicosatrienoic acid (EET) analogs and investigated their prophylactic effect in cisplatin-induced nephrotoxicity in rats. Cisplatin-induced nephrotoxicity was manifested by increases in blood urea nitrogen, plasma creatinine, urinary N-acetyl-β-(d)-glucosaminidase activity, kidney injury molecule 1, and histopathology. EET analogs (10 mg/kg/d) attenuated cisplatin-induced nephrotoxicity by reducing these renal injury markers by 40–80% along with a 50–70% reduction in renal tubular cast formation. This attenuated renal injury is associated with reduced oxidative stress, inflammation, and ER stress evident from reduction in related biomarkers and in the renal expression of genes involved in these pathways. Moreover, we demonstrated that the attenuated nephrotoxicity correlated with decreased apoptosis that is associated with 50–90% reduction in Bcl-2 protein family mediated proapoptotic signaling, reduced renal caspase-12 expression, and a 50% reduction in renal caspase-3 activity. We further demonstrated in vitro that the protective activity of EET analogs does not compromise the anticancer effects of cisplatin. Collectively, our data provide evidence that EET analogs attenuate cisplatin-induced nephrotoxicity by reducing oxidative stress, inflammation, ER stress, and apoptosis without affecting the chemotherapeutic effects of cisplatin.—Khan, Md. A. H., Liu, J., Kumar, G., Skapek, S. X., Falck, J. R., Imig, J. D. Novel orally active epoxyeicosatrienoic acid (EET) analogs attenuate cisplatin nephrotoxicity. PMID:23603837

  14. Systems biology of cisplatin resistance: past, present and future.

    PubMed

    Galluzzi, L; Vitale, I; Michels, J; Brenner, C; Szabadkai, G; Harel-Bellan, A; Castedo, M; Kroemer, G

    2014-01-01

    The platinum derivative cis-diamminedichloroplatinum(II), best known as cisplatin, is currently employed for the clinical management of patients affected by testicular, ovarian, head and neck, colorectal, bladder and lung cancers. For a long time, the antineoplastic effects of cisplatin have been fully ascribed to its ability to generate unrepairable DNA lesions, hence inducing either a permanent proliferative arrest known as cellular senescence or the mitochondrial pathway of apoptosis. Accumulating evidence now suggests that the cytostatic and cytotoxic activity of cisplatin involves both a nuclear and a cytoplasmic component. Despite the unresolved issues regarding its mechanism of action, the administration of cisplatin is generally associated with high rates of clinical responses. However, in the vast majority of cases, malignant cells exposed to cisplatin activate a multipronged adaptive response that renders them less susceptible to the antiproliferative and cytotoxic effects of the drug, and eventually resume proliferation. Thus, a large fraction of cisplatin-treated patients is destined to experience therapeutic failure and tumor recurrence. Throughout the last four decades great efforts have been devoted to the characterization of the molecular mechanisms whereby neoplastic cells progressively lose their sensitivity to cisplatin. The advent of high-content and high-throughput screening technologies has accelerated the discovery of cell-intrinsic and cell-extrinsic pathways that may be targeted to prevent or reverse cisplatin resistance in cancer patients. Still, the multifactorial and redundant nature of this phenomenon poses a significant barrier against the identification of effective chemosensitization strategies. Here, we discuss recent systems biology studies aimed at deconvoluting the complex circuitries that underpin cisplatin resistance, and how their findings might drive the development of rational approaches to tackle this clinically relevant

  15. Carnitine deficiency provokes cisplatin-induced hepatotoxicity in rats.

    PubMed

    Al-Majed, Abdulhakeem A

    2007-03-01

    This study investigates whether or not carnitine deficiency is a risk factor and could contribute to cisplatin-induced liver toxicity. A total of 60 adult male Wistar albino rats were divided into six groups. The first three groups were injected intraperitoneally with normal saline, propionyl-l-carnitine (500 mg/kg), and d-carnitine (500 mg/kg), respectively, for 10 successive days. The fourth, fifth and sixth groups were injected intraperitoneally with the same doses of normal saline, propionyl-l-carnitine and d-carnitine, respectively, for 5 successive days before and after a single dose of cisplatin (7 mg/kg). Administration of the standard nephrotoxic dose of cisplatin did not produce any changes in serum alanine transaminase and gamma-glutamyl transferase and no morphological changes in liver tissues. However, it did produce a significant increase in thiobarbituric acid reactive substances and total nitrate/nitrite and a significant decrease in reduced glutathione content in liver tissues. On the other hand, combined treatment with cisplatin and d-carnitine induced a dramatic increase in serum alanine transaminase and gamma-glutamyl transferase, as well as progressive reduction in total carnitine and ATP content in liver tissue. Moreover, histopathological examination of liver tissues confirmed the biochemical data, where cisplatin and d-carnitine combination showed signs of liver injury manifested as focal necro-inflammatory changes and portal inflammation. Interestingly, in carnitine supplemented rats using propionyl-l-carnitine, cisplatin did not produce any biochemical and histopathological changes in liver tissues. In conclusion, data from this study suggest for the first time that (1) carnitine deficiency is a risk factor and could precipitate cisplatin-induced hepatotoxicity, (2) oxidative stress is not the main cause of cisplatin-related hepatotoxicity and (3) propionyl-l-carnitine prevents the development of cisplatin-induced liver injury. PMID

  16. Macrophages increase the resistance of pancreatic adenocarcinoma cells to gemcitabine by upregulating cytidine deaminase

    PubMed Central

    Amit, Moran; Gil, Ziv

    2013-01-01

    Tumor-associated macrophages play a central role in tumor progression and metastasis. Macrophages can also promote the resistance of malignant cells to chemotherapy by stimulating the upregulation of cytidine deaminase, an intracellular enzyme that catabolizes the active form of gemcitabine. Targeting macrophage-dependent chemoresistance may reduce tumor-associated morbidity and mortality. PMID:24498570

  17. S-phase–specific radiosensitization by gemcitabine for therapeutic carbon ion exposure in vitro

    PubMed Central

    Harrabi, Semi B.; Adeberg, Sebastian; Winter, Marcus; Haberer, Thomas; Debus, Jürgen; Weber, Klaus-Josef

    2016-01-01

    Densely ionizing charged particle irradiation offers physical as well as biological advantages compared with photon irradiation. Radiobiological data for the combination of such particle irradiation (i.e. therapeutic carbon ions) with commonly used chemotherapeutics are still limited. Recent in vitro results indicate a general prevalence of additive cytotoxic effects in combined treatments, but an extension of established multimodal treatment regimens with photons to the inclusion of particle therapy needs to evaluate possible peculiarities of using high linear energy transfer (LET) radiation. The present study investigates the effect of combined radiochemotherapy using gemcitabine and high-LET irradiation with therapeutic carbon ions. In particular, the earlier observation of S-phase specific radiosensitization with photon irradiation should be evaluated with carbon ions. In the absence of the drug gemcitabine, carbon ion irradiation produced the typical survival behavior seen with X-rays—increased relative biological efficiency, and depletion of the survival curve's shoulder. By means of serum deprivation and subsequent replenishment, ∼70% S-phase content of the cell population was achieved, and such preparations showed radioresistance in both treatment arms—,photon and carbon ion irradiation. Combined modality treatment with gemcitabine caused significant reduction of clonogenic survival especially for the S-phase cells. WIDR cells exhibited S-phase–specific radioresistance with high-LET irradiation, although this was less pronounced than for X-ray exposure. The combined treatment with therapeutic carbon ions and gemcitabine caused the resistance phenomenon to disappear phenotypically. PMID:26747201

  18. Synergistic antitumor activity of gemcitabine combined with triptolide in pancreatic cancer cells

    PubMed Central

    QIAO, ZHIXIN; HE, MIN; HE, MU; LI, WEIJING; WANG, XUANLIN; WANG, YANBING; KUAI, QIYUAN; LI, CHANGLAN; REN, SUPING; YU, QUN

    2016-01-01

    Pancreatic cancer is a fatal human malignancy associated with an exceptionally poor prognosis. Novel therapeutic strategies are urgently required to treat this disease. In addition to immunosuppressive activity, triptolide possesses strong antitumor activity and synergistically enhances the antitumor activities of conventional chemotherapeutic drugs in preclinical models of pancreatic cancer. The present study investigated the antitumor effects of triptolide in pancreatic cancer cells, either in combination with gemcitabine, or alone. The pancreatic cancer BxPC-3 and PANC-1 cell lines were treated with triptolide, which resulted in time- and dose-dependent growth arrest. When incorporated into a sequential schedule, triptolide synergistically increased gemcitabine-induced cell growth inhibition and apoptosis, in addition to the cooperative regulation of B-cell lymphoma 2 family proteins and loss of mitochondrial membrane potential. Furthermore, triptolide enhanced gemcitabine-induced S phase arrest and DNA double-strand breaks, possibly through checkpoint kinase 1 suppression. The results of the present study suggest that triptolide has therapeutic potential for the treatment of pancreatic cancer, particularly when administered in combination with gemcitabine. PMID:27123146

  19. Synthesis and Cytostatic Evaluation of 4-N-Alkanoyl and 4-N-Alkyl Gemcitabine Analogues

    PubMed Central

    Pulido, Jesse; Sobczak, Adam J.; Balzarini, Jan; Wnuk, Stanislaw F.

    2014-01-01

    Couplings of gemcitabine with the functionalized carboxylic acids (C9-C13) or reactions of 4-N-tosylgemcitabine with the corresponding alkyl amines afforded 4-N-alkanoyl and 4-N-alkyl gemcitabine derivatives. The analogues with a terminal hydroxyl group on the alkyl chain were efficiently fluorinated under conditions that are compatible with protocols for 18F labeling. The 4-N-alkanoylgemcitabines showed potent cytostatic activities in the low nM range against a panel of tumor cell lines while cytotoxicity of the 4-N-alkylgemcitabines were in the low μM range. The cytotoxicity for the 4-N-alkanoylgemcitabine analogues were reduced approximately by two orders of magnitude in the 2′-deoxycytidine kinase (dCK)-deficient CEM/dCK- cell line whereas cytotoxicity of the 4-N-alkylgemcitabines were only 2-5 times lower. None of the compounds acted as efficient substrates for cytosolic dCK, and therefore, the 4-N-alkanoyl analogues need to be converted first to gemcitabine to display a significant cytostatic potential, while 4-N-alkyl derivatives attain the modest activity without “measurable” conversion to gemcitabine. PMID:24341356

  20. hENT1 expression is predictive of gemcitabine outcome in pancreatic cancer: a systematic review.

    PubMed

    Nordh, Stina; Ansari, Daniel; Andersson, Roland

    2014-07-14

    High human equilibrative nucleoside transporter 1 (hENT1)-expression has shown a survival benefit in pancreatic cancer patients treated with gemcitabine in several studies. The aim of this systematic review was to summarize the results and try to assess the predictive value of hENT1 for determining gemcitabine outcome in pancreatic cancer. Relevant articles were obtained from PubMed, Embase and Cochrane databases. Studies evaluating hENT1-expression in pancreatic tumor cells from patients treated with gemcitabine were selected. Outcome measures were overall survival, disease-free survival (DFS), toxicity and response rate. The database searches identified 10 studies that met the eligibility criteria, and a total of 855 patients were included. Nine of 10 studies showed a statistically significant longer overall survival in univariate analyses in patients with high hENT1-expression compared to those with low expression. In the 7 studies that reported DFS as an outcome measure, 6 had statistically longer DFS in the high hENT1 groups. Both toxicity and response rate were reported in only 2 articles and it was therefore hard to draw any major conclusions. This review provides evidence that hENT1 is a predictive marker for pancreatic cancer patients treated with gemcitabine. Some limitations of the review have to be taken into consideration, the majority of the included studies had a retrospective design, and there was no standardized scoring protocol for hENT1-expression. PMID:25024604

  1. Second-line therapy after nab-paclitaxel plus gemcitabine or after gemcitabine for patients with metastatic pancreatic cancer

    PubMed Central

    Chiorean, E Gabriela; Von Hoff, Daniel D; Tabernero, Josep; El-Maraghi, Robert; Ma, Wen Wee; Reni, Michele; Harris, Marion; Whorf, Robert; Liu, Helen; Li, Jack Shiansong; Manax, Victoria; Romano, Alfredo; Lu, Brian; Goldstein, David

    2016-01-01

    Background: This exploratory analysis evaluated second-line (2L) therapy for metastatic pancreatic cancer in a large phase 3 trial (MPACT). Methods: Patients who received first-line (1L) nab-paclitaxel+gemcitabine (nab-P+Gem) or Gem were assessed for survival based on 2L treatment received. Multivariate analyses tested influence of treatment effect and prognostic factors on survival. Results: The majority of 2L treatments (267 out of 347, 77%) contained a fluoropyrimidine (5-fluorouracil or capecitabine). Median total survival (1L randomisation to death) for patients who received 2L treatment after 1L nab-P+Gem vs Gem alone was 12.8 vs 9.9 months (P=0.015). Median total survival for patients with a fluoropyrimidine-containing 2L therapy after nab-P+Gem vs Gem was 13.5 vs 9.5 months (P=0.012). Median 2L survival (duration from start of 2L therapy to death) was 5.3 vs 4.5 months for nab-P+Gem vs Gem, respectively (P=0.886). Factors significantly associated with longer post-1L survival by multivariate analyses included 1L nab-P+Gem, receiving 2L treatment, longer 1L progression-free survival, and Karnofsky performance status⩾70 and neutrophil-to-lymphocyte ratio⩽5 at the end of 1L treatment. Conclusions: These findings support the use of 2L therapy for patients with metastatic pancreatic cancer. Fluoropyrimidine-containing treatment after 1L nab-P+Gem is an active regimen with significant clinical effect. PMID:27351217

  2. Probenecid Sensitizes Neuroblastoma Cancer Stem Cells to Cisplatin.

    PubMed

    Campos-Arroyo, Denise; Maldonado, Vilma; Bahena, Ivan; Quintanar, Valeria; Patiño, Nelly; Carlos Martinez-Lazcano, Juan; Melendez-Zajgla, Jorge

    2016-03-15

    We used both in vitro cultures of neuroblastoma cell lines and nude-mice xenotransplants to explore the effects of co-administration of cisplatin and probenecid. Probenecid sensitized neuroblastoma cells, including tumor cells with stem features, to the effects of cisplatin, both in vitro and in vivo. This effect was mediated by an increase in the apoptotic cell death and a concomitant decrease in cell proliferation. This effect is accompanied by modulation of the mRNA and protein of the drug efflux transporters MDR1, MRP2, and BCRP. The co-administration of probenecid with cisplatin should be explored as a possible therapeutic strategy. PMID:26963048

  3. Effect of ATM and HDAC Inhibition on Etoposide-Induced DNA Damage in Porcine Early Preimplantation Embryos

    PubMed Central

    Wang, HaiYang; Luo, YiBo; Lin, ZiLi; Lee, In-Won; Kwon, Jeongwoo; Cui, Xiang-Shun; Kim, Nam-Hyung

    2015-01-01

    Oocyte maturation and embryonic development are sensitive to DNA damage. Compared with somatic cells or oocytes, little is known about the response to DNA damage in early preimplantation embryos. In this study, we examined DNA damage checkpoints and DNA repair mechanisms in parthenogenetic preimplantation porcine embryos. We found that most of the etoposide-treated embryos showed delay in cleavage and ceased development before the blastocyst stage. In DNA-damaged embryos, the earliest positive TUNEL signals were detected on Day 5 of in vitro culture. Caffeine, which is an ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3-related protein) kinase inhibitor, and KU55933, which is an ATM kinase inhibitor, were equally effective in rescuing the etoposide-induced cell-cycle blocks. This indicates that ATM plays a central role in the regulation of the checkpoint mechanisms. Treating the embryos with histone deacetylase inhibitors (HDACi) increased embryonic development and reduced etoposide-induced double-strand breaks (DSBs). The mRNA expression of genes involved in non-homologous end-joining (NHEJ) or homologous recombination (HR) pathways for DSB repair was reduced upon HDACi treatment in 5-day-old embryos. Furthermore, HDACi treatment increased the expression levels of pluripotency-related genes (OCT4, SOX2 and NANOG) and decreased the expression levels of apoptosis-related genes (CASP3 and BAX). These results indicate that early embryonic cleavage and development are disturbed by etoposide-induced DNA damage. ATMi (caffeine or KU55933) treatment bypasses the checkpoint while HDACi treatment improves the efficiency of DSB repair to increase the cleavage and blastocyst rate in porcine early preimplantation embryos. PMID:26556501

  4. Etoposide encapsulation in surface-modified poly(lactide-co-glycolide) nanoparticles strongly enhances glioma antitumor efficiency.

    PubMed

    Callewaert, Maïté; Dukic, Sylvain; Van Gulick, Laurence; Vittier, Mélanie; Gafa, Valérie; Andry, Marie-Christine; Molinari, Michaël; Roullin, V Gaëlle

    2013-05-01

    Etoposide (VP-16) is a hydrophobic anticancer agent inhibiting Topoisomerase II, commonly used in pediatric brain chemotherapeutic schemes as mildly toxic. Unfortunately, despite its appropriate solubilization in vehicle solvents, its poor bioavailability and limited passage of the blood-brain barrier concur to disappointing results requiring the development of new delivery system forms. In this study, etoposide formulated as a parenteral injectable solution (Teva®) was loaded into all-biocompatible poly(lactide-co-glycolide) (PLGA) or PLGA/P188-blended nanoparticles (size 110-130 nm) using a fully biocompatible nanoprecipitation technique. The presence of coprecipitated P188 on encapsulation efficacies and in vitro drug release was investigated. Drug encapsulation was determined using HPLC. Inflammatory response was checked by FACS analysis on human monocytes. Cytotoxic activity of the various simple (Teva®) or double (Teva®-loaded NPs) formulations was studied on the murine C6 and F98 cell lines. Obtained results suggest that, although noninflammatory neither nontoxic by themselves, the use of PLGA and PLGA/P188 nanoencapsulations over pre-existing etoposide formulation could induce a greatly improved cytotoxic activity. This approach demonstrated a promising perspective for parenteral delivery of VP16 and potential development of a therapeutic entity. PMID:23065812

  5. A Randomized Study on Postrelapse Disease-Free Survival with Adjuvant Mistletoe versus Oral Etoposide in Osteosarcoma Patients.

    PubMed

    Longhi, Alessandra; Reif, Marcus; Mariani, Erminia; Ferrari, Stefano

    2014-01-01

    Background. Osteosarcoma is a highly malignant bone tumour. After the second relapse, the 12-month postrelapse disease-free survival (PRDFS) rate decreases below 20%. Oral Etoposide is often used in clinical practice after surgery as an "adjuvant" outside any protocol and with only limited evidence of improved survival. Viscum album fermentatum Pini (Viscum) is an extract of mistletoe plants grown on pine trees for subcutaneous (sc) injection with immunomodulatory activity. Methods. Encouraged by preliminary findings, we conducted a study where osteosarcoma patients free from disease after second metastatic relapse were randomly assigned to Viscum sc or Oral Etoposide. Our goal was to compare 12-month PRDFS rates with an equivalent historical control group. Results. Twenty patients have been enrolled, with a median age of 34 years (range 11-65) and a median follow-up time of 38.5 months (3-73). The median PRDSF is currently 4 months (1-47) in the Etoposide and 39 months (2-73) in the Viscum group. Patients getting Viscum reported a higher quality of life due to lower toxicity. Conclusion. Viscum shows promise as adjuvant treatment in prolonging PRDFS after second relapse in osteosarcoma patients. A larger study is required to conclusively determine efficacy and immunomodulatory mechanisms of Viscum therapy in osteosarcoma patients. PMID:24803944

  6. Characterization of the ATPase activity of topoisomerase II from Leishmania donovani and identification of residues conferring resistance to etoposide

    PubMed Central

    2005-01-01

    We have cloned and expressed the 43 kDa N-terminal domain of Leishmania donovani topoisomerase II. This protein has an intrinsic ATPase activity and obeys Michaelis–Menten kinetics. Cross-linking studies indicate that the N-terminal domain exists as a dimer both in the presence and absence of nucleotides. Etoposide, an effective antitumour drug, traps eukaryotic DNA topoisomerase II in a covalent complex with DNA. In the present study, we report for the first time that etoposide inhibits the ATPase activity of the recombinant N-terminal domain of L. donovani topoisomerase II. We have modelled the structure of this 43 kDa protein and performed molecular docking analysis with the drug. Mutagenesis of critical amino acids in the vicinity of the ligand-binding pocket reveals less efficient inhibition of the ATPase activity of the enzyme by etoposide. Taken together, these results provide an insight for the development of newer therapeutic agents with specific selectivity. PMID:15901238

  7. Depletion of tyrosyl DNA phosphodiesterase 2 activity enhances etoposide-mediated double-strand break formation and cell killing.

    PubMed

    Kont, Yasemin Saygideger; Dutta, Arijit; Mallisetty, Apurva; Mathew, Jeena; Minas, Tsion; Kraus, Christina; Dhopeshwarkar, Priyanka; Kallakury, Bhaskar; Mitra, Sankar; Üren, Aykut; Adhikari, Sanjay

    2016-07-01

    DNA topoisomerase 2 (Top2) poisons, including common anticancer drugs etoposide and doxorubicin kill cancer cells by stabilizing covalent Top2-tyrosyl-DNA 5'-phosphodiester adducts and DNA double-strand breaks (DSBs). Proteolytic degradation of the covalently attached Top2 leaves a 5'-tyrosylated blocked termini which is removed by tyrosyl DNA phosphodiesterase 2 (TDP2), prior to DSB repair through non-homologous end joining (NHEJ). Thus, TDP2 confers resistance of tumor cells to Top2-poisons by repairing such covalent DNA-protein adducts, and its pharmacological inhibition could enhance the efficacy of Top2-poisons. We discovered NSC111041, a selective inhibitor of TDP2, by optimizing a high throughput screening (HTS) assay for TDP2's 5'-tyrosyl phosphodiesterase activity and subsequent validation studies. We found that NSC111041 inhibits TDP2's binding to DNA without getting intercalated into DNA and enhanced etoposide's cytotoxicity synergistically in TDP2-expressing cells but not in TDP2 depleted cells. Furthermore, NSC111041 enhanced formation of etoposide-induced γ-H2AX foci presumably by affecting DSB repair. Immuno-histochemical analysis showed higher TDP2 expression in a sub-set of different type of tumor tissues. These findings underscore the feasibility of clinical use of suitable TDP2 inhibitors in adjuvant therapy with Top2-poisons for a sub-set of cancer patients with high TDP2 expression. PMID:27235629

  8. A Randomized Study on Postrelapse Disease-Free Survival with Adjuvant Mistletoe versus Oral Etoposide in Osteosarcoma Patients

    PubMed Central

    Longhi, Alessandra; Reif, Marcus; Mariani, Erminia; Ferrari, Stefano

    2014-01-01

    Background. Osteosarcoma is a highly malignant bone tumour. After the second relapse, the 12-month postrelapse disease-free survival (PRDFS) rate decreases below 20%. Oral Etoposide is often used in clinical practice after surgery as an “adjuvant” outside any protocol and with only limited evidence of improved survival. Viscum album fermentatum Pini (Viscum) is an extract of mistletoe plants grown on pine trees for subcutaneous (sc) injection with immunomodulatory activity. Methods. Encouraged by preliminary findings, we conducted a study where osteosarcoma patients free from disease after second metastatic relapse were randomly assigned to Viscum sc or Oral Etoposide. Our goal was to compare 12-month PRDFS rates with an equivalent historical control group. Results. Twenty patients have been enrolled, with a median age of 34 years (range 11–65) and a median follow-up time of 38.5 months (3–73). The median PRDSF is currently 4 months (1–47) in the Etoposide and 39 months (2–73) in the Viscum group. Patients getting Viscum reported a higher quality of life due to lower toxicity. Conclusion. Viscum shows promise as adjuvant treatment in prolonging PRDFS after second relapse in osteosarcoma patients. A larger study is required to conclusively determine efficacy and immunomodulatory mechanisms of Viscum therapy in osteosarcoma patients. PMID:24803944

  9. Uptake of Etoposide in CT-26 Cells of Colorectal Cancer Using Folate Targeted Dextran Stearate Polymeric Micelles

    PubMed Central

    Varshosaz, Jaleh; Hassanzadeh, Farshid; Sadeghi-Aliabadi, Hojjat; Firozian, Farzin

    2014-01-01

    Targeted drug delivery using folate receptors is one of the most interesting chemotherapeutic research areas over the past few years. A novel folate targeted copolymer was synthesized using dextran stearate coupled to folic acid. FT-IR and NMR spectroscopy were used to confirm successful conjugation. Micelles prepared using this copolymer were characterized for their particle size, zeta potential, critical micelle concentration (CMC), drug loading capacity, and release efficiency. Cytotoxicity and cellular uptake of the micelles were estimated using CT-26 colorectal carcinoma cell line. FT-IR and NMR spectroscopy confirmed production of folate grafted dextran stearate copolymer. Low CMC value indicates that the copolymers are suitable for preparation of stable micelles useful in parenteral dosage forms. Particle size and zeta potential of the targeted nanoparticles were 105.5 ± 2.0 nm and −21.2 mV, respectively. IC50 of etoposide loaded in folate grafted dextran stearate enhanced about 20-fold compared to the pure drug (0.49 ± 0.11 μg/mL versus 9.41 ± 0.52 μg/mL). It seems that etoposide loaded in micelles of folate grafted dextran stearate copolymer is promising in reducing drug resistance of colorectal cancer by boosting etoposide cellular uptake. PMID:24689050

  10. Acyl-CoA synthetase as a cancer survival factor: its inhibition enhances the efficacy of etoposide.

    PubMed

    Mashima, Tetsuo; Sato, Shigeo; Okabe, Sachiko; Miyata, Satoshi; Matsuura, Masaaki; Sugimoto, Yoshikazu; Tsuruo, Takashi; Seimiya, Hiroyuki

    2009-08-01

    Lipid metabolism is often elevated in cancer cells and plays an important role in their growth and malignancy. Acyl-CoA synthetase (ACS), which converts long-chain fatty acids to acyl-CoA, is overexpressed in various types of cancer. However, the role of ACS in cancer remains unknown. Here, we found that ACS enzyme activity is required for cancer cell survival. Namely, the ACS inhibitor Triacsin c induced massive apoptosis in glioma cells while this cell death was completely suppressed by overexpression of ACSL5, the Triacsin c-resistant ACS isozyme, but not by overexpression of a catalytically inactive ACSL5 mutant. ACS inhibition by Triacsin c markedly potentiated the Bax-induced intrinsic apoptotic pathway by promoting cytochrome c release and subsequent caspase activation. These effects were abrogated by ACSL5 overexpression. Correspondingly, ACS inhibition synergistically potentiated the glioma cell death induced by etoposide, a well-known activator of apoptosis. Furthermore, in a nude mouse xenograft model, Triacsin c at a non-toxic dose enhanced the antitumor efficacy of a low-dose chemotherapy with etoposide. These results indicate that ACS is an apoptosis suppressor and that ACS inhibition could be a rational strategy to amplify the antitumor effect of etoposide. PMID:19459852

  11. Transarterial Chemoembolization Using Cisplatin Powder in a Rabbit Model of Liver Cancer

    SciTech Connect

    Morimoto, Kengo Sakaguchi, Hiroshi; Tanaka, Toshihiro; Yamamoto, Kiyosei; Anai, Hiroshi; Hayashi, Takayuki; Satake, Mitsuo; Kichikawa, Kimihiko

    2008-09-15

    The purpose of this study was to investigate the pharmacological advantages of transarterial chemoembolization (TACE) with cisplatin powder for hypervascular hepatic tumors in animal experiments. VX2 tumors were transplanted to the livers of nine rabbits. Cisplatin (1 mg/kg) was infused into the proper hepatic artery. In the cisplatin-HAI group, cisplatin solution was infused. In the cisplatin-GS-TACE group, after infusion of cisplatin solution, gelatin sponge particles were used for embolization. In the cisplatin-Lp-TACE group, after infusion of a cisplatin powder and lipiodol (10 mg/ml) suspension, gelatin sponge particles were used for embolization. Before and after administration, platinum concentrations in plasma were measured. Using liver specimens that were excised 60 min after infusion, platinum concentrations in tumorous and nontumorous liver tissues were measured. The mean platinum concentration in tumorous tissue was 0.88 {mu}g/ml for the cisplatin-HAI group, 1.23 {mu}g/ml for the cisplatin-GS-TACE group, and 12.65 {mu}g/ml for the cisplatin-Lp-TACE group. The platinum concentration for the cisplatin-Lp-TACE group was significantly higher than that for the cisplatin-HAI group (p = 0.004) and the cisplatin-GS-TAE group (p = 0.004). The mean platinum concentration in nontumorous liver tissue was 0.98 {mu}g/ml for the cisplatin-HAI group, 1.13 {mu}g/ml for the cisplatin-GS-TACE group, and 1.09 {mu}g/ml for the cisplatin-Lp-TACE group; no significant differences were seen. At both 5 and 10 min after infusion, the platinum concentrations for the cisplatin-Lp-TACE group were lower than those for the other two groups. The present results suggest that TACE using cisplatin powder/lipiodol suspension and gelatin sponge for hypervascular hepatic tumors has a number of pharmacological advantages.

  12. Downregulation of deoxycytidine kinase in cytarabine-resistant mantle cell lymphoma cells confers cross-resistance to nucleoside analogs gemcitabine, fludarabine and cladribine, but not to other classes of anti-lymphoma agents

    PubMed Central

    2014-01-01

    Background Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma associated with poor prognosis. Implementation of high-dose cytarabine (araC) into induction therapy became standard-of-care for all newly diagnosed younger MCL patients. However, many patients relapse even after araC-based regimen. Molecular mechanisms responsible for araC resistance in MCL are unknown and optimal treatment strategy for relapsed/refractory MCL patients remains elusive. Methods Five araC-resistant (R) clones were derived by long-term culture of five MCL cell lines (CTRL) with increasing doses of araC up to 50 microM. Illumina BeadChip and 2-DE proteomic analysis were used to identify gene and protein expression changes associated with araC resistance in MCL. In vitro cytotoxicity assays and experimental therapy of MCL xenografts in immunodeficient mice were used to analyze their relative responsiveness to a set of clinically used anti-MCL drugs. Primary MCL samples were obtained from patients at diagnosis and after failure of araC-based therapies. Results Marked downregulation of deoxycytidine-kinase (DCK) mRNA and protein expression was identified as the single most important molecular event associated with araC-resistance in all tested MCL cell lines and in 50% primary MCL samples. All R clones were highly (20-1000x) cross-resistant to all tested nucleoside analogs including gemcitabine, fludarabine and cladribine. In vitro sensitivity of R clones to other classes of clinically used anti-MCL agents including genotoxic drugs (cisplatin, doxorubicin, bendamustine) and targeted agents (bortezomib, temsirolimus, rituximab) remained unaffected, or was even increased (ibrutinib). Experimental therapy of immunodeficient mice confirmed the anticipated loss of anti-tumor activity (as determined by overall survival) of the nucleoside analogs gemcitabine and fludarabine in mice transplanted with R clone compared to mice transplanted with CTRL cells, while the anti

  13. Bitter melon juice targets molecular mechanisms underlying gemcitabine resistance in pancreatic cancer cells

    PubMed Central

    SOMASAGARA, RANGANATHA R.; DEEP, GAGAN; SHROTRIYA, SANGEETA; PATEL, MANISHA; AGARWAL, CHAPLA; AGARWAL, RAJESH

    2015-01-01

    Pancreatic cancer (PanC) is one of the most lethal malignancies, and resistance towards gemcitabine, the front-line chemotherapy, is the main cause for dismal rate of survival in PanC patients; overcoming this resistance remains a major challenge to treat this deadly malignancy. Whereas several molecular mechanisms are known for gemcitabine resistance in PanC cells, altered metabolism and bioenergetics are not yet studied. Here, we compared metabolic and bioenergetic functions between gemcitabine-resistant (GR) and gemcitabine-sensitive (GS) PanC cells and underlying molecular mechanisms, together with efficacy of a natural agent bitter melon juice (BMJ). GR PanC cells showed distinct morphological features including spindle-shaped morphology and a decrease in E-cadherin expression. GR cells also showed higher ATP production with an increase in oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Molecular studies showed higher expression of glucose transporters (GLUT1 and 4) suggesting an increase in glucose uptake by GR cells. Importantly, GR cells showed a significant increase in Akt and ERK1/2 phosphorylation and their inhibition decreased cell viability, suggesting their role in survival and drug resistance of these cells. Recently, we reported strong efficacy of BMJ against a panel of GS cells in culture and nude mice, which we expanded here and found that BMJ was also effective in decreasing both Akt and ERK1/2 phosphorylation and viability of GR PanC cells. Overall, we have identified novel mechanisms of gemcitabine resistance in PanC cells which are targeted by BMJ. Considering the short survival in PanC patients, our findings could have high translational potential in controlling this deadly malignancy. PMID:25672620

  14. Phase I study of conformal radiotherapy with concurrent gemcitabine in locally advanced bladder cancer

    SciTech Connect

    Sangar, Vijay K.; McBain, Catherine A.; Lyons, Jeanette; Ramani, Vijay; Logue, John; Wylie, James; Clarke, Noel W.; Cowan, Richard A. . E-mail: richard.cowan@christie-tr.nwest.nhs.uk

    2005-02-01

    Purpose: A prospective phase I trial was conducted to determine the maximal tolerated dose of gemcitabine given once weekly during hypofractionated conformal radiotherapy to patients with locally advanced transitional cell carcinoma of the bladder. Eight male patients, median age 69 years, with Stage T2 (n = 4) or T3 (n = 4) N0M0, were enrolled in cohorts of 3. Treatment comprised conformal radiotherapy (52.5 Gy in 20 fractions) within 4 weeks, with concurrent gemcitabine once weekly for four cycles. The weekly gemcitabine dose was escalated from 100 mg/m{sup 2} in increments of 50 mg/m{sup 2} per cohort. Dose-limiting toxicity was defined as any acute Radiation Therapy Oncology Group (RTOG) toxicity Grade 3 or greater arising in >1 of 3 patients in each cohort. Tumor response was assessed cystoscopically and radiologically at 3 months. Results: All 8 patients completed radiotherapy, and 6 of 8 completed chemoradiotherapy. No acute toxicity greater than RTOG Grade 1 was seen with gemcitabine at 100 mg/m{sup 2}. Dose-limiting toxicity was observed at 150 mg/m{sup 2} with Grade 3 toxicity seen in 2 of 2 patients (one bladder, one bowel). An additional 3 patients received 100 mg/m{sup 2} with minimal toxicity. No hematologic toxicity was encountered. A complete response was seen in 7 (87.5%) of 8 patients, all of whom were disease free at a median follow-up of 19.5 months (range, 14-23 months). No late toxicity (greater than RTOG Grade 0) has been observed. Conclusion: The maximal tolerated dose for gemcitabine given once weekly with concurrent hypofractionated conformal bladder radiotherapy was 150 mg/m{sup 2}, with a maximal recommended dose of 100 mg/m{sup 2}. This dose regimen has now entered Phase II clinical trials.

  15. Derived neutrophil/lymphocyte ratio predicts gemcitabine therapy outcome in unresectable pancreatic cancer

    PubMed Central

    SUZUKI, REI; TAKAGI, TADAYUKI; HIKICHI, TAKUTO; KONNO, NAOKI; SUGIMOTO, MITSURU; WATANABE, KO; NAKAMURA, JUN; WARAGAI, YUICHI; KIKUCHI, HITOMI; TAKASUMI, MIKA; WATANABE, HIROSHI; OHIRA, HIROMASA

    2016-01-01

    As gemcitabine is a key anti-tumor agent for unresectable pancreatic ductal adenocarcinoma (PDAC), it is important to predict the outcomes of gemcitabine chemotherapy. The present study aimed to confirm whether the derived neutrophil-to-lymphocyte ratio (dNLR) is able to predict chemotherapy outcomes. To elucidate the role of dNLR in patients that underwent chemotherapy, the current study evaluated clinicopathological variables in 31 patients with unresectable PDAC treated with gemcitabine. The correlation between clinicopathological variables, and progression-free survival (PFS) and overall survival (OS) time were investigated. Univariate analysis revealed that there were no significant differences in PFS and OS as a function of age (<65 vs. ≥65 years), gender, tumor location (pancreas head vs. body/tail), tumor diameter (<23 vs. ≥23 mm) or serum carbohydrate antigen 19–9 concentration level (<3,800 vs. ≥3,800 U/ml). However, disease stage (locally advanced vs. metastatic) and the dNLR (<2.5 vs. ≥2.5) significantly affected PFS and OS. Multivariate analysis subsequently revealed that a dNLR of ≥2.5 was an independent prognostic factor for poor PFS (P=0.003) and OS (P=0.026). In conclusion, data from the present study suggests that the pre-treatment dNLR is an independent prognostic factor to predict PFS and OS in patients with unresectable PDAC treated with gemcitabine. This indicates that dNLR has a potential role in stratifying patients that may benefit from gemcitabine therapy. PMID:27123132

  16. Bitter melon juice targets molecular mechanisms underlying gemcitabine resistance in pancreatic cancer cells.

    PubMed

    Somasagara, Ranganatha R; Deep, Gagan; Shrotriya, Sangeeta; Patel, Manisha; Agarwal, Chapla; Agarwal, Rajesh

    2015-04-01

    Pancreatic cancer (PanC) is one of the most lethal malignancies, and resistance towards gemcitabine, the front-line chemotherapy, is the main cause for dismal rate of survival in PanC patients; overcoming this resistance remains a major challenge to treat this deadly malignancy. Whereas several molecular mechanisms are known for gemcitabine resistance in PanC cells, altered metabolism and bioenergetics are not yet studied. Here, we compared metabolic and bioenergetic functions between gemcitabine-resistant (GR) and gemcitabine-sensitive (GS) PanC cells and underlying molecular mechanisms, together with efficacy of a natural agent bitter melon juice (BMJ). GR PanC cells showed distinct morphological features including spindle-shaped morphology and a decrease in E-cadherin expression. GR cells also showed higher ATP production with an increase in oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Molecular studies showed higher expression of glucose transporters (GLUT1 and 4) suggesting an increase in glucose uptake by GR cells. Importantly, GR cells showed a significant increase in Akt and ERK1/2 phosphorylation and their inhibition decreased cell viability, suggesting their role in survival and drug resistance of these cells. Recently, we reported strong efficacy of BMJ against a panel of GS cells in culture and nude mice, which we expanded here and found that BMJ was also effective in decreasing both Akt and ERK1/2 phosphorylation and viability of GR PanC cells. Overall, we have identified novel mechanisms of gemcitabine resistance in PanC cells which are targeted by BMJ. Considering the short survival in PanC patients, our findings could have high translational potential in controlling this deadly malignancy. PMID:25672620

  17. Conjugation of Cisplatin Analogues and Cyclooxygenase Inhibitors to Overcome Cisplatin Resistance

    PubMed Central

    Neumann, Wilma; Crews, Brenda C.; Sárosi, Menyhárt B.; Daniel, Cristina M.; Ghebreselasie, Kebreab; Scholz, Matthias S.; Marnett, Lawrence J.

    2015-01-01

    Cyclooxygenase (COX) is an enzyme involved in tumorigenesis and is associated with tumor cell resistance against platinum-based antitumor drugs. Cisplatin analogues were conjugated with COX inhibitors (indomethacin, ibuprofen) to study the synergistic effects that were previously observed in combination treatments. The conjugates ensure concerted transport of both drugs into cells, and subsequent intracellular cleavage enables a dual-action mode. Whereas the platinum(II) complexes showed cytotoxicities similar to those of cisplatin, the platinum(IV) conjugates revealed highly increased cytotoxic activities and were able to completely overcome cisplatin-related resistance. Although some of the complexes are potent COX inhibitors, the conjugates appear to execute their cytotoxic action via COX-independent mechanisms. Instead, the increased lipophilicity and kinetic inertness of the conjugates seem to facilitate cellular accumulation of the platinum drugs and thus improve the efficacy of the antitumor agents. These conjugates are important tools for the elucidation of the direct influence of COX inhibitors on platinum-based anticancer drugs in tumor cells. PMID:25318459

  18. Adult medulloblastoma: multiagent chemotherapy with cisplatinum and etoposide: a single institutional experience.

    PubMed

    Silvani, A; Gaviani, P; Lamperti, E; Botturi, A; Dimeco, F; Franzini, A; Ferroli, P; Fariselli, L; Milanesi, I; Erbetta, A; Pollo, B; Salmaggi, A

    2012-02-01

    In 1991, a prospective phase II trial was initiated to evaluate the efficacy of treatment for adults with medulloblastoma (MB). After surgery, patients were staged with a neuroradiologic examination of the brain and neuroaxis and by cerebrospinal fluid cytology. All patients received three cycles of upfront cisplatinum (cisplatinum) and etoposide (VP16) chemotherapy followed by cranio-spinal radiation therapy. The current article reports on the long-term results from that trial. After a median follow-up of 14.9 years, among a total of 28 adults with MB, the overall progression-free survival and overall survival (OS) rates at 5 years were 57.6 and 80%, respectively. The median OS for the whole group of patients was 11.3 years. The observed toxicity was mainly hematological, with leukopenia and thrombocytopenia (16% of grades 3 and 4). In summary, in our small series of patients, the role of combination administration of CDDP + VP16 started before the initiation of radiotherapy in reducing recurrences, particularly distant recurrences, remains unclear. To know whether adding chemotherapy to craniospinal radiation in adult therapy increases relapse-free and overall survival, we must await the results of a larger randomized controlled clinical trial. PMID:21874383

  19. Chloroquine alleviates etoposide-induced centrosome amplification by inhibiting CDK2 in adrenocortical tumor cells

    PubMed Central

    Chen, T-Y; Syu, J-S; Lin, T-C; Cheng, H-l; Lu, F-l; Wang, C-Y

    2015-01-01

    The antitumor drug etoposide (ETO) is widely used in treating several cancers, including adrenocortical tumor (ACT). However, when used at sublethal doses, tumor cells still survive and are more susceptible to the recurring tumor due to centrosome amplification. Here, we checked the effect of sublethal dose of ETO in ACT cells. Sublethal dose of ETO treatment did not induce cell death but arrested the ACT cells in G2/M phase. This resulted in centrosome amplification and aberrant mitotic spindle formation leading to genomic instability and cellular senescence. Under such conditions, Chk2, cyclin A/CDK2 and ERK1/2 were aberrantly activated. Pharmacological inactivation of Chk2, CDK2 or ERK1/2 or depletion of CDK2 or Chk2 inhibited the centrosome amplification in ETO-treated ACT cells. In addition, autophagy was activated by ETO and was required for ACT cell survival. Chloroquine, the autophagy inhibitor, reduced ACT cell growth and inhibited ETO-induced centrosome amplification. Chloroquine alleviated CDK2 and ERK, but not Chk2, activation and thus inhibited centrosome amplification in either ETO- or hydroxyurea-treated ACT cells. In addition, chloroquine also inhibited centrosome amplification in osteosarcoma U2OS cell lines when treated with ETO or hydroxyurea. In summary, we have demonstrated that chloroquine inhibited ACT cell growth and alleviated DNA damage-induced centrosome amplification by inhibiting CDK2 and ERK activity, thus preventing genomic instability and recurrence of ACT. PMID:26690546

  20. Electrochemical sensing of etoposide using carbon quantum dot modified glassy carbon electrode.

    PubMed

    Nguyen, Hoai Viet; Richtera, Lukas; Moulick, Amitava; Xhaxhiu, Kledi; Kudr, Jiri; Cernei, Natalia; Polanska, Hana; Heger, Zbynek; Masarik, Michal; Kopel, Pavel; Stiborova, Marie; Eckschlager, Tomas; Adam, Vojtech; Kizek, Rene

    2016-04-25

    In this study, enhancement of the electrochemical signals of etoposide (ETO) measured by differential pulse voltammetry (DPV) by modifying a glassy carbon electrode (GCE) with carbon quantum dots (CQDs) is demonstrated. In comparison with a bare GCE, the modified GCE exhibited a higher sensitivity towards electrochemical detection of ETO. The lowest limit of detection was observed to be 5 nM ETO. Furthermore, scanning electron microscopy (SEM), fluorescence microscopy (FM), and electrochemical impedance spectroscopy (EIS) were employed for the further study of the working electrode surface after the modification with CQDs. Finally, the GCE modified with CQDs under optimized conditions was used to analyse real samples of ETO in the prostate cancer cell line PC3. After different incubation times (1, 3, 6, 9, 12, 18 and 24 h), these samples were then prepared prior to electrochemical detection by the GCE modified with CQDs. High performance liquid chromatography with an electrochemical detection method was employed to verify the results from the GCE modified with CQDs. PMID:26882954

  1. The in vitro sustained release profile and antitumor effect of etoposide-layered double hydroxide nanohybrids.

    PubMed

    Qin, Lili; Wang, Mei; Zhu, Rongrong; You, Songhui; Zhou, Ping; Wang, Shilong

    2013-01-01

    Magnesium-aluminum layered double hydroxides intercalated with antitumor drug etoposide (VP16) were prepared for the first time using a two-step procedure. The X-ray powder diffraction data suggested the intercalation of VP16 into layers with the increased basal spacing from 0.84-1.18 nm was successful. Then, it was characterized by X-ray powder diffraction, Fourier transform infrared spectroscopy, thermogravimetry and differential thermal analysis, and transmission electron microscopy. The prepared nanoparticles, VP16-LDH, showed an average diameter of 62.5 nm with a zeta potential of 20.5 mV. Evaluation of the buffering effect of VP16-LDH indicated that the nanohybrids were ideal for administration of the drugs that treat human stomach irritation. The loading amount of intercalated VP16 was 21.94% and possessed a profile of sustained release. The mechanism of VP16-LDH release in the phosphate buffered saline solution at pH 7.4 is likely controlled by the diffusion of VP16 anions from inside to the surface of LDH particles. The in vitro cytotoxicity and antitumor assays indicated that VP16-LDH hybrids were less toxic to GES-1 cells while exhibiting better antitumor efficacy on MKN45 and SGC-7901 cells. These results imply that VP16-LDH is a potential antitumor drug for a broad range of gastric cancer therapeutic applications. PMID:23737669

  2. The in vitro sustained release profile and antitumor effect of etoposide-layered double hydroxide nanohybrids

    PubMed Central

    Qin, Lili; Wang, Mei; Zhu, Rongrong; You, Songhui; Zhou, Ping; Wang, Shilong

    2013-01-01

    Magnesium-aluminum layered double hydroxides intercalated with antitumor drug etoposide (VP16) were prepared for the first time using a two-step procedure. The X-ray powder diffraction data suggested the intercalation of VP16 into layers with the increased basal spacing from 0.84–1.18 nm was successful. Then, it was characterized by X-ray powder diffraction, Fourier transform infrared spectroscopy, thermogravimetry and differential thermal analysis, and transmission electron microscopy. The prepared nanoparticles, VP16-LDH, showed an average diameter of 62.5 nm with a zeta potential of 20.5 mV. Evaluation of the buffering effect of VP16-LDH indicated that the nanohybrids were ideal for administration of the drugs that treat human stomach irritation. The loading amount of intercalated VP16 was 21.94% and possessed a profile of sustained release. The mechanism of VP16-LDH release in the phosphate buffered saline solution at pH 7.4 is likely controlled by the diffusion of VP16 anions from inside to the surface of LDH particles. The in vitro cytotoxicity and antitumor assays indicated that VP16-LDH hybrids were less toxic to GES-1 cells while exhibiting better antitumor efficacy on MKN45 and SGC-7901 cells. These results imply that VP16-LDH is a potential antitumor drug for a broad range of gastric cancer therapeutic applications. PMID:23737669

  3. Tuftsin Augments Antitumor Efficacy of Liposomized Etoposide against Fibrosarcoma in Swiss Albino Mice

    PubMed Central

    Khan, Arif; Khan, Aijaz A; Dwivedi, Varun; Ahmad, Manzoor G; Hakeem, Seema; Owais, Mohammad

    2007-01-01

    Anticancer drugs are generally plagued by toxic manifestations at doses necessary for control of various forms of cancer. Incorporating such drugs into liposomes not only reduces toxicity but also enhances the therapeutic index. Some antioxidants and potent immunomodulators have also been shown to impart significant antitumor activity presumably by nonspecific activation of the host immune system. In the present study, we evaluated augmentation of the antitumor activity of etoposide (ETP) by the immunomodulator tuftsin in Swiss albino mice with fibrosarcoma. The efficacies of the free form of ETP, liposomized ETP (Lip-ETP), and tuftsin-bearing liposomized ETP (Tuft-Lip-ETP) formulations were evaluated on the basis of tumor regression, effect on expression level of p53wt and p53mut, and survival of the treated animals. Tuft-Lip-ETP, when administered at a dosage of 10 mg/kg body weight/day for five days, significantly reduced tumor volume, delayed tumor growth, and also up-regulated the expression of p53wt. In contrast, although Lip-ETP delayed tumor growth, it did not decrease tumor size. The results of the present study suggest that tuftsin incorporation in drug-loaded liposomes is a promising treatment strategy for various forms of cancers, including fibrosarcoma. PMID:17622310

  4. Can pharmacogenetics explain efficacy and safety of cisplatin pharmacotherapy?

    PubMed Central

    Roco, Ángela; Cayún, Juan; Contreras, Stephania; Stojanova, Jana; Quiñones, Luis

    2014-01-01

    Several recent pharmacogenetic studies have investigated the variability in both outcome and toxicity in cisplatin-based therapies. These studies have focused on the genetic variability of therapeutic targets that could affect cisplatin response and toxicity in diverse type of cancer including lung, gastric, ovarian, testicular, and esophageal cancer. In this review, we seek to update the reader in this area of investigation, focusing primarily on DNA reparation enzymes and cisplatin metabolism through Glutathione S-Transferases (GSTs). Current evidence indicates a potential application of pharmacogenetics in therapeutic schemes in which cisplatin is the cornerstone of these treatments. Therefore, a collaborative effort is required to study these molecular characteristics in order to generate a genetic panel with clinical utility. PMID:25452763

  5. [Cisplatin influence on: the radiosensitivity and recovery of yeast cells].

    PubMed

    Evstratova, E S; Petin, V G

    2013-01-01

    The effect of the simultaneous combined action of ionizing radiation and cisplatin on the radiosensitivity and liquid holding recovery (LHR) of diploid yeast cells was studied. It was shown that regardless of the cisplatin concentration (0; 0.002; 0.01; 0.02 g/ml) the radiosensitivity of cells was increased by 1.3 times. The ability of a cell to the LHR was progressively decreased with the increasing cisplatin concentration up to the complete inhibition. It was shown that the LHR of yeast cells after a combined action of ionizing radiation and chemical agents is mainly inhibited due to formation of a greater proportion of irreversible damage. The constant of recovery, characterizing the probability of recovery per a unit of time, was independent on cisplatine concentration. PMID:25486742

  6. [Cisplatin influence on: the radiosensitivity and recovery of yeast cells].

    PubMed

    2013-01-01

    The effect of the simultaneous combined action of ionizing radiation and cisplatin on the radiosensitivity and liquid holding recovery (LHR) of diploid yeast cells was studied. It was shown that regardless of the cisplatin concentration (0; 0.002; 0.01; 0.02 g/ml) the radiosensitivity of cells was increased by 1.3 times. The ability of a cell to the LHR was progressively decreased with the increasing cisplatin concentration up to the complete inhibition. It was shown that the LHR of yeast cells after a combined action of ionizing radiation and chemical agents is mainly inhibited due to formation of a greater proportion of irreversible damage. The con- stant of recovery, characterizing the probability of recovery per a unit of time, was independent on cisplatine concentration. PMID:25508873

  7. Hypersensitivity reaction to cisplatin during chemoradiation therapy for gynecologic malignancy.

    PubMed

    Koren, Claude; Yerushalmi, Rinat; Katz, Alan; Malik, Hana; Sulkes, Aaron; Fenig, Eyal

    2002-12-01

    Hypersensitivity reactions to intravenous cisplatin are rare. The appearance of hypersensitivity reactions in 4 of 25 consecutive patients treated with concomitant pelvic radiation and weekly intravenous cisplatin for gynecologic malignancies is reported. The reactions appeared within hours of cisplatin delivery and included primarily fever, rash, and pruritus. Infection was ruled out by blood cultures and other laboratory studies. Affected patients were treated prophylactically with an antihistamine before subsequent courses of cisplatin, with excellent results. The high rate of hypersensitivity reactions in our series may be attributable to tumor necrosis and cytokine release caused by the pelvic irradiation. Clinicians should be aware of this potential side effect so that early premedication regimens can be instituted to prevent unnecessary toxicity. PMID:12478013

  8. The effect of resveratrol on the prevention of cisplatin ototoxicity.

    PubMed

    Erdem, T; Bayindir, Tuba; Filiz, A; Iraz, M; Selimoglu, E

    2012-10-01

    One of the most important adverse effects of cisplatin, a chemotherapeutic agent which is widely used in the treatment of cancer patients, is hearing loss. This has primarily been associated with the loss of inner ear hairy and spiral ganglion cells due to oxidative stress. Resveratrol is known to be an antioxidant agent, which has the theoretical potential of preventing cisplatin-related ototoxicity. This experimental study was approved by Animal Ethics Committee of Inonu University (2008-20) and supported by Inonu University Scientific Research Projects Support Fund (2009-17). Thirty-four 3-month-old Wistar albino female rats weighing 210-270 g were used in the study. The animals were allocated into four groups: in cisplatin group (Group A), a single dose of 12 mg/kg cisplatin was administered intraperitoneally to 10 rats; in cisplatin + resveratrol group (Group B), a single dose of 12 mg/kg cisplatin and 10 mg/kg resveratrol were administered intraperitoneally for 5 days to 10 rats; in resveratrol group (Group C), 10 mg/kg resveratrol was administered intraperitoneally for 5 days to seven rats and in control group (Group D), resveratrol solvent (5% alcohol-95% physiological saline) was administered intraperitoneally for 5 days to seven rats. Resveratrol administration has begun 1 day before cisplatin administration in the group treated with cisplatin and resveratrol combination. Distortion product otoacoustic emission (DPOAE) (Grason Stadler, Madison, USA) measurements were performed in the same ear of all rats (right ear) under general anesthesia at baseline, 1st and 5th days after drug administration. Statistically significant distortion product amplitude reductions were found in the cisplatin group at 1,418, 2,003, 3,363, 5,660, 8,003 and 9,515 Hz frequencies. Whereas in the cisplatin + resveratrol group, statistically significant difference was found between 1st and 5th day measurements only at 3,996 Hz frequency. No significant differences were noted

  9. Hydrolysis of cisplatin--a first-principles metadynamics study.

    PubMed

    Lau, Justin Kai-Chi; Ensing, Bernd

    2010-09-21

    Cisplatin, or cis-[Pt(NH(3))(2)Cl(2)], was the first member of a new revolutionary class of anticancer drugs that is still used today for the treatment of a wide variety of cancers. The mode of action of cisplatin starts inside the cell with the hydrolysis of Pt-Cl bonds to form a Pt-aqua complex. The solvent environment plays an essential role in many biochemical processes in general, and is expected to have a particular strong effect on the activation (hydrolysis) of cisplatin and cisplatin derivatives. To investigate these solvent effects, we have studied the explicit solvent structures during cisplatin hydrolysis by means of Car-Parrinello molecular dynamics simulations. Since hydrolysis is an activated process, and thus a rare event on the simulation timescale, we have applied the metadynamics sampling technique to map out the free energy landscape from which the reaction mechanism and activation free energy are obtained. Our simulations show that hydrogen bonding between solvent water molecules and metal complexes in the hydrolyzed product systems is stronger than that in the reactant cisplatin system. In addition, the free energy profiles from our metadynamics simulations for the cisplatin hydrolysis shows that the second hydrolysis of cisplatin is thermodynamically favourable, which is in good agreement with experimental results and previous static density functional theory calculations. The reactant channels for both hydrolysis steps are rather wide and flat, indicative of a continuous spectrum of allowed mechanisms with no strong preference for either concerted dissociative or concerted associative pathways. Three or five coordinated metastable intermediates do not exist in aqueous solution. PMID:20582358

  10. Glucose regulated protein 78 (GRP78) inhibits apoptosis and attentinutes chemosensitivity of gemcitabine in breast cancer cell via AKT/mitochondrial apoptotic pathway.

    PubMed

    Xie, Jie; Tao, Zhong-Hua; Zhao, Jiang; Li, Ting; Wu, Zheng-Hua; Zhang, Jin-Feng; Zhang, Jian; Hu, Xi-Chun

    2016-06-01

    The underlying mechanism of gemcitabine resistance during breast cancer treatment remains unclear. Glucose regulated protein 78 (GRP78) frequently triggered by anticancer agents, was substantially elevated in gemcitabine resistant sublines. Ectopic expression of GRP78 changes gemcitabine chemosensitivity and apoptosis levels in breast cancer cells. Further experiments showed an involvement of caspase 9, not caspase 8, in gemcitabine resistance and GRP78-mediated chemosensitivity, suggesting that mitochondria apoptotic pathway was activated by GRP78. This finding was further supported by the observations of AKT activation, Bcl-2 increase, Bax and Bim decrease. Conclusively, GRP78 plays a vital role in gemcitabine resistance and clinical strategy to improve gemcitabine efficacy in breast cancer by manipulating GRP78 should be explored. PMID:27012209

  11. MiRNA-21 induces epithelial to mesenchymal transition and gemcitabine resistance via the PTEN/AKT pathway in breast cancer.

    PubMed

    Wu, Zhen-Hua; Tao, Zhong-Hua; Zhang, Jian; Li, Ting; Ni, Chen; Xie, Jie; Zhang, Jin-Feng; Hu, Xi-Chun

    2016-06-01

    Acquisition of gemcitabine resistance in breast cancer has not been fully clarified. Prior studies suggest that miRNAs are important to chemoresistance in solid tumors and we confirmed that miR-21 is involved in the development of gemcitabine resistance. Epithelial-to-mesenchymal transition (EMT) and AKT pathway activation were noted to be important to this resistance as well. PTEN, a direct target gene of miR-21, was significantly downregulated in gemcitabine-resistant breast cancer cells and restoration of PTEN expression blocked miR-21-induced EMT and gemcitabine resistance. Our data offer novel insight into gemcitabine resistance in breast cancer and suggest that miR-21 may be used to predict optimal breast cancer therapy and may be a potential therapeutic target for reversing gemcitabine resistance. PMID:26666820

  12. Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity

    PubMed Central

    Zhu, Jing; Carozzi, Valentina Alda; Reed, Nicole; Mi, Ruifa; Marmiroli, Paola; Cavaletti, Guido; Hoke, Ahmet

    2016-01-01

    Ethoxyquin was recently identified as a neuroprotective compound against toxic neuropathies and efficacy was demonstrated against paclitaxel-induced neurotoxicity in vivo. In this study we examined the efficacy of ethoxyquin in preventing neurotoxicity of cisplatin in rodent models of chemotherapy-induced peripheral neuropathy and explored its mechanism of action. Ethoxyquin prevented neurotoxicity of cisplatin in vitro in a sensory neuronal cell line and primary rat dorsal root ganglion neurons. In vivo, chronic co-administration of ethoxyquin partially abrogated cisplatin-induced behavioral, electrophysiological and morphological abnormalities. Furthermore, ethoxyquin did not interfere with cisplatin’s ability to induce tumor cell death in ovarian cancer cell line in vitro and in vivo. Finally, ethoxyquin reduced the levels of two client proteins (SF3B2 and ataxin-2) of a chaperone protein, heat shock protein 90 (Hsp90) when co-administered with cisplatin in vitro. These results implied that the neuroprotective effect of ethoxyquin is mediated through these two client proteins of Hsp90. In fact, reducing levels of SF3B2 in tissue-cultured neurons was effective against neurotoxicity of cisplatin. These findings suggest that ethoxyquin or other compounds that inhibit chaperone activity of Hsp90 and reduce levels of its client protein, SF3B2 may be developed as an adjuvant therapy to prevent neurotoxicity in cisplatin-based chemotherapy protocols. PMID:27350330

  13. Curcumin alleviates cisplatin-induced learning and memory impairments.

    PubMed

    Oz, Mehmet; Nurullahoglu Atalik, K Esra; Yerlikaya, F Humeyra; Demir, Enver Ahmet

    2015-09-01

    The present study has been designed to investigate the role of curcumin on cisplatin-inducedcognitive impairment and to reveal mechanisms of cisplatin's detrimental actions on cognition in rats. Animals were treated with cisplatin (5mg/kg/week) and/or curcumin (300mg/kg/day) for 5weeks. Morris water maze test was used to assess spatial learning and memory. Enzymatic activities of acetylcholinesterase (AChE) and superoxide dismutase (SOD) were evaluated from hippocampus and plasma samples, and malondialdehyde (MDA), which is the end-product of lipid peroxidation, was determined by a colorimetric method. Our results showed that cisplatin (5mg/kg/week, 5weeks) caused learning and memory deficits, elevated MDA content, decreased SOD activity in the hippocampus and plasma, and AChE activity in the hippocampus. Curcumin improved learning and memory in rats with administration of cisplatin. In addition, curcumin significantly reduced the level of MDA and increased the activities of SOD and AChE. Taken together, our findings indicate that curcumin ameliorates cisplatin-induced spatial learning and memory impairment, possibly through restored cholinergic function and enhanced oxidative status. PMID:25982942

  14. Molecular mechanisms of cisplatin cytotoxicity in acute promyelocytic leukemia cells

    PubMed Central

    Kumar, Sanjay; Tchounwou, Paul B.

    2015-01-01

    Cis-diamminedichloroplatinum (II) (cisplatin) is a widely used anti-tumor drug for the treatment of a broad range of human malignancies with successful therapeutic outcomes for head and neck, ovarian, and testicular cancers. It has been found to inhibit cell cycle progression and to induce oxidative stress and apoptosis in acute promyelocytic leukemia (APL) cells. However, its molecular mechanisms of cytotoxic action are poorly understood. We hypothesized that cisplatin induces cytotoxicity through DNA adduct formation, oxidative stress, transcriptional factors (p53 and AP-1), cell cycle regulation, stress signaling and apoptosis in APL cells. We used the APL cell line as a model, and applied a variety of molecular tools to elucidate the cytototoxic mode of action of cisplatin. We found that cisplatin inhibited cell proliferation by a cytotoxicity, characterized by DNA damage and modulation of oxidative stress. Cisplatin also activated p53 and phosphorylated activator protein (AP-1) component, c-Jun at serine (63, 73) residue simultaneously leading to cell cycle arrest through stimulation of p21 and down regulation of cyclins and cyclin dependent kinases in APL cell lines. It strongly activated the intrinsic pathway of apoptosis through alteration of the mitochondrial membrane potential, release of cytochrome C, and up-regulation of caspase 3 activity. It also down regulated the p38MAPK pathway. Overall, this study highlights the molecular mechanisms that underline cisplatin toxicity to APL cells, and provides insights into selection of novel targets and/or design of therapeutic agents to treat APL. PMID:26486083

  15. Galectin-1-Induced Autophagy Facilitates Cisplatin Resistance of Hepatocellular Carcinoma.

    PubMed

    Su, Yu-Chi; Davuluri, Goutham Venkata Naga; Chen, Cheng-Hao; Shiau, Dong-Che; Chen, Chien-Chin; Chen, Chia-Ling; Lin, Yee-Shin; Chang, Chih-Peng

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers in Taiwan. Although chemotherapy is the primary treatment for HCC patients, drug resistance often leads to clinical failure. Galectin-1 is a beta-galactoside binding lectin which is up-regulated in HCC patients and promotes tumor growth by mediating cancer cell adhesion, migration and proliferation, but its role in chemoresistance of HCC is poorly understood. In this study we found that galectin-1 is able to lead to chemoresistance against cisplatin treatment, and subsequent inhibition has reversed the effect of cell death in HCC cells. Moreover, galectin-1 was found to induce autophagic flux in HCC cells. Inhibition of autophagy by inhibitors or knockdown of Atg5 cancels galectin-1-induced cisplatin resistance in HCC cells. Increase of mitophagy triggered by galectin-1 was found to reduce the mitochondrial potential loss and apoptosis induced by cisplatin treatment. Finally, using an in situ hepatoma mouse model, we clearly demonstrated that inhibition of galectin-1 by thiodigalactoside could significantly augment the anti-HCC effect of cisplatin. Taken together, our findings offer a new insight into the chemoresistance galectin-1 causes against cisplatin treatment, and points to a potential approach to improve the efficacy of cisplatin in the treatment of HCC patients. PMID:26859293

  16. Gemcitabine Compared With Gemcitabine and S-1 Combination Therapy in Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis.

    PubMed

    Li, Doudou; Chen, Changhao; Zhou, Yu; Chen, Rufu; Fan, Xinxiang; Bi, Zhuofei; Li, Zhihua; Liu, Yimin

    2015-09-01

    Several reports suggest that gemcitabine (GEM) plus S-1 combination (GS) is associated to prolong the survival in patients with unresectable pancreatic cancer (PC). We conducted a systemic review and meta-analysis of studies comparing the safety and efficacy of GS versus GEM.Summary data from randomized trials and retrospective studies were searched in PubMed, EMBASE, Web of Science, and the Cochrane Library. Statistical analyses were conducted to calculate the hazard ratios (HRs) and relative risk (RR) with 95% confidence intervals (CIs) using random-effects models. Subgroup analyses based on the chemotherapy cycles were performed to explore the efficacy and toxicity for therapy. Sensitivity analyses were conducted by removing specific studies to assess the effects of study quality.Between January 2004 and August 2012, 4 RCTs and 2 retrospective studies including a total of 1025 cases were identified. The overall survival (OS) (HR: 0.82; 95% CI, 0.70-0.96; P = 0.01) and progression-free survival (PFS) (HR: 0.65; 95% CI, 0.55-0.77; P < 0.001) for the GS arm were significantly longer than the GEM arm. The differences in objective response rate (ORR) (RR: 1.24; 95% CI, 1.17-1.33; P < 0.001) and disease control rate (DCR) were also better in the GS arm (RR: 1.37; 95% CI, 1.19-1.59; P < 0.001). Grades 3 to 4 toxicities in both the groups were similar except neutropenia and diarrhea, which were more frequent in the GS arm (P < 0.001). In the subgroup analysis, the cycle for chemotherapy every 4 weeks has equivalent efficacy and less toxicity than regimens every 3 weeks in the GS arm.The current meta-analysis suggested that GEM significantly prolonged OS and PFS when added to S-1 combination in patients with unresectable PC. GS therapy also offers better ORR and DCR than GEM monotherapy and no unexpected toxicity was evident. PMID:26334891

  17. Dissociation of gemcitabine chemosensitization by CHK1 inhibition from cell cycle checkpoint abrogation and aberrant mitotic entry.

    PubMed

    Parsels, Leslie A; Tanska, Daria M; Parsels, Joshua D; Zabludoff, Sonya D; Cuneo, Kyle C; Lawrence, Theodore S; Maybaum, Jonathan; Morgan, Meredith A

    2016-03-01

    In order to determine the relative contribution of checkpoint abrogation and subsequent aberrant mitotic entry to gemcitabine chemosensitization by CHK1 inhibition, we established a model utilizing the CDK inhibitors roscovitine or purvalanol A to re-establish cell cycle arrest and prevent aberrant mitotic entry in pancreatic cancer cells treated with gemcitabine and the CHK inhibitor AZD7762. In this study, we report that the extent of aberrant mitotic entry, as determined by flow cytometry for the mitotic marker phospho-Histone H3 (Ser10), did not reflect the relative sensitivities of pancreatic cancer cell lines to gemcitabine chemosensitization by AZD7762. In addition, re-establishing gemcitabine-induced cell cycle arrest either pharmacologically, with roscovitine or purvalanol A, or genetically, with cyclin B1 siRNA, did not inhibit chemosensitization uniformly across the cell lines. Furthermore, we found that AZD7762 augmented high-intensity γH2AX signaling in gemcitabine-treated cells, suggesting the presence of replication stress when CHK1 is inhibited. Finally, the ability of roscovitine to prevent chemosensitization correlated with its ability to inhibit AZD7762-induced high-intensity γH2AX, but not aberrant pHH3, suggesting that the effects of AZD7762 on DNA replication or repair rather than aberrant mitotic entry determine gemcitabine chemosensitization in pancreatic cancer cells. PMID:26890478

  18. A phase II study of adjuvant gemcitabine plus docetaxel followed by concurrent chemoradation in resected pancreaticobiliary carcinoma

    PubMed Central

    Cho, May; Wang-Gillam, Andrea; Myerson, Robert; Gao, Feng; Strasberg, Steven; Picus, Joel; Sorscher, Steven; Fournier, Chloe; Nagaraj, Gayathri; Parikh, Parag; Suresh, Rama; Linehan, David; Tan, Benjamin R

    2015-01-01

    Objectives Adjuvant gemcitabine with or without chemoradiation is a standard therapeutic option for patients with resected pancreatic cancer. The feasibility and toxicity of gemcitabine with docetaxel before and after 5-fluorouracil (5FU)-based chemoradiation in the adjuvant pancreatic and biliary cancer setting were investigated. Methods After a curative-intent resection, eligible patients with pancreaticobiliary cancers were treated with two cycles of gemcitabine and docetaxel followed by 5FU-based chemoradiation. Four weeks after completing chemoradiation, two cycles of gemcitabine and docetaxel were administered. The primary endpoint was the incidence of severe toxicities. Secondary endpoints included disease-free survival (DFS) and overall survival (OS). Results Fifty patients with pancreaticobiliary cancers were enrolled. Twenty-nine patients had pancreatic cancer whereas 21 patients had biliary tract or ampullary cancers. There was one death as a result of pneumonia, and 15% of patients experienced grade 3 or greater non-haematological toxicities. The median DFS and OS for patients with pancreatic cancer were 9.6 and 17 months, respectively, and for those with resected biliary tract cancer were 12 and 23 months, respectively. Conclusions This combination of gemcitabine and docetaxel with chemoradiation is feasible and tolerable in the adjuvant setting. Future studies utilizing a different gemcitabine/taxane combination and schedule may be appropriate in the adjuvant treatment of both pancreatic cancer and biliary tumours. PMID:25800066

  19. Updates on treatment of gemcitabine-refractory pancreatic adenocarcinoma. Highlights from the "2011 ASCO Annual Meeting". Chicago, IL, USA; June 3-7, 2011.

    PubMed

    Makrilia, Nektaria; Syrigos, Kostas N; Saif, Muhammad W

    2011-07-01

    Gemcitabine monotherapy and gemcitabine-based regimens are the current standard of care for locally advanced or metastatic pancreatic adenocarcinoma. However, there is still great controversy over the role of salvage chemotherapy after failure of gemcitabine. This review is an update on the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting regarding the most important developments in the treatment of refractory pancreatic cancer, as they were reported in Abstracts #e14542 and #e14588. PMID:21737894

  20. Cisplatin and Doxorubicin Induce Distinct Mechanisms of Ovarian Follicle Loss; Imatinib Provides Selective Protection Only against Cisplatin

    PubMed Central

    Morgan, Stephanie; Lopes, Federica; Gourley, Charlie; Anderson, Richard A.; Spears, Norah

    2013-01-01

    Purpose Chemotherapy treatment in premenopausal women has been linked to ovarian follicle loss and premature ovarian failure; the exact mechanism by which this occurs is uncertain. Here, two commonly used chemotherapeutic agents (cisplatin and doxorubicin) were added to a mouse ovary culture system, to compare the sequence of events that leads to germ cell loss. The ability of imatinib mesylate to protect the ovary against cisplatin or doxorubicin-induced ovarian damage was also examined. Experimental design Newborn mouse ovaries were cultured for a total of six days, exposed to a chemotherapeutic agent on the second day: this allowed for the examination of the earliest stages of follicle development. Cleaved PARP and TUNEL were used to assess apoptosis following drug treatment. Imatinib was added to cultures with cisplatin and doxorubicin to determine any protective effect. Results Histological analysis of ovaries treated with cisplatin showed oocyte-specific damage; in comparison doxorubicin preferentially caused damage to the granulosa cells. Cleaved PARP expression significantly increased for cisplatin (16 fold, p<0.001) and doxorubicin (3 fold, p<0.01). TUNEL staining gave little evidence of primordial follicle damage with either drug. Imatinib had a significant protective effect against cisplatin-induced follicle damage (p<0.01) but not against doxorubicin treatment. Conclusion Cisplatin and doxorubicin both induced ovarian damage, but in a markedly different pattern, with imatinib protecting the ovary against damage by cisplatin but not doxorubicin. Any treatment designed to block the effects of chemotherapeutic agents on the ovary may need to be specific to the drug(s) the patient is exposed to. PMID:23922929

  1. PP2A inhibition with LB100 enhances cisplatin cytotoxicity and overcomes cisplatin resistance in medulloblastoma cells

    PubMed Central

    Maric, Dragan; Amable, Lauren; Hall, Matthew D.; Feldman, Gerald M.; Ray-Chaudhury, Abhik; Lizak, Martin J.; Vera, Juan-Carlos; Robison, R. Aaron; Zhuang, Zhengping; Heiss, John D.

    2016-01-01

    The protein phosphatase 2A (PP2A) inhibitor, LB100, has been shown in pre-clinical studies to be an effective chemo- and radio-sensitizer for treatment of various cancers. We investigated effects associated with LB100 treatment alone and in combination with cisplatin for medulloblastoma (MB) in vitro and in vivo in an intracranial xenograft model. We demonstrated that LB100 had a potent effect on MB cells. By itself, LB100 inhibited proliferation and induced significant apoptosis in a range of pediatric MB cell lines. It also attenuated MB cell migration, a pre-requirement for invasion. When used in combination, LB100 enhanced cisplatin-mediated cytotoxic effects. Cell viability in the presence of 1 uM cisplatin alone was 61% (DAOY), 100% (D341), and 58% (D283), but decreased with the addition of 2 μM of LB100 to 26% (DAOY), 67% (D341), and 27% (D283), (p < 0.005). LB100 suppressed phosphorylation of the STAT3 protein and several STAT3 downstream targets. Also, LB100 directly increased cisplatin uptake and overcame cisplatin-resistance in vitro. Finally, LB100 exhibited potent in vivo anti-neoplastic activity in combination with cisplatin in an intracranial xenograft model. PMID:26799670

  2. Outpatient treatment with epirubicin and oral etoposide in patients with small-cell lung cancer.

    PubMed Central

    Gogas, H.; Lofts, F. J.; Evans, T. R.; Millard, F. J.; Wilson, R.; Mansi, J. L.

    1997-01-01

    To assess the efficacy and toxicity of an outpatient combination chemotherapy in small-cell lung cancer (SCLC), we treated 70 consecutive patients with epirubicin 80 mg m(-2) i.v. on day 1 and etoposide 200 mg o.d. p.o. on days 1-4 (EE) at 3-weekly intervals. The median age of patients was 64 years (range 39-84). The male-female ratio was 42:28 and 35 (50%) had metastatic disease. Fifty-seven patients were evaluable for response. The overall response rate was 64.4%, including 14 (23.7%) complete responses and 24 (40.7%) partial responses. Median time to progression was 7 months in responders and 8 months in patients with limited disease. The median survival in patients with limited disease was 10.5 months (range 0.5-70 +) and 7 months (range 0.5-24) in those with extensive disease. Improvement of symptoms occurred in 79% of patients with shortness of breath, 80% with cough, 81% with haemoptysis and 68% with pain. In 19 patients an increase in body weight was noted. Major (WHO grade 3/4) toxicities were neutropenia in 13 (18.5%) patients, alopecia in 33 (47.1%) patients, mucositis in 15 (21.4%) patients, anorexia in eight patients (11.4%), nausea and vomiting in six patients (8.5%) and diarrhoea in 4 (5.7%) patients. In conclusion, EE is an active and well-tolerated outpatient regimen in the treatment of SCLC. The survival data in this unselected group of patients were disappointing and the possible explanations for this are discussed. PMID:9303364

  3. [The cause of polyurethane catheter cracking during constant infusion of etoposide (VP-16) injection].

    PubMed

    Yokoyama, H; Aoyama, T; Matsuyama, T; Yamamura, Y; Nakajima, K; Nakamura, K; Sato, H; Kotaki, H; Chiba, S; Hirai, H; Yazaki, Y; Iga, T

    1998-12-01

    We studied the cause of cracking of a clinically used polyurethane (PU) catheter during the constant infusion of etoposide (VP-16) injection (Lastet), administered without dilution to patients as a part of combination high-dose chemotherapy. After VP-16 injection was infused into the PU catheter at a constant infusion rate (30 ml/h) for 24 h, a decrease in the elasticity (36% of untreated) and on increase in the length of the catheter (3.7%) were observed. These changes were significantly higher than those treated with the control saline. The similar changes of the PU catheter were observed after treatment with a basal solution containing polyethylene glycol 400 (PEG 400), polysorbate 80 and ethanol, which is the vehicle of the VP-16 injection, and with ethanol alone. Moreover, obvious degeneration of the internal wall (occurrence of spots like melting) and cutting face (micro-cracking) of the catheter was observed with an electron microscope after treatment with the vehicle. On the other hand, the elasticity or extension of the PU catheter were not changed after treatment with saline or PEG 400. From these findings, it was suggested that the degeneration and subsequent cracking of the PU catheter during the infusion of VP-16 injection was caused by ethanol contained in its injection solution. No cracking or morphological changes of polyvinyl chloride (PVC) and silicone catheters were found after treatment with the vehicle solution. However, since it has been reported in previous reports that di(2-ethylhexyl)phthalate was leached from PVC bags, the high dose chemotherapy with the dilution-free VP-16 injection should be achieved safely and effectively using a silicon catheter, rather than the PU catheter. PMID:9921266

  4. High-dose cytosine-arabinoside and cisplatin regimens as salvage therapy for refractory or relapsed AIDS-related non-Hodgkin's lymphoma.

    PubMed

    Bi, J; Espina, B M; Tulpule, A; Boswell, W; Levine, A M

    2001-12-15

    No effective salvage regimen has been defined for patients with AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) who do not respond to first-line chemotherapy that contains anthracycline. Combined dexamethasone, cytosine arabinoside, and cisplatin (DHAP) and etoposide, methylprednisolone, cytosine arabinoside, and cisplatin (ESHAP) have shown good response rates in HIV-negative patients with relapsed lymphomas. We retrospectively analyzed patients with refractory or relapsed AIDS-NHL who had been treated with either DHAP or ESHAP to evaluate the feasibility and efficacy of these regimens. Twenty-six patients with refractory or relapsed AIDS-NHL were treated between 1990 and 1999 either with DHAP ( n = 13) or with ESHAP ( n = 13). Only 1 patient from each group (8%) had achieved complete remission with any previous therapy, and most had progressive disease after the regimen immediately preceding DHAP or ESHAP. In the ESHAP group, 4 patients (31%) achieved complete remission (CR) and 3 patients (23%) attained partial remission (PR) for an overall response rate of 54%. The median survival was 7.1 months (range, 1-58.9+ months) from the time ESHAP was begun. Among the 3 patients with primary refractory lymphoma, there was 1 CR, 1 PR, and one patient with stable disease. In contrast, only 1 PR (7%) was observed with DHAP; the median survival was 3 months. Myelosuppression was the most significant toxicity with grade 4 neutropenia occurring in all who received ESHAP and in 54% of patients treated with DHAP. Neutropenic fever occurred in 8 (62%) ESHAP-treated and 6 (46%) DHAP-treated patients. Although hematologic toxicity is profound, ESHAP appears to be an active salvage regimen for patients with relapsed or refractory AIDS-NHL. PMID:11744828

  5. A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer

    PubMed Central

    Deplanque, G.; Demarchi, M.; Hebbar, M.; Flynn, P.; Melichar, B.; Atkins, J.; Nowara, E.; Moyé, L.; Piquemal, D.; Ritter, D.; Dubreuil, P.; Mansfield, C. D.; Acin, Y.; Moussy, A.; Hermine, O.; Hammel, P.

    2015-01-01

    Background Masitinib is a selective oral tyrosine–kinase inhibitor. The efficacy and safety of masitinib combined with gemcitabine was compared against single-agent gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC). Patients and methods Patients with inoperable, chemotherapy-naïve, PDAC were randomized (1 : 1) to receive gemcitabine (1000 mg/m2) in combination with either masitinib (9 mg/kg/day) or a placebo. The primary endpoint was overall survival (OS) in the modified intent-to-treat population. Secondary OS analyses aimed to characterize subgroups with poor survival while receiving single-agent gemcitabine with subsequent evaluation of masitinib therapeutic benefit. These prospectively declared subgroups were based on pharmacogenomic data or a baseline characteristic. Results Three hundred and fifty-three patients were randomly assigned to receive either masitinib plus gemcitabine (N = 175) or placebo plus gemcitabine (N = 178). Median OS was similar between treatment-arms for the overall population, at respectively, 7.7 and 7.1 months, with a hazard ratio (HR) of 0.89 (95% CI [0.70; 1.13]. Secondary analyses identified two subgroups having a significantly poor survival rate when receiving single-agent gemcitabine; one defined by an overexpression of acyl–CoA oxidase-1 (ACOX1) in blood, and another via a baseline pain intensity threshold (VAS > 20 mm). These subgroups represent a critical unmet medical need as evidenced from median OS of 5.5 months in patients receiving single-agent gemcitabine, and comprise an estimated 63% of patients. A significant treatment effect was observed in these subgroups for masitinib with median OS of 11.7 months in the ‘ACOX1’ subgroup [HR = 0.23 (0.10; 0.51), P = 0.001], and 8.0 months in the ‘pain’ subgroup [HR = 0.62 (0.43; 0.89), P = 0.012]. Despite an increased toxicity of the combination as compared with single-agent gemcitabine, side-effects remained manageable. Conclusions The

  6. The efficacy of prophylactic outpatient antibiotics for the prevention of neutropenic fever associated with high-dose etoposide (VP-16) for stem cell mobilization.

    PubMed

    Avery, R K; Pohlman, B L; Mossad, S B; Goormastic, M; Longworth, D L; Kalaycio, M E; Sobecks, R M; Andresen, S W; Kuczkowski, E; Bernhard, L; Ostendorf, H; Wise, K; Bolwell, B J

    2002-09-01

    High-dose etoposide (2 g/m(2)) plus G-CSF is a very effective regimen for peripheral blood progenitor cell (PBPC) mobilization. Unfortunately, neutropenia is common. The infectious complications associated with high-dose etoposide have not been previously described. After noting a high incidence of hospitalizations for neutropenic fever, we began a vigorous prophylactic antibiotic regimen for patients receiving high-dose etoposide plus G-CSF, attempting to reduce infectious complications. Ninety-eight patients underwent etoposide mobilization between December 1997 and June 2000. Three chronological patient groups received: (1) no specific antibiotic prophylaxis (n = 44); (2) vancomycin i.v., cefepime i.v., clarithromycin p.o., and ciprofloxacin p.o. (n = 27); and (3) vancomycin i.v., clarithromycin p.o., and ciprofloxacin p.o. (n = 27). The patients not receiving antibiotic prophylaxis had a 68% incidence of hospitalization for neutropenic fever. In the patients receiving prophylaxis, the incidence was reduced to 26% and 15% respectively, for an overall incidence of 20% (P < 0.001 for comparison between prophylaxed and unprophylaxed groups). We conclude that etoposide mobilization is associated with a significant incidence of neutropenic fever, which can be substantially reduced by a vigorous antimicrobial prophylactic program. PMID:12209353

  7. Dose-escalated CHOP plus etoposide (MegaCHOEP) followed by repeated stem cell transplantation for primary treatment of aggressive high-risk non-Hodgkin lymphoma.

    PubMed

    Glass, Bertram; Kloess, Marita; Bentz, Martin; Schlimok, Günter; Berdel, Wolfgang E; Feller, Alfred; Trümper, Lorenz; Loeffler, Markus; Pfreundschuh, Michael; Schmitz, Norbert

    2006-04-15

    Feasibility, safety, and efficacy of a 4-course high-dose chemotherapy (HDT) protocol including autologous stem cell transplantation (SCT) after courses 2, 3, and 4 was investigated in 110 patients, aged 18 to 60 years, with primary diagnosis of aggressive NHL (aNHL), and lactic dehydrogenase (LDH) levels above normal. At dose level 1 (DL1), course 1 consisted of cyclophosphamide 1500 mg/m2, doxorubicin (Adriamycin) 70 mg/m2, vincristine 2 mg, etoposide 450 mg/m2, and prednisone 500 mg. With courses 2 and 3 cyclophosphamide and etoposide were escalated to 4500 mg/m2 and 600 mg/m2, respectively. With course 4 cyclophosphamide and etoposide were given at 6000 mg/m2 and 1000 mg/m2, respectively. At DL2 etoposide was further increased to 600, 960, 960, and 1480 mg/m2 with courses 1 to 4, respectively. Therapy as per protocol was completed by 81.8% of patients. Overall survival at 5 years was 67.2%, freedom from treatment failure (FFTF) was 62.1%, and treatment-related mortality was 4.5%. There was a trend to better FFTF at DL2 compared to DL1 (66.9% versus 54.2%). Repetitive HDT with escalated CHOP plus etoposide is feasible and effective treatment of patients with aNHL. DL2 of this therapy is being used in an ongoing phase 3 study. PMID:16384932

  8. Estimation of changes in vimentin filaments induced by etoposide and doxorubicin in human leukemia cell line K-562 by using immunofluorescence microscopy.

    PubMed

    Grzanka, A

    2001-01-01

    This study was undertaken to examine the influence of etoposide and doxorubicin on the distribution of vimentin in cells of human leukemia cell line K-562 by using immunofluorescence microscopy. The cells were cultured with 5 different doses of etoposide: 0.02, 0.2, 2, 20, 200 microM/l and three doses of doxorubicin: 0.5, 5, 10 microM/l. Changes in vimentin filaments were dependent on concentration of drugs compared to untreated control cells. Cells treated with 20 microM/l, especially with 200 microM/l etoposide were much bigger from other cells exposed to lower doses of etoposide and control cells, and their number decreased. In most control cells vimentin was seen as a ring with the increased concentration on one pole of the cells. In 20 microM/l and 200 microM/l etoposide the cells showed rather a diffuse cytoplasmic staining pattern. Vimentin filaments were organized as a dense network in cytoplasm of these cells. Immunofluorescence studies on K-562 cells treated with doxorubicin showed that cells incubated with 5 microM/l doxorubicin have much diffuse staining pattern of vimentin with delicate reticular structure and with intense staining near one pool of the cells. Addition of 10 microM/l doxorubicin to cells resulted in increasing of fluorescence staining, which appeared in the cells as enough dense network with intense staining rather in the centre of the cell. PMID:11712680

  9. Cell fate determination in cisplatin resistance and chemosensitization.

    PubMed

    Luong, Khanh V; Wang, Ling; Roberts, Brett J; Wahl, James K; Peng, Aimin

    2016-04-26

    Understanding the determination of cell fate choices after cancer treatment will shed new light on cancer resistance. In this study, we quantitatively analyzed the individual cell fate choice in resistant UM-SCC-38 head and neck cancer cells exposed to cisplatin. Our study revealed a highly heterogeneous pattern of cell fate choices in UM-SCC-38 cells, in comparison to that of the control, non-tumorigenic keratinocyte HaCaT cells. In both UM-SCC-38 and HaCaT cell lines, the majority of cell death occurred during the immediate interphase without mitotic entry, whereas significant portions of UM-SCC-38 cells survived the treatment via either checkpoint arrest or checkpoint slippage. Interestingly, checkpoint slippage occurred predominantly in cells treated in late S and G2 phases, and cells in M-phase were hypersensitive to cisplatin. Moreover, although the cisplatin-resistant progression of mitosis exhibited no delay in general, prolonged mitosis was correlated with the induction of cell death in mitosis. The finding thus suggested a combinatorial treatment using cisplatin and an agent that blocks mitotic exit. Consistently, we showed a strong synergy between cisplatin and the proteasome inhibitor Mg132. Finally, targeting the DNA damage checkpoint using inhibitors of ATR, but not ATM, effectively sensitized UM-SCC-38 to cisplatin treatment. Surprisingly, checkpoint targeting eliminated both checkpoint arrest and checkpoint slippage, and augmented the induction of cell death in interphase without mitotic entry. Taken together, our study, by profiling cell fate determination after cisplatin treatment, reveals new insights into chemoresistance and suggests combinatorial strategies that potentially overcome cancer resistance. PMID:26993599

  10. Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma

    PubMed Central

    Morfouace, Marie; Shelat, Anang; Jacus, Megan; Freeman, Burgess B.; Turner, David; Robinson, Sarah; Zindy, Frederique; Wang, Yong-Dong; Finkelstein, David; Ayrault, Olivier; Bihannic, Laure; Li, Xiao-Nan; Olson, James M.; Robinson, Giles W.; Guy, R. Kiplin; Stewart, Clinton F.; Gajjar, Amar; Roussel, Martine F.

    2014-01-01

    SUMMARY We devised a high-throughput, cell-based assay to identify compounds to treat Group3 medulloblastoma (G3 MB). Mouse G3 MBs neurospheres were screened against a library of approximately 7,000 compounds including U.S. Food and Drug Administration (FDA)-approved drugs. We identified pemetrexed and gemcitabine that preferentially inhibited G3 MB proliferation in vitro compared to control neurospheres and substantially inhibited G3 MB proliferation in vivo. When combined, these two drugs significantly increased survival of mice bearing cortical implants of mouse and human G3 MBs that overexpress MYC compared to each agent alone, while having little effect on mouse MBs of the Sonic Hedgehog (SHH) subgroup. Our findings strongly suggest that combination therapy of pemetrexed and gemcitabine is a promising treatment for G3 MBs. PMID:24684846

  11. Laser induced fluorescence spectroscopy of chemo-drugs as biocompatible fluorophores: irinotecan, gemcitabine and navelbine

    NASA Astrophysics Data System (ADS)

    Motlagh, N. S. Hosseini; Parvin, P.; Ghasemi, F.; Atyabi, F.; Jelvani, S.; Abolhosseini, S.

    2016-07-01

    The fluorescence nature of chemo-drugs is useful for simultaneous cancer diagnosis and therapy. Here, the laser induced fluorescence (LIF) properties of irinotecan, gemcitabine and navelbine are extensively investigated. The UV photons provoke the desired transitions of the several chemo-drugs by virtue of the XeCl laser at 308 nm. It is shown that LIF spectra are strongly dependent on the fluorophore concentration, while no spectral shift is measured for irinotecan, gemcitabine and navelbine because of a large Stokes shift. On the other hand, doxorubicin is characterized by a large overlapping between absorption and emission spectra giving rise to a sensible red shift. The fluorescence extinction α and self-quenching k coefficients as well as the quantum yield η f of those chemo-drugs are determined accordingly. In fact, irinotecan shows the highest quantum efficiency among the chemo-drugs of interest.

  12. TM4SF1 Promotes Gemcitabine Resistance of Pancreatic Cancer In Vitro and In Vivo

    PubMed Central

    Ramachandran, Vijaya; Arumugam, Thiruvengadam; Deng, Defeng; Li, Zhaoshen; Xu, Leiming; Logsdon, Craig D.

    2015-01-01

    Background TM4SF1 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and affects the development of this cancer. Also, multidrug resistance (MDR) is generally associated with tumor chemoresistance in pancreatic cancer. However, the correlation between TM4SF1 and MDR remains unknown. This research aims to investigate the effect of TM4SF1 on gemcitabine resistance in PDAC and explore the possible molecular mechanism between TM4SF1 and MDR. Methods The expression of TM4SF1 was evaluated in pancreatic cancer cell lines and human pancreatic duct epithelial (HPDE) cell lines by quantitative RT-PCR. TM4SF1 siRNA transfection was carried out using Hiperfect transfection reagent to knock down TM4SF1. The transcripts were analyzed by quantitative RT-PCR, RT-PCR and western blotting for further study. The cell proliferation and apoptosis were obtained to investigate the sensitivity to gemcitabine of pancreatic cancer cells after silencing TM4SF1 in vitro. We demonstrated that cell signaling of TM4SF1 mediated chemoresistance in cancer cells by assessing the expression of multidrug resistance (MDR) genes using quantitative RT-PCR. In vivo, we used orthotopic pancreatic tumor models to investigate the effect of proliferation after silencing TM4SF1 by a lentivirus-mediated shRNA in MIA PaCa-2 cell lines. Results The mRNA expression of TM4SF1 was higher in seven pancreatic cancer cell lines than in HPDE cell lines. In three gemcitabine-sensitive cell lines (L3.6pl, BxPC-3, SU86.86), the expression of TM4SF1 was lower than that in four gemcitabine-resistant cell lines (MIA PaCa-2, PANC-1, Hs766T, AsPC-1). We evaluated that TM4SF1 was a putative target for gemcitabine resistance in pancreatic cancer cells. Using AsPC-1, MIA PaCa-2 and PANC-1, we investigated that TM4SF1 silencing affected cell proliferation and increased the percentages of cell apoptosis mediated by treatment with gemcitabine compared with cells which were treated with negative control. This resistance was

  13. [R0 Resection of Locally Advanced Pancreatic Cancer after Combination Chemotherapy with Gemcitabine and S-1].

    PubMed

    Kametaka, Hisashi; Makino, Hironobu; Fukada, Tadaomi; Seike, Kazuhiro; Koyama, Takashi; Hasegawa, Akio

    2015-11-01

    A 68-year-old female was referred to our institution in October 2014 for additional therapy for cancer of the head of the pancreas. Utilizing a computed tomography scan, he was initially diagnosed with locally advanced unresectable cancer because of massive invasion to the superior mesenteric artery (SMA). Combination chemotherapy consisting of gemcitabine and S-1 was administrated for 10 months. Since the tumor was remarkably reduced after chemotherapy, pancreaticoduodenectomy combined with portal vein resection was performed. Since the histopathological findings indicated few residual cancer tissues, our chemotherapy was considered dramatically effective. The postoperative course was uneventful and the patient remains well and without any recurrences 14 months after the surgery. We therefore report a case of locally unresectable pancreatic cancer, which achieved R0 resection after combination chemotherapy with gemcitabine and S-1. PMID:26805123

  14. Predictive Modeling of In Vivo Response to Gemcitabine in Pancreatic Cancer

    PubMed Central

    Lee, James J.; Huang, Justin; England, Christopher G.; McNally, Lacey R.; Frieboes, Hermann B.

    2013-01-01

    A clear contradiction exists between cytotoxic in-vitro studies demonstrating effectiveness of Gemcitabine to curtail pancreatic cancer and in-vivo studies failing to show Gemcitabine as an effective treatment. The outcome of chemotherapy in metastatic stages, where surgery is no longer viable, shows a 5-year survival <5%. It is apparent that in-vitro experiments, no matter how well designed, may fail to adequately represent the complex in-vivo microenvironmental and phenotypic characteristics of the cancer, including cell proliferation and apoptosis. We evaluate in-vitro cytotoxic data as an indicator of in-vivo treatment success using a mathematical model of tumor growth based on a dimensionless formulation describing tumor biology. Inputs to the model are obtained under optimal drug exposure conditions in-vitro. The model incorporates heterogeneous cell proliferation and death caused by spatial diffusion gradients of oxygen/nutrients due to inefficient vascularization and abundant stroma, and thus is able to simulate the effect of the microenvironment as a barrier to effective nutrient and drug delivery. Analysis of the mathematical model indicates the pancreatic tumors to be mostly resistant to Gemcitabine treatment in-vivo. The model results are confirmed with experiments in live mice, which indicate uninhibited tumor proliferation and metastasis with Gemcitabine treatment. By extracting mathematical model parameter values for proliferation and death from monolayer in-vitro cytotoxicity experiments with pancreatic cancer cells, and simulating the effects of spatial diffusion, we use the model to predict the drug response in-vivo, beyond what would have been expected from sole consideration of the cancer intrinsic resistance. We conclude that this integrated experimental/computational approach may enhance understanding of pancreatic cancer behavior and its response to various chemotherapies, and, further, that such an approach could predict resistance based on

  15. Enhanced cellular uptake and intracellular drug controlled release of VESylated gemcitabine prodrug nanocapsules.

    PubMed

    Fang, Yanfen; Du, Fang; Xu, Yanyun; Meng, Haijing; Huang, Jin; Zhang, Xiongwen; Lu, Wei; Liu, Shiyuan; Yu, Jiahui

    2015-04-01

    Gemcitabine, 2',2'-difluoro-2'-deoxycytidine (dFdC), is the first-line antitumor agent in the treatment of pancreatic tumors. However, it possesses certain drawbacks, such as poor biological half-life resulted from rapid metabolism and the induction of resistance, leading to its restricted therapeutic potential. With the purpose of overcoming the above drawbacks, we developed a novel VESylated gemcitabine (VES-dFdC) prodrug by coupling the N4-amino group of the pyrimidine ring of dFdC to the carboxylic group of vitamin E succinate (VES). The resulting amphiphilic compound could protect the N4-amino group of the pyrimidine ring of dFdC from being degraded by cytidine deaminase. What is more, the prodrug was able to form nanocapsules in aqueous media (similar to the structure of cytomembrane), confirmed by transmission electron microscope (TEM). Their average particle size is about 107 nm with zeta potential of -33.4 mV measured by dynamic light scattering (DLS). VES-dFdC nanocapsules showed accelerated accumulative drug release profile in simulated lysosome environment (sodium acetate buffer pH 5+cathepsin B, an enzyme in lysosome), due to the easily hydrolyzed property of amide bond by cathepsin B, while rather stable in PBS (pH 7.4) or sodium acetate buffer (pH 5.0) without cathepsin B, indicating their enhanced intracellular drug controlled release manner. Besides, VES-dFdC prodrug nanocapsules showed enhanced cellular uptake ability, and the amount of cellular uptake of the nanocapsules by the pancreatic cancer cell line BxPC-3 is seventy times higher than that of native gemcitabine in the first 1.5 h. Compared with free gemcitabine, VES-dFdC nanocapsules showed essentially increased growth inhibition activity against BxPC-3 cells, indicating its great potential as prodrug for pancreatic tumor therapy with improved antitumor activity. PMID:25746328

  16. Gemcitabine Chemotherapy and Single-Fraction Stereotactic Body Radiotherapy for Locally Advanced Pancreatic Cancer

    SciTech Connect

    Schellenberg, Devin; Goodman, Karyn A.; Lee, Florence; Chang, Stephanie; Kuo, Timothy; Quon, Andrew; Desser, Terry S.; Norton, Jeffrey; Greco, Ralph; Yang, George P.; Koong, Albert C.

    2008-11-01

    Purpose: Fractionated radiotherapy and chemotherapy for locally advanced pancreatic cancer achieves only modest local control. This prospective trial evaluated the efficacy of a single fraction of 25 Gy stereotactic body radiotherapy (SBRT) delivered between Cycle 1 and 2 of gemcitabine chemotherapy. Methods and Materials: A total of 16 patients with locally advanced, nonmetastatic, pancreatic adenocarcinoma received gemcitabine with SBRT delivered 2 weeks after completion of the first cycle. Gemcitabine was resumed 2 weeks after SBRT and was continued until progression or dose-limiting toxicity. The gross tumor volume, with a 2-3-mm margin, was treated in a single 25-Gy fraction by Cyberknife. Patients were evaluated at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT. Results: All 16 patients completed SBRT. A median of four cycles (range one to nine) of chemotherapy was delivered. Three patients (19%) developed local disease progression at 14, 16, and 21 months after SBRT. The median survival was 11.4 months, with 50% of patients alive at 1 year. Patients with normal carbohydrate antigen (CA)19-9 levels either at diagnosis or after Cyberknife SBRT had longer survival (p <0.01). Acute gastrointestinal toxicity was mild, with 2 cases of Grade 2 (13%) and 1 of Grade 3 (6%) toxicity. Late gastrointestinal toxicity was more common, with five ulcers (Grade 2), one duodenal stenosis (Grade 3), and one duodenal perforation (Grade 4). A trend toward increased duodenal volumes radiated was observed in those experiencing late effects (p = 0.13). Conclusion: SBRT with gemcitabine resulted in comparable survival to conventional chemoradiotherapy and good local control. However, the rate of duodenal ulcer development was significant.

  17. Chitosan and glyceryl monooleate nanostructures containing gemcitabine: potential delivery system for pancreatic cancer treatment.

    PubMed

    Trickler, William J; Khurana, Jatin; Nagvekar, Ankita A; Dash, Alekha K

    2010-03-01

    The objectives of this study are to enhance cellular accumulation of gemcitabine with chitosan/glyceryl monooleate (GMO) nanostructures, and to provide significant increase in cell death of human pancreatic cancer cells in vitro. The delivery system was prepared by a multiple emulsion solvent evaporation method. The nanostructure topography, size, and surface charge were determined by atomic force microscopy (AFM), and a zetameter. The cellular accumulation, cellular internalization and cytotoxicity of the nanostructures were evaluated by HPLC, confocal microscopy, or MTT assay in Mia PaCa-2 and BxPC-3 cells. The average particle diameter for 2% and 4% (w/w) drug loaded delivery system were 382.3 +/- 28.6 nm, and 385.2 +/- 16.1 nm, respectively with a surface charge of +21.94 +/- 4.37 and +21.23 +/- 1.46 mV. The MTT cytotoxicity dose-response studies revealed the placebo at/or below 1 mg/ml has no effect on MIA PaCa-2 or BxPC-3 cells. The delivery system demonstrated a significant decrease in the IC50 (3 to 4 log unit shift) in cell survival for gemcitabine nanostructures at 72 and 96 h post-treatment when compared with a solution of gemcitabine alone. The nanostructure reported here can be resuspended in an aqueous medium that demonstrate increased effective treatment compared with gemcitabine treatment alone in an in vitro model of human pancreatic cancer. The drug delivery system demonstrates capability to entrap both hydrophilic and hydrophobic compounds to potentially provide an effective treatment option in human pancreatic cancer. PMID:20238190

  18. Telomerase (GV1001) vaccination together with gemcitabine in advanced pancreatic cancer patients.

    PubMed

    Staff, Caroline; Mozaffari, Fariba; Frödin, Jan-Erik; Mellstedt, Håkan; Liljefors, Maria

    2014-09-01

    Telomerase is expressed in 85-90 % of pancreatic adenocarcinomas and might be a target for active cancer immunotherapy. A study was conducted to investigate safety and immunogenicity in non-resectable pancreatic carcinoma patients using a 16-amino acid telomerase peptide (GV1001) for vaccination in combination with GM-CSF and gemcitabine as first line treatment. Three different vaccine treatment schedules were used; [A (n=6), B (n=6) and C (n=5)]. Groups A/B received GV1001, GM-CSF and gemcitabine concurrently. Group C received initially GV1001 and GM-CSF while gemcitabine was added at disease progression. Group D (n=4) was treated with gemcitabine alone. Adverse events (AE) related to vaccination were mild (grades I-II). Grade III AEs were few and transient. An induced GV 1001‑specific immune response was defined as an increase ≥2 above the baseline value in one of the assays (DTH, proliferation, ELISPOT and cytokine secretion assays, respectively). A telomerase‑specific immune response was noted in 4/6 patients in group A, 4/6 patients in group B and 2/5 patients in group C. An induced ras‑specific immune response (antigenic spreading) was seen in 5 of the 17 patients. The cytokine pattern was that of a Th1-like profile. A treatment induced telomerase or ras response was also noted in group D. All responses were weak and transient. A significant decrease in regulatory T-cells over time was noted in patients in groups A and B (p<0.05). Telomerase vaccination (GV1001) in combination with chemotherapy appeared to be safe but the immune responses were weak and transient. Measures have to be taken to optimize immune responses of GV1001 for it to be considered of clinical interest. PMID:24919654

  19. Long term survivors with metastatic pancreatic adenocarcinoma treated with gemcitabine: a retrospective analysis

    PubMed Central

    Goulart, Bernardo HL; Clark, Jeffrey W; Lauwers, Gregory Y; Ryan, David P; Grenon, Nina; Muzikansky, Alona; Zhu, Andrew X

    2009-01-01

    Background Metastatic pancreatic adenocarcinoma has a short median overall survival (OS) of 5–6 months. However, a subgroup of patients survives more than 1 year. We analyzed the survival outcomes of this subgroup and evaluated clinical and pathological factors that might affect survival durations. Methods We identified 20 patients with metastatic or recurrent pancreatic adenocarcinoma who received single-agent gemcitabine and had an OS longer than 1 year. Baseline data available after the diagnosis of metastatic or recurrent disease was categorized as: 1) clinical/demographic data (age, gender, ECOG PS, number and location of metastatic sites); 2) Laboratory data (Hematocrit, hemoglobin, glucose, LDH, renal and liver function and CA19-9); 3) Pathologic data (margins, nodal status and grade); 4) Outcomes data (OS, Time to Treatment Failure (TTF), and 2 year-OS). The lowest CA19-9 levels during treatment with gemcitabine were also recorded. We performed a univariate analysis with OS as the outcome variable. Results Baseline logarithm of CA19-9 and total bilirubin had a significant impact on OS (HR = 1.32 and 1.31, respectively). Median OS and TTF on gemcitabine were 26.9 (95% CI = 18 to 32) and 11.5 (95% CI = 9.0 to 14.3) months, respectively. Two-year OS was 56.4%, with 7 patients alive at the time of analysis. Conclusion A subgroup of patients with metastatic pancreatic cancer has prolonged survival after treatment with gemcitabine. Only bilirubin and CA 19-9 levels were predictive of longer survival in this population. Further analysis of potential prognostic and predictive markers of response to treatment and survival are needed. PMID:19291303

  20. Phase II study of trastuzumab plus gemcitabine in chemotherapy-pretreated patients with metastatic breast cancer.

    PubMed

    O'Shaughnessy, Joyce A; Vukelja, Sasha; Marsland, Thomas; Kimmel, Gary; Ratnam, Suresh; Pippen, John E

    2004-06-01

    We evaluated the efficacy and toxicity of trastuzumab plus gemcitabine in patients with HER2-positive metastatic breast cancer (MBC). Sixty-four patients were enrolled, the majority of whom (95%) had been treated with an anthracycline and a taxane before study enrollment. Eligible women were treated with gemcitabine (1200 mg/m(2) weekly for 2 weeks with the third week off on a 21-day cycle) plus weekly doses of trastuzumab (4-mg/kg loading dose; 2 mg/kg thereafter) until disease progression. The median patient age was 55 years, and the median number of previously administered (including adjuvant) chemotherapy regimens was 3. Twenty-two patients were scored as 2+ for HER2 expression by immunohistochemistry; 39 patients scored 3+. Three patients were assessed as HER2-negative on central pathology review and were ineligible for evaluation. Fifty-nine of the 61 patients remained evaluable for response. The objective response rates were 38% in the intent-to-treat population (23 of 61) and 44% among the 39 patients with HER2 3+ expression. The median response duration was 5.8 months, median overall survival was 14.7 months, and median time to disease progression was 5.8 months. Trastuzumab plus gemcitabine was well tolerated. No cases of clinical congestive heart failure occurred. Grade 3/4 toxicities included asthenia in 4 patients, fever in 4, neutropenia in 18, dyspnea in 6, abdominal or back pain in 3, and edema and nausea in 1 patient each. The combination of trastuzumab plus gemcitabine appears to be well tolerated and effective for patients with HER2-positive MBC previously treated with chemotherapy. PMID:15245619

  1. Discovery – Cisplatin and The Treatment of Testicular and Other Cancers

    Cancer.gov

    Prior to the discovery of cisplatin in 1965, men with testicular cancer had few medical options. Now, thanks to NCI research, cisplatin and similar chemotherapy drugs are known for curing testicular and other forms of cancer.

  2. Knockdown of retinoblastoma protein may sensitize glioma cells to cisplatin through inhibition of autophagy.

    PubMed

    Liu, Xiangyu; Sun, Kangjian; Wang, Handong; Dai, Yuyuan

    2016-05-01

    Glioblastoma multiforme (GBM) is one of the deadliest forms of cancer due to its limited sensitivity to chemotherapy and radiotherapy. Cisplatin (CCDP) is a widely used chemotherapeutic agent for tumors, but the agent often results in the development of chemo-resistance. In several cancers, cisplatin resistance is associated with autophagy induction. Here, we found that in glioma cells cisplatin treatment induced autophagy. Our data indicates that the autophagy induction plays a critical role in cisplatin resistance of glioma cells, knockdown of RB inhibited autophagy induced by cisplatin, and inhibition of autophagy improved cisplatin-induced apoptosis. It suggests that a combination of autophagy inhibitors with cisplatin may improve the therapeutic efficiency of cisplatin towards GBM with acquired resistance. PMID:27048711

  3. Multidrug-resistant hela cells overexpressing MRP1 exhibit sensitivity to cell killing by hyperthermia: Interactions with etoposide

    SciTech Connect

    Souslova, Tatiana; Averill-Bates, Diana A. . E-mail: averill.diana@uqam.ca

    2004-12-01

    Purpose: Multidrug resistance (MDR) remains one of the primary obstacles in cancer chemotherapy and often involves overexpression of drug efflux transporters such as P-glycoprotein and multidrug resistance protein 1 (MRP1). Regional hyperthermia is undergoing clinical investigation in combination with chemotherapy or radiotherapy. This study evaluates whether hyperthermia can reverse MDR mediated by MRP1 in human cervical adenocarcinoma (HeLa) cells. Methods and materials: Cytotoxicity of hyperthermia and/or etoposide was evaluated using sulforhodamine-B in HeLa cells overexpressing MRP1 and their drug-sensitive counterparts. Glutathione, glutathione peroxidase (GPx), and glutathione S-transferase (GST) were quantified by spectrophotometry. GST isoenzymes were quantified by immunodetection. Caspase activation was evaluated by fluorometry and chromatin condensation by fluorescence microscopy using Hoechst 33258. Necrosis was determined using propidium iodide. Results: The major finding is that HeLa and HeLaMRP cells are both sensitive to cytotoxicity of hyperthermia (41-45 deg C). Hyperthermia induced activation of caspase 3 and chromatin condensation. Although total levels of cell killing were similar, there was a switch from apoptotic to necrotic cell death in MDR cells. This could be explained by decreased glutathione and GPx in MDR cells. MDR cells also contained very low levels of GST and were resistant to etoposide-induced apoptosis. Hyperthermia caused a modest increase in etoposide-induced apoptosis in HeLa and HeLaMRP cells, which required appropriate heat-drug scheduling. Conclusions: Hyperthermia could be useful in eliminating MDR cells that overexpress MRP1.

  4. High-dose cyclophosphamide, carboplatin, and etoposide with autologous stem cell rescue in patients with breast cancer.

    PubMed

    deMagalhaes-Silverman, M; Rybka, W B; Lembersky, B; Bloom, E J; Lister, J; Pincus, S M; Voloshin, M; Wilson, J; Ball, E D

    1996-04-01

    This study was designed to establish the toxicity and response rates o observed with a combination of high-dose cyclophosphamide, carboplatin, and etoposide with stem cell rescue in patients with breast carcinoma. Eligibility criteria included metastatic or locally advanced breast carcinoma ; aged < or equal to 60 years; performance status Eastern Cooperative Oncology Group (ECOG) 0-1; and creatinine clearance > or equal to 65 ml/min. Chemotherapy consisted of cyclophosphamide 25 mg/kg i.v. X 4 days, etoposide 400 mg/m(2) i.v. X 4 days, and carboplatin 375 mg/m(2) X 4 days. Bone marrow or peripheral blood stem cells were reinfused 48 h after completion of chemotherapy. Seventeen patients were treated in this study. The major toxicity was gastrointestinal (grades I and II). Fevers associated with neutropenia were observed in all the patients, but no episodes of bacteremia were documented. Hematopoietic toxicities were acceptable. No toxic deaths were observed. Six patients had chemotherapy-sensitive disease at time of transplant, nine had refractory disease, and two were untested. A response rate of 62% with 18% complete response (CR) was achieved. Two patients are free of disease at +7 and +9 months after transplantation. The combination of high-dose cyclophosphamide, carboplatin, and etoposide is well tolerated with a response rate comparable to previously reported high-dose chemotherapy regimens. However, in a poor prognostic risk group, namely patients with chemoinsensitive disease, this therapeutic approach seems to be of no advantage over standard chemotherapy. PMID:8610643

  5. A novel mouse PKC{delta} splice variant, PKC{delta}IX, inhibits etoposide-induced apoptosis

    SciTech Connect

    Kim, Jung D.; Seo, Kwang W.; Lee, Eun A.; Quang, Nguyen N.; Cho, Hong R.; Kwon, Byungsuk

    2011-07-01

    Highlights: {yields} A novel PKC{delta} isoform, named PKC{delta}IX, that lacks the C1 domain and the ATP-binding site is ubiquitously expressed. {yields} PKC{delta}IX inhibits etoposide-induced apoptosis. {yields} PKC{delta}IX may function as an endogenous dominant negative isoform for PKC{delta}. -- Abstract: Protein kinase C (PKC) {delta} plays an important role in cellular proliferation and apoptosis. The catalytic fragment of PKC{delta} generated by caspase-dependent cleavage is essential for the initiation of etoposide-induced apoptosis. In this study, we identified a novel mouse PKC{delta} isoform named PKC{delta}IX (Genebank Accession No. (HQ840432)). PKC{delta}IX is generated by alternative splicing and is ubiquitously expressed, as seen in its full-length PKC{delta}. PKC{delta}IX lacks the C1 domain, the caspase 3 cleavage site, and the ATP binding site but preserves an almost intact c-terminal catalytic domain and a nuclear localization signal (NLS). The structural characteristics of PKC{delta}IX provided a possibility that this PKC{delta} isozyme functions as a novel dominant-negative form for PKC{delta} due to its lack of the ATP-binding domain that is required for the kinase activity of PKC{delta}. Indeed, overexpression of PKC{delta}IX significantly inhibited etoposide-induced apoptosis in NIH3T3 cells. In addition, an in vitro kinase assay showed that recombinant PKC{delta}IX protein could competitively inhibit the kinase activity of PKC{delta}. We conclude that PKC{delta}IX can function as a natural dominant-negative inhibitor of PKC{delta}in vivo.

  6. Prolonged complete response following gemcitabine-erlotinib combined therapy in advanced pancreatic cancer

    PubMed Central

    CZARNECKA, ANNA M.; KORZEŃ, PIOTR; NOWAK-DEMENT, ANNA; KUKWA, WOJCIECH; KORNILUK, JAN; SZCZYLIK, CEZARY

    2016-01-01

    Pancreatic cancer is one of the most lethal types of malignant solid tumor and is typically associated with a poor prognosis. The majority of patients are diagnosed with advanced-stage disease, therefore, the median survival period is <6 months. Recently, a number of basic research projects and clinical trials were undertaken with the aim of improving treatment outcomes in pancreatic cancer; however, only one agent, erlotinib, passed the clinical trials. Erlotinib is an inhibitor of epidermal growth factor receptor, which when overexpressed in cancer, promotes angiogenesis, cell proliferation and inhibits apoptosis. The US Food and Drug Administration and European Medicines Agency approved erlotinib in combination with gemcitabine for the first-line treatment of advanced pancreatic cancer. To the best of our knowledge, the current study is the first to report a case of pancreatic cancer treated with this regimen alone to achieve a complete response (CR). A 40-year-old male with a medical history of chronic pancreatitis and hypertension was diagnosed with medically inoperable adenocarcinoma of the pancreas. Following palliative surgery, the patient began palliative gemcitabine and erlotinib chemotherapy. After three months, this treatment strategy resulted in a CR, as determined by imaging studies. Therapy was discontinued after 14 months due to the development of peritoneal metastases and the patient was referred for treatment with the folinic acid, 5-fluorouracil, irinotecan and oxaliplatin regimen. A CR is rarely reported in pancreatic cancer, however, a treatment strategy of gemcitabine and erlotinib may induce rapid regression of advanced-stage disease. PMID:26893699

  7. Development and Characterization of Nanoparticles for the Delivery of Gemcitabine Hydrochloride

    PubMed Central

    Khaira, Rekha; Sharma, Jyoti; Saini, Vinay

    2014-01-01

    Gemcitabine (2,2-difluorodeoxycytidine) is a deoxycytidine analog, currently being used as a first-choice drug in pancreatic metastatic cancer. Gemcitabine is administered weekly as 30-minute infusion with starting dose ranging from 800 to 1250 mg/m2. The aim of the present work was to develop starch nanoparticles (NPs) for the delivery of gemcitabine hydrochloride that could reduce its dose related side effects and may prolong its retention time (24 hrs) for the treatment of pancreatic cancer. Nanoparticles were prepared by emulsification diffusion method with slight modifications. Size and morphology of nanoparticles were investigated. Particles were spherical in shape with slightly rough surfaces. Particle size and polydispersity index were 231.4 nm and 1.0, respectively while zeta potential of blank NPs and drug loaded NPs were found to be −11.8 mV and −9.55 mV, respectively. Percent entrapment efficiency of different formulations was around ∼54% to 65%. In vitro release profile studies showed that around 70%–83% of drug was released from different formulations. Anticancerous cell line studies were also performed in human pancreatic cell lines (MIA-PA-CA-2). PMID:24592173

  8. Mild Hyperthermia Enhances Transport of Liposomal Gemcitabine and Improves in vivo Therapeutic Response

    PubMed Central

    Kirui, Dickson K; Celia, Christian; Molinaro, Roberto; Bansal, Shyam S.; Cosco, Donato; Fresta, Massimo; Shen, Haifa; Ferrari, Mauro

    2015-01-01

    Obstructive biological barriers limit the transport and efficacy of cancer nanotherapeutics. Creative manipulation of tumor microenvironment provides promising avenues towards improving chemotherapeutic response. Such strategies include the use of mechanical stimuli to overcome barriers, and increase drug delivery and therapeutic efficacy. The rational use of gold nanorod-mediated mild hyperthermia treatment (MHT) alters tumor transport properties, increases liposomal gemcitabine (Gem Lip) delivery and anti-tumor efficacy in pancreatic cancer CAPAN-1 tumor model. MHT treatment led to a 3-fold increase in accumulation of 80-nm liposomes and enhanced spatial interstitial distribution. I.v. injection of Gem Lip and MHT treatment led to a 3-fold increase in intratumor gemcitabine concentration compared to chemotherapeutic infusion alone. Furthermore, combination of MHT treatment with infusion of 12 mg/kg Gem Lip led to a 2-fold increase in therapeutic efficacy and inhibition of CAPAN-1 tumor growth when compared to equimolar chemotherapeutic treatment alone. Enhanced therapeutic effect was confirmed by reduction in tumor size and increase in apoptotic index where MHT treatment combined with 12 mg/kg Gem Lip achieved similar therapeutic efficacy as the use of 60 mg/kg free gemcitabine. In conclusion, we demonstrated improvements in vivo efficacy resulting from MHT treatment that overcome transport barriers, promote delivery, improve efficacy of nanomedicines. PMID:25721343

  9. Transcatheter arterial chemoembolization with gemcitabine and oxaliplatin for the treatment of advanced biliary tract cancer

    PubMed Central

    Zhao, Qing; Qian, Sheng; Zhu, Liang; Qu, Xu-Dong; Zhang, Wei; Yan, Zhi-Ping; Cheng, Jie-Min; Liu, Qing-Xin; Liu, Rong; Wang, Jian-Hua

    2015-01-01

    Background The aim of this study was to determine the therapeutic efficacy and safety of transarterial chemoembolization (TACE) with gemcitabine and oxaliplatin in patients with advanced biliary tract cancer (BTC). Methods We retrospectively analyzed the outcomes for 65 patients with advanced BTC treated by TACE with gemcitabine 1,000 mg/m2 and oxaliplatin 100 mg/m2. Follow-up laboratory tests and computed tomography or magnetic resonance imaging were performed routinely to evaluate the response of the tumor to treatment. All patients were assessed for adverse effects. Results Of the 65 patients, 19 (29.2%) achieved a partial response, 36 (55.4%) showed stable disease, and ten (15.4%) showed progressive disease. The overall response rate was 29.2%. At the end of this study, five patients were still alive. The median overall survival was 12.0 months (95% confidence interval 8.5–15.5). There were no serious complications after TACE. Conclusion The disease control rate and overall survival in this retrospective study were consistent with those in previous reports. TACE with gemcitabine and oxaliplatin was well tolerated and highly effective in patients with advanced BTC. PMID:25792843

  10. PEGylated squalenoyl-gemcitabine nanoparticles for the treatment of glioblastoma.

    PubMed

    Gaudin, Alice; Song, Eric; King, Amanda R; Saucier-Sawyer, Jennifer K; Bindra, Ranjit; Desmaële, Didier; Couvreur, Patrick; Saltzman, W Mark

    2016-10-01

    New treatments for glioblastoma multiforme (GBM) are desperately needed, as GBM prognosis remains poor, mainly due to treatment resistance, poor distribution of therapeutics in the tumor tissue, and fast metabolism of chemotherapeutic drugs in the brain extracellular space. Convection-enhanced delivery (CED) of nanoparticles (NPs) has been shown to improve the delivery of chemotherapeutic drugs to the tumor bed, providing sustained release, and enhancing survival of animals with intracranial tumors. Here we administered gemcitabine, a nucleoside analog used as a first line treatment for a wide variety of extracranial solid tumors, within squalene-based NPs using CED, to overcome the above-mentioned challenges of GBM treatment. Small percentages of poly(ethylene) glycol (PEG) dramatically enhanced the distribution of squalene-gemcitabine nanoparticles (SQ-Gem NPs) in healthy animals and tumor-bearing animals after administration by CED. When tested in an orthotopic model of GBM, SQ-Gem-PEG NPs demonstrated significantly improved therapeutic efficacy compared to free gemcitabine, both as a chemotherapeutic drug and as a radiosensitizer. Furthermore, MR contrast agents were incorporated into the SQ-Gem-PEG NP formulation, providing a way to non-invasively track the NPs during infusion. PMID:27521616

  11. Development and bioorthogonal activation of palladium-labile prodrugs of gemcitabine.

    PubMed

    Weiss, Jason T; Dawson, John C; Fraser, Craig; Rybski, Witold; Torres-Sánchez, Carmen; Bradley, Mark; Patton, E Elizabeth; Carragher, Neil O; Unciti-Broceta, Asier

    2014-06-26

    Bioorthogonal chemistry has become one of the main driving forces in current chemical biology, inspiring the search for novel biocompatible chemospecific reactions for the past decade. Alongside the well-established labeling strategies that originated the bioorthogonal paradigm, we have recently proposed the use of heterogeneous palladium chemistry and bioorthogonal Pd(0)-labile prodrugs to develop spatially targeted therapies. Herein, we report the generation of biologically inert precursors of cytotoxic gemcitabine by introducing Pd(0)-cleavable groups in positions that are mechanistically relevant for gemcitabine's pharmacological activity. Cell viability studies in pancreatic cancer cells showed that carbamate functionalization of the 4-amino group of gemcitabine significantly reduced (>23-fold) the prodrugs' cytotoxicity. The N-propargyloxycarbonyl (N-Poc) promoiety displayed the highest sensitivity to heterogeneous palladium catalysis under biocompatible conditions, with a reaction half-life of less than 6 h. Zebrafish studies with allyl, propargyl, and benzyl carbamate-protected rhodamines confirmed N-Poc as the most suitable masking group for implementing in vivo bioorthogonal organometallic chemistry. PMID:24867590

  12. Mild hyperthermia enhances transport of liposomal gemcitabine and improves in vivo therapeutic response.

    PubMed

    Kirui, Dickson K; Celia, Christian; Molinaro, Roberto; Bansal, Shyam S; Cosco, Donato; Fresta, Massimo; Shen, Haifa; Ferrari, Mauro

    2015-05-01

    Obstructive biological barriers limit the transport and efficacy of cancer nanotherapeutics. Creative manipulation of tumor microenvironment provides promising avenues towards improving chemotherapeutic response. Such strategies include the use of mechanical stimuli to overcome barriers, and increase drug delivery and therapeutic efficacy. The rational use of gold nanorod-mediated mild hyperthermia treatment (MHT) alters tumor transport properties, increases liposomal gemcitabine (Gem Lip) delivery, and antitumor efficacy in pancreatic cancer CAPAN-1 tumor model. MHT treatment leads to a threefold increase in accumulation of 80-nm liposomes and enhances spatial interstitial distribution. I.v. injection of Gem Lip and MHT treatment lead to a threefold increase in intratumor gemcitabine concentration compared to chemotherapeutic infusion alone. Furthermore, combination of MHT treatment with infusion of 12 mg kg(-1) Gem Lip leads to a twofold increase in therapeutic efficacy and inhibition of CAPAN-1 tumor growth when compared to equimolar chemotherapeutic treatment alone. Enhanced therapeutic effect is confirmed by reduction in tumor size and increase in apoptotic index where MHT treatment combined with 12 mg kg(-1) Gem Lip achieves similar therapeutic efficacy as the use of 60 mg kg(-1) free gemcitabine. In conclusion, improvements in vivo efficacy are demonstrated resulting from MHT treatment that overcome transport barriers, promote delivery, improve efficacy of nanomedicines. PMID:25721343

  13. Phase II trial of carboplatin plus oral etoposide for elderly patients with small-cell lung cancer.

    PubMed Central

    Matsui, K.; Masuda, N.; Fukuoka, M.; Yana, T.; Hirashima, T.; Komiya, T.; Kobayashi, M.; Kawahara, M.; Atagi, S.; Ogawara, M.; Negoro, S.; Kudoh, S.; Furuse, K.

    1998-01-01

    A phase II trial was conducted to evaluate the efficacy and toxicity of the Egorin's carboplatin dosing formula with 14-day oral etoposide in 38 elderly patients with small-cell lung cancer (SCLC). The overall response rate was 81%. Median survival times were 15.1 months for 16 limited-disease (LD) and 8.6 months for 22 extensive-disease (ED) patients. Myelosuppression was the principal side-effect. This regimen is an active regimen in the treatment of elderly SCLC patients. PMID:9667675

  14. Long-circulatory nanoparticles for gemcitabine delivery: Development and investigation of pharmacokinetics and in-vivo anticancer efficacy.

    PubMed

    Khare, Vaibhav; Singh, Amarinder; Mahajan, Girish; Alam, Noor; Kour, Smit; Gupta, Mehak; Kumar, Ajay; Singh, Gurdarshan; Singh, Shashank K; Saxena, Ajit K; Mondhe, Dilip M; Gupta, Prem N

    2016-09-20

    The anticancer potential of gemcitabine, a nucleoside analog, is compromised due to the enzymatic degradation into inactive form leading to the short half-life in systemic circulation. Novel delivery strategies are required to improve therapeutic efficacy of this potential drug. Monomethoxy polyethylene glycol amine-polylactide-co-glycolide (mPEG-PLGA) co-polymer was synthesized and characterized by FTIR and (1)H NMR. Gemcitabine loaded mPEG-PLGA nanoparticles (NPs) were developed and investigated for pharmacokinetic profile and in vivo anticancer activity. The mPEG-PLGA NPs (size: 267±10nm, zeta potential: -17.5±0.2mV) exhibited sustained drug release profile and were found to be compatible with blood. The mPEG-PLGA NPs were able to evade the uptake by macrophages (i.e. THP-1 and J774A) by reducing the adsorption of proteins on the surface of NPs. The enhanced cellular uptake and cell cytotoxicity was observed by mPEG-PLGA NPs in MiaPaCa-2 and MCF-7 cells. The half-life of gemcitabine in mPEG-PLGA NPs was remarkably enhanced (19 folds) than native gemcitabine. Further, the pharmacokinetic modulation of gemcitabine using mPEG-PLGA-NPs was translated in improved anticancer efficacy as compared to native gemcitabine in Ehrlich ascites bearing Balb-c mice. The results demonstrated the potential of long-circulatory nanoparticles in improving the pharmacokinetic profile and in-turn the anticancer efficacy of gemcitabine. PMID:27404580

  15. Efficacy of low-dose oral metronomic dosing of the prodrug of gemcitabine, LY2334737, in human tumor xenografts.

    PubMed

    Pratt, Susan E; Durland-Busbice, Sara; Shepard, Robert L; Donoho, Gregory P; Starling, James J; Wickremsinhe, Enaksha R; Perkins, Everett J; Dantzig, Anne H

    2013-04-01

    LY2334737, an oral prodrug of gemcitabine, is cleaved in vivo, releasing gemcitabine and valproic acid. Oral dosing of mice results in absorption of intact prodrug with slow systemic hydrolysis yielding higher plasma levels of LY2334737 than gemcitabine and prolonged gemcitabine exposure. Antitumor activity was evaluated in human colon and lung tumor xenograft models. The dose response for efficacy was examined using 3 metronomic schedules, once-a-day dosing for 14 doses, every other day for 7 doses, and once a day for 7 doses, 7 days rest, followed by an additional 7 days of once-a-day dosing. These schedules gave significant antitumor activity and were well tolerated. Oral gavage of 6 mg/kg LY2334737 daily for 21 days gave equivalent activity to i.v. 240 mg/kg gemcitabine. HCl administered once a week for 3 weeks to mice bearing a patient mesothelioma tumor PXF 1118 or a non-small cell lung cancer tumor LXFE 937. The LXFE 397 tumor possessed elevated expression of the equilibrative nucleoside transporter-1 (ENT1) important for gemcitabine uptake but not prodrug uptake and responded significantly better to treatment with LY2334737 than gemcitabine (P ≤ 0.001). In 3 colon xenografts, antitumor activity of LY2334737 plus a maximally tolerated dose of capecitabine, an oral prodrug of 5-fluorouracil, was significantly greater than either monotherapy. During treatment, the expression of carboxylesterase 2 (CES2) and concentrative nucleoside transporter-3 was induced in HCT-116 tumors; both are needed for the activity of the prodrugs. Thus, metronomic oral low-dose LY2334737 is efficacious, well tolerated, and easily combined with capecitabine for improved efficacy. Elevated CES2 or ENT1 expression may enhance LY2334737 tumor response. PMID:23371859

  16. Original Article A phase I study of imexon plus gemcitabine as first-line therapy for advanced pancreatic cancer

    PubMed Central

    Cohen, Steven J.; Zalupski, Mark M.; Modiano, Manuel R.; Conkling, Paul; Patt, Yehuda Z.; Davis, Peg; Dorr, Robert T.; Boytim, Michelle L.; Hersh, Evan M.

    2010-01-01

    Purpose Imexon is an aziridine-derived iminopyrrolidone which has synergy with gemcitabine in pancreatic cancer cell lines. Gemcitabine is a standard therapy for pancreatic cancer. We performed a phase I trial of imexon and gemcitabine to evaluate safety, dose limiting toxicity (DLT), and maximum tolerated dose (MTD) in patients with advanced pancreatic cancer. Methods Patients with untreated locally advanced or metastatic pancreatic adenocarcinoma received therapy in sequential cohorts on regimen A (n=19; imexon 200 or 280 mg/m2 intravenously (IV) over 30 minutes days 1–5, 15–19 and gemcitabine 800 or 1,000 mg/m2 IV over 30 minutes on days 1,8,15 every 28 days) or regimen B (n=86; imexon 280–1,300 mg/m2 IV over 30–60 minutes days 1, 8, and 15 and gemcitabine 1,000 mg/m2 IV over 30 minutes on days 1, 8, and 15 every 28 days). Results One hundred-five patients received 340 treatment cycles (median 2, range 1–16). Patient characteristics: median age 63, 61% male, ECOG PS 0/1 50%/50%, 93% metastatic. DLT was abdominal cramping and pain, often with transient, acute diarrhea. Best response was confirmed partial response (PR) in 11.4%, 8.9% unconfirmed PR, and 48.1% with stable disease. There was a dose proportional increase in imexon AUC across the doses tested with terminal half-life 69 minutes at the MTD and no alteration of gemcitabine pharmacokinetics. Conclusions The recommended phase II dose of imexon is 875 mg/m2 with gemcitabine 1,000 mg/m2. DLT was acute abdominal pain and cramping. Encouraging antitumor responses support further evaluation of this combination in advanced pancreatic cancer. PMID:19855966

  17. Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells

    PubMed Central

    Bocci, G; Fioravanti, A; Orlandi, P; Bernardini, N; Collecchi, P; Del Tacca, M; Danesi, R

    2005-01-01

    The new combination between the nucleoside analogue gemcitabine and the cholesterol-lowering drug fluvastatin was investigated in vitro and in vivo on the human pancreatic tumour cell line MIAPaCa-2. The present study demonstrates that fluvastatin inhibits proliferation, induces apoptosis in pancreatic cancer cells harbouring a p21ras mutation at codon 12 and synergistically potentiates the cytotoxic effect of gemcitabine. The pharmacologic activities of fluvastatin are prevented by administration of mevalonic acid, suggesting that the shown inhibition of geranyl-geranylation and farnesylation of cellular proteins, including p21rhoA and p21ras, plays a major role in its anticancer effect. Fluvastatin treatment also indirectly inhibits the phosphorylation of p42ERK2/mitogen-activated protein kinase, the cellular effector of ras and other signal transduction peptides. Moreover, fluvastatin administration significantly increases the expression of the deoxycytidine kinase, the enzyme required for the activation of gemcitabine, and simultaneously reduces the 5′-nucleotidase, responsible for deactivation of gemcitabine, suggesting a possible additional role of these enzymes in the enhanced cytotoxic activity of gemcitabine. Finally, a significant in vivo antitumour effect on MIAPaCa-2 xenografts was observed with the simultaneous combination of fluvastatin and gemcitabine, resulting in an almost complete suppression and a marked delay in relapse of tumour growth. In conclusion, the combination of fluvastatin and gemcitabine is an effective cytotoxic, proapoptotic treatment in vitro and in vivo against MIAPaCa-2 cells by a mechanism of action mediated, at least in part, by the inhibition of p21ras and rhoA prenylation. The obtained experimental findings might constitute the basis for a novel translational research in humans. PMID:16052215

  18. Fasting cycles potentiate the efficacy of gemcitabine treatment in in vitro and in vivo pancreatic cancer models

    PubMed Central

    Mazza, Tommaso; Panebianco, Concetta; Saracino, Chiara; Pereira, Stephen P.; Graziano, Paolo; Pazienza, Valerio

    2015-01-01

    Background/aims Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. Short-term fasting cycles have been shown to potentiate the efficacy of chemotherapy against glioma. The aim of this study was to assess the effect of fasting cycles on the efficacy of gemcitabine, a standard treatment for PC patients, in vitro and in an in vivo pancreatic cancer mouse xenograft model. Materials and Methods BxPC-3, MiaPaca-2 and Panc-1 cells were cultured in standard and fasting mimicking culturing condition to evaluate the effects of gemcitabine. Pancreatic cancer xenograft mice were subjected to 24h starvation prior to gemcitabine injection to assess the tumor volume and weight as compared to mice fed ad libitum. Results Fasted pancreatic cancer cells showed increased levels of equilibrative nucleoside transporter (hENT1), the transporter of gemcitabine across the cell membrane, and decreased ribonucleotide reductase M1 (RRM1) levels as compared to those cultured in standard medium. Gemcitabine was more effective in inducing cell death on fasted cells as compared to controls. Consistently, xenograft pancreatic cancer mice subjected to fasting cycles prior to gemcitabine injection displayed a decrease of more than 40% in tumor growth. Conclusion Fasting cycles enhance gemcitabine effect in vitro and in the in vivo PC xenograft mouse model. These results suggest that restrictive dietary interventions could enhance the efficacy of existing cancer treatments in pancreatic cancer patients. PMID:26176887

  19. Cisplatin inhibits bone healing during distraction osteogenesis.

    PubMed

    Stine, Kimo C; Wahl, Elizabeth C; Liu, Lichu; Skinner, Robert A; Vanderschilden, Jacquelyn; Bunn, Robert C; Montgomery, Corey O; Suva, Larry J; Aronson, James; Becton, David L; Nicholas, Richard W; Swearingen, Christopher J; Lumpkin, Charles K

    2014-03-01

    Osteosarcoma (OS) is the most common malignant bone tumor affecting children and adolescents. Many patients are treated with a combination of chemotherapy, resection, and limb salvage protocols. Surgical reconstructions after tumor resection include structural allografts, non-cemented endoprostheses, and distraction osteogenesis (DO), which require direct bone formation. Although cisplatin (CDP) is extensively used for OS chemotherapy, the effects on bone regeneration are not well studied. The effects of CDP on direct bone formation in DO were compared using two dosing regimens and both C57BL/6 (B6) and tumor necrosis factor receptor 1 knockout (TNFR1KO) mice, as CDP toxicity is associated with elevated TNF levels. Detailed evaluation of the five-dose CDP regimen (2 mg/kg/day), demonstrated significant decreases in new bone formation in the DO gaps of CDP treated versus vehicle treated mice (p < 0.001). Further, no significant inhibitory effects from the five-dose CDP regimen were observed in TNFR1KO mice. The two-dose regimen significantly inhibited new bone formation in B6 mice. These results demonstrate that CDP has profound short term negative effects on the process of bone repair in DO. These data provide the mechanistic basis for modeling peri-operative chemotherapy doses and schedules and may provide new opportunities to identify molecules that spare normal cells from the inhibitory effects of CDP. PMID:24259375

  20. Uncoupling protein-2 knockdown mediates the cytotoxic effects of cisplatin.

    PubMed

    Santandreu, Francisca M; Roca, Pilar; Oliver, Jordi

    2010-08-15

    Cisplatin is among the most important chemotherapeutic agents ever developed. However, more than a generation after its clinical introduction, its exact mechanism of action on tumor cells is not fully defined. The aim of this study was to investigate the role of oxidative stress as a mediator of cisplatin action on colon cancer cells, studying the influence of mitochondrial physiology and composition on its effectiveness. The chemosensitivity shown by cancer cells to mechanistically dissimilar antitumor drugs is shown to be associated with their capacity to induce early alterations in mitochondrial and redox metabolism. Specifically, cisplatin exerted a marked pro-oxidative action on mitochondria by inhibiting resting respiration and stimulating the immediate generation of ROS in isolated mitochondria. Antioxidants and mitochondrial uncouplers counteracted cisplatin-induced cytotoxicity in tumor cells, reflecting that oxidative stress and the inhibition of mitochondrial uncoupling are relevant to its antiproliferative activity. Additionally, inhibition of uncoupling protein-2 (UCP2) caused cytotoxicity in colon cancer cells via ROS of mitochondrial origin. In conclusion, we show for the first time that UCP2 knockdown participates in the mechanism of action of cisplatin, thus providing evidence that targeting UCP2 may offer clinical benefit in the treatment of cancer. PMID:20595066

  1. Cisplatin and CCNU synergism in spheroid cell subpopulations.

    PubMed Central

    Durand, R. E.

    1990-01-01

    The cytotoxicity of two antineoplastic drugs, cisplatin and CCNU, was evaluated in Chinese hamster V79 multicell spheroids using the drugs as single agents or combinations. Cells obtained from different depths within spheroids 550-750 microns in diameter showed different sensitivities to the two agents; the external cells of the spheroids were more sensitive than the internal cells to cisplatin, whereas the internal cells were most effectively killed by CCNU. Combining the two agents produced the expected 'complementary' activity, and in addition, synergism was observed between the drugs at exposure levels practical for clinical use. For the combination treatments, both the net pattern of cell killing through the spheroid and the degree of interaction between the agents (quantified using the combination index method) were a function of the dose ratio of the two drugs, and of overall treatment intensity. BCNU produced patterns of cell killing similar to CCNU, but showed little interaction with cisplatin. Our results suggest significant clinical potential in using CCNU with cisplatin, particularly since CCNU-cisplatin combinations were synergistic even in the cell subpopulations most resistant to each drug as a single agent. PMID:2257225

  2. DFT study of cisplatin@carbon nanohorns complexes.

    PubMed

    De Souza, Leonardo A; Nogueira, Camila A S; Lopes, Juliana F; Dos Santos, Hélio F; De Almeida, Wagner B

    2013-12-01

    This paper reports a quantum chemical investigation of the inclusion complex formation between a carbon nanohorn structure and cisplatin molecule, using the density functional theory (DFT) with the B3LYP functional and 6-31G(d,p)/LanL2DZ standard basis sets. The inclusion of the drug in host molecules such as carbon nanohorns (CNHs), aims to reduce the toxicity and enhance the effectiveness of cisplatin. In this work we carried out a search for minimum energy structures on the potential energy surface (PES) for CNH-cisplatin interaction, and then calculated the stabilization energy, charge distribution and NMR spectra, which can be of great aid for the experimental identification of the inclusion compound. Our results indicate that the CNH and cisplatin can indeed form stable inclusion complex, with the calculated (1)H NMR and (15)N NMR chemical shifts for cisplatin atoms revealing very substantial changes due to complex formation (~20ppm) that can be easily experimentally observed, which is helpful to the spectra assignment and the inclusion compound structural elucidation. PMID:24091348

  3. Cisplatin induces loop structures and condensation of single DNA molecules

    PubMed Central

    Hou, Xi-Miao; Zhang, Xing-Hua; Wei, Kong-Ji; Ji, Chao; Dou, Shuo-Xing; Wang, Wei-Chi; Li, Ming; Wang, Peng-Ye

    2009-01-01

    Structural properties of single λ DNA treated with anti-cancer drug cisplatin were studied with magnetic tweezers and AFM. Under the effect of low-concentration cisplatin, the DNA became more flexible, with the persistence length decreased significantly from ∼52 to 15 nm. At a high drug concentration, a DNA condensation phenomenon was observed. Based on experimental results from both single-molecule and AFM studies, we propose a model to explain this kind of DNA condensation by cisplatin: first, di-adducts induce local distortions of DNA. Next, micro-loops of ∼20 nm appear through distant crosslinks. Then, large aggregates are formed through further crosslinks. Finally, DNA is condensed into a compact globule. Experiments with Pt(dach)Cl2 indicate that oxaliplatin may modify the DNA structures in the same way as cisplatin. The observed loop structure formation of DNA may be an important feature of the effect of platinum anti-cancer drugs that are analogous to cisplatin in structure. PMID:19129234

  4. Magnetic nanoparticle hyperthermia enhancement of cisplatin chemotherapy cancer treatment

    PubMed Central

    Petryk, Alicia A.; Giustini, Andrew J.; Gottesman, Rachel E.; Kaufman, Peter A.; Hoopes, P. Jack

    2016-01-01

    Purpose The purpose of this study was to examine the therapeutic effect of magnetic nanoparticle hyperthermia (mNPH) combined with systemic cisplatin chemotherapy in a murine mammary adenocarcinoma model (MTGB). Materials and methods An alternating magnetic field (35.8 kA/m at 165 kHz) was used to activate 110 nm hydroxyethyl starch-coated magnetic nanoparticles (mNP) to a thermal dose of 60 min at 43 °C. Intratumoral mNP were delivered at 7.5 mg of Fe/cm3 of tumour (four equal tumour quadrants). Intraperitoneal cisplatin at 5 mg/kg body weight was administered 1 h prior to mNPH. Tumour regrowth delay time was used to assess the treatment efficacy. Results mNP hyperthermia, combined with cisplatin, was 1.7 times more effective than mNP hyperthermia alone and 1.4 times more effective than cisplatin alone (p<0.05). Conclusions Our results demonstrate that mNP hyperthermia can result in a safe and significant therapeutic enhancement for cisplatin cancer therapy. PMID:24144336

  5. DNA-crosslinker cisplatin eradicates bacterial persister cells.

    PubMed

    Chowdhury, Nityananda; Wood, Thammajun L; Martínez-Vázquez, Mariano; García-Contreras, Rodolfo; Wood, Thomas K

    2016-09-01

    For all bacteria, nearly every antimicrobial fails since a subpopulation of the bacteria enter a dormant state known as persistence, in which the antimicrobials are rendered ineffective due to the lack of metabolism. This tolerance to antibiotics makes microbial infections the leading cause of death worldwide and makes treating chronic infections, including those of wounds problematic. Here, we show that the FDA-approved anti-cancer drug cisplatin [cis-diamminodichloroplatinum(II)], which mainly forms intra-strand DNA crosslinks, eradicates Escherichia coli K-12 persister cells through a growth-independent mechanism. Additionally, cisplatin is more effective at killing Pseudomonas aeruginosa persister cells than mitomycin C, which forms inter-strand DNA crosslinks, and cisplatin eradicates the persister cells of several pathogens including enterohemorrhagic E. coli, Staphylococcus aureus, and P. aeruginosa. Cisplatin was also highly effective against clinical isolates of S. aureus and P. aeruginosa. Therefore, cisplatin has broad spectrum activity against persister cells. Biotechnol. Bioeng. 2016;113: 1984-1992. © 2016 Wiley Periodicals, Inc. PMID:26914280

  6. Mass spectrometric studies on the interaction of cisplatin and insulin.

    PubMed

    Li, Jing; Yue, Lei; Liu, Yaqin; Yin, Xinchi; Yin, Qi; Pan, Yuanjiang; Yang, Lirong

    2016-04-01

    The interaction of antitumor drug, cisplatin (cis-[PtCl2(NH3)2], CDDP) with insulin from porcine pancreas has been investigated by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and high resolution hybrid ion trap/time-of-flight mass spectrometry (MALIDI-TOF/TOF-MS and ESI-IT/TOF MS). The MALDI-TOF/TOF-MS results demonstrated that the presence of cisplatin complex resulted in the reduction of the disulfide bond in porcine pancreas after the incubations of the two substances were performed in vitro. It indicated that the presence of cisplatin would destroy the native configuration of insulin, which may lead to the inactivation of insulin. High resolution mass values and the characteristic isotopic pattern of the platinated insulin ions allowed the analysis of platinated mono-, di- and triadducts of cisplatin and insulin in the incubations under different conditions. The laser-induced dissociation of the monoadduct obtained in MALDI source was carried out and one platinum was found to bind to insulin B chain was determined. The platinum binding sites were further identified to be the N terminus (B chain), cysteine 7 (B chain) and cysteine 19 (B chain) residues by electrospray ionization tandem mass spectrometry. The identification of the interaction between insulin and cisplatin broadens the horizon of the knowledge in the interaction of the proteins and metallodrugs. PMID:26724920

  7. Structural changes of linear DNA molecules induced by cisplatin

    SciTech Connect

    Liu, Zhiguo; Liu, Ruisi; Zhou, Zhen; Zu, Yuangang; Xu, Fengjie

    2015-02-20

    Interaction between long DNA molecules and activated cisplatin is believed to be crucial to anticancer activity. However, the exact structural changes of long DNA molecules induced by cisplatin are still not very clear. In this study, structural changes of long linear double-stranded DNA (dsDNA) and short single-stranded DNA (ssDNA) induced by activated cisplatin have been investigated by atomic force microscopy (AFM). The results indicated that long DNA molecules gradually formed network structures, beads-on-string structures and their large aggregates. Electrostatic and coordination interactions were considered as the main driving forces producing these novel structures. An interesting finding in this study is the beads-on-string structures. Moreover, it is worth noting that the beads-on-string structures were linked into the networks, which can be ascribed to the strong DNA–DNA interactions. This study expands our knowledge of the interactions between DNA molecules and cisplatin. - Highlights: • We investigate structural changes of dsDNA and ssDNA induced by cisplatin. • AFM results indicated long dsDNA formed network, beads-on-string and aggregates. • ssDNA can form very similar structures as those of long linear dsDNA. • A possible formation process of theses novel structure is proposed.

  8. Peripheral neuropathy induced by combination chemotherapy of docetaxel and cisplatin.

    PubMed Central

    Hilkens, P. H.; Pronk, L. C.; Verweij, J.; Vecht, C. J.; van Putten, W. L.; van den Bent, M. J.

    1997-01-01

    Docetaxel, a new semisynthetic taxoid that has demonstrated promising activity as an antineoplastic agent, was administered in combination with cisplatin to 63 patients in a dose-escalating study. As both drugs were known to be potentially neurotoxic, peripheral neurotoxicity was prospectively assessed in detail. Neuropathy was evaluated by clinical sum-score for signs and symptoms and by measurement of the vibration perception threshold (VPT). The severity of neuropathy was graded according to the National Cancer Institute's 'Common Toxicity Criteria'. The docetaxel-cisplatin combination chemotherapy induced a predominantly sensory neuropathy in 29 (53%) out of 55 evaluable patients. At cumulative doses of both cisplatin and docetaxel above 200 mg m(-2), 26 (74%) out of 35 patients developed a neuropathy which was mild in 15, moderate in ten and severe in one patient. Significant correlations were present between both the cumulative dose of docetaxel and cisplatin and the post-treatment sum-score of neuropathy (P < 0.01) as well as the post-treatment VPT (P < 0.01). The neurotoxic effects of this combination were more severe than either cisplatin or docetaxel as single agent at similar doses. PMID:9020489

  9. Global transcriptional responses to cisplatin in Dictyostelium discoideum identify potential drug targets

    PubMed Central

    Van Driessche, Nancy; Alexander, Hannah; Min, Junxia; Kuspa, Adam; Alexander, Stephen; Shaulsky, Gad

    2007-01-01

    Dictyostelium discoideum is a useful model for studying mechanisms of cisplatin drug sensitivity. Our previous findings, that mutations in sphingolipid metabolism genes confer cisplatin resistance in D. discoideum and in human cells, raised interest in the resistance mechanisms and their implications for cisplatin chemotherapy. Here we used expression microarrays to monitor physiological changes and to identify pathways that are affected by cisplatin treatment of D. discoideum. We found >400 genes whose regulation was altered by cisplatin treatment of wild-type cells, including groups of genes that participate in cell proliferation and in nucleotide and protein metabolism, showing that the cisplatin response is orderly and multifaceted. Transcriptional profiling of two isogenic cisplatin-resistant mutants, impaired in different sphingolipid metabolism steps, showed that the effect of cisplatin treatment was greater than the effect of the mutations, indicating that cisplatin resistance in the mutants is due to specific abilities to overcome the drug effects rather than to general drug insensitivity. Nevertheless, the mutants exhibited significantly different responses to cisplatin compared with the parent, and >200 genes accounted for that difference. Mutations in five cisplatin response genes (sgkB, csbA, acbA, smlA, and atg8) resulted in altered drug sensitivity, implicating novel pathways in cisplatin response. Our data illustrate how modeling complex cellular responses to drugs in genetically stable and tractable systems can uncover new targets with the potential for improving chemotherapy. PMID:17878305

  10. Single-agent erlotinib versus oral etoposide in patients with recurrent or refractory pediatric ependymoma: a randomized open-label study.

    PubMed

    Jakacki, Regina I; Foley, Margaret A; Horan, Julie; Wang, Jiuzhou; Kieran, Mark W; Bowers, Daniel C; Bouffet, Eric; Zacharoulis, Stergios; Gill, Stan C

    2016-08-01

    Overexpression of human epidermal growth factor receptor (HER/EGFR) is associated with various tumors, including ependymomas. To investigate whether EGFR inhibition was of benefit in pediatric patients with recurrent ependymoma, a multi-center, randomized, open-label, phase 2 study of oral erlotinib versus oral etoposide was undertaken. Twenty-five patients were randomized to receive erlotinib 85 mg/m(2) daily or etoposide 50 mg/m(2)/day for 21 consecutive days followed by a 7-day rest period. Courses were repeated every 28 days. In the erlotinib arm, no patient achieved a complete, partial, or minor response, and only 2 (15.4 %) patients showed stable disease as their best response. In the etoposide arm, 2 patients (16.7 %) demonstrated partial responses, 1 (8.3 %) patient demonstrated a minor response, and 2 (16.7 %) showed prolonged stable disease, for a prolonged disease control rate of 41.7 %. Three patients received at least nine cycles of etoposide (range 9-24 cycles) before discontinuing at the request of the physician and/or family. Four patients who failed etoposide in this study received erlotinib in a companion single arm study; none had a response. The futility criteria were met at the second interim analysis, and both studies were discontinued. Pharmacokinetics of erlotinib were similar to previous observations in pediatric patients. Overall, erlotinib was well tolerated and safety was consistent with its established profile in adults. The overall risk-benefit profile does not support the use of erlotinib in pediatric patients with recurrent ependymoma, whereas single-agent etoposide appears to have efficacy in a subset of patients. PMID:27287856

  11. Mangiferin activates Nrf2-antioxidant response element signaling without reducing the sensitivity to etoposide of human myeloid leukemia cells in vitro

    PubMed Central

    Zhang, Ben-ping; Zhao, Jie; Li, Shan-shan; Yang, Li-jing; Zeng, Ling-lan; Chen, Yan; Fang, Jun

    2014-01-01

    Aim: Mangiferin is glucosylxanthone extracted from plants of the Anacardiaceae and Gentianaceae families. The aim of this study was to investigate the effects of mangiferin on Nrf2-antioxidant response element (ARE) signaling and the sensitivity to etoposide of human myeloid leukemia cells in vitro. Methods: Human HL-60 myeloid leukemia cells and mononuclear human umbilical cord blood cells (MNCs) were examined. Nrf2 protein was detected using immunofluorescence staining and Western blotting. Binding of Nrf2 to ARE was examined with electrophoretic mobility shift assay. The level of NQO1 was assessed with real-time RT-PCR and Western blotting. DCFH-DA was used to evaluate intracellular ROS level. Cell proliferation and apoptosis were analyzed using MTT and flow cytometry, respectively. Results: Mangiferin (50 μmol/L) significantly increased Nrf2 protein accumulation in HL-60 cells, particularly in the nucleus. Mangiferin also enhanced the binding of Nrf2 to an ARE, significantly up-regulated NQO1 expression and reduced intracellular ROS in HL60 cells. Mangiferin alone dose-dependently inhibited the proliferation of HL-60 cells. Mangiferin (50 mol/L) did not attenuate etoposide-induced cytotoxicity in HL-60 cells, and combined treatment of mangiferin with low concentration of etoposide (0.8 μg/mL) even increased the cell inhibition rate. Nor did mangiferin change the rate of etoposide-induced apoptosis in HL-60 cells. In MNCs, mangiferin significantly relieved oxidative stress, but attenuated etoposide-induced cytotoxicity. Conclusion: Mangiferin is a novel Nrf2 activator that reduces oxidative stress and protects normal cells without reducing the sensitivity to etoposide of HL-60 leukemia cells in vitro. Mangiferin may be a potential chemotherapy adjuvant. PMID:24374812

  12. A selective and sensitive stability-indicating HPLC method for the validated assay of etoposide from commercial dosage form and polymeric tubular nanocarriers.

    PubMed

    Algan, Aslihan Hilal; Gumustas, Mehmet; Karatas, Aysegul; Ozkan, Sibel A

    2016-05-30

    Etoposide is a topoisomerase II enzyme inhibitor type chemotherapeutic agent which is widely used in the therapy of various cancers. Its short half-life and toxicity to normal tissues are the major drawbacks in its clinical applications. Polymeric nanoparticulate drug delivery systems are rational carriers to deliver etoposide with higher efficiency and fewer side effects. In addition tubular shaped drug carriers are found to show a great potential for drug delivery on the basis of promising results regarding particle shape and cellular uptake. In this study, etoposide loaded polymeric tubular nanocarriers have been developed by template wetting method using porous anodic aluminum oxide membranes as templates. The developed poly(methyl methacrylate) nanocarriers were evaluated for structural analysis, in vitro drug release studies and drug release kinetics. Accurate and reliable determination of the drug release from newly developed nanocarriers, is of great importance. For this reason a selective and sensitive reversed phase liquid chromatography method was developed and fully validated from the point of system suitability, specificity, linearity and range, limit of detection (LOD), limit of quantification (LOQ), precision, accuracy and robustness for the reliable determination of etoposide. Stability indicating capability was shown with forced degradation studies and the chromatographic conditions were optimized on ACE 5C18 (150 mm × 4.6mm I.D., 5 μm) analytical column. Related to the calibration results ETP was found linear in the range between 0.2 from 100 μg mL(-1) with the LOD as 0.015 μg.mL(-1). The resultant conditions were applied for the selective and sensitive determination of etoposide from its commercial dosage form with the high accuracy values (99.82-100.65%). The method was successfully detected assay of etoposide release from newly developed polymeric tubular nanocarriers, which was found as 72.2% at the end of 24h. PMID:26971031

  13. Etoposide, carboplatin, cyclophosphamide and vincristine in previously untreated patients with small-cell lung cancer.

    PubMed

    Bishop, J F; Kefford, R; Raghavan, D; Zalcberg, J; Stuart-Harris, R; Ball, D; Olver, I N; Friedlander, M; Bull, C; Yuen, K

    1990-01-01

    The efficacy and toxicity of 120 mg/m2 etoposide and 100 mg/m2 carboplatin given i.v. daily x 3 together with 750 mg/m2 cyclophosphamide and 1.4 mg/m2 vincristine given i.v. on day 1 (ECCO) in a regimen given every 28 days for 6 courses was assessed in 90 (40 limited stage, 50 extensive stage) previously untreated patients with small-cell lung cancer. Mediastinal irradiation using 50 Gy in 25 fractions was given to limited-stage patients without progression after 3 courses of chemotherapy. Cranial irradiation with 30 Gy in 10 fractions was given to all patients attaining a complete response (CR). Objective responses were seen in 83% [CR, 60%; partial response (PR), 23%] of patients with limited and 76% (CR, 22%; PR, 54%) of those with extensive disease. The median relapse-free survival for objective responders with limited disease was 13.4 months, with a median of 8.0 months for extensive-stage patients. The median relapse-free survival for patients achieving a CR was 13.4 months, with a median of 7.8 months for those undergoing a PR. The median survival was 13.3 months for patients with limited disease, with a median of 9.6 months for those with extensive disease. The median survival following a CR was 18.2 months, with a median survival of 9.9 months for those showing a PR. The combination was well tolerated, with either no nausea or nausea only (WHO grade 0 or 1) in 56% of patients and minimal mucositis, renal toxicity, neurotoxicity or ototoxicity. Neutropenia measuring less than 1.0 x 10(9) WBC/l (WHO grade 3 or 4) was seen in 74% of patients, with two deaths due to infection occurring during neutropenia. Thrombocytopenia of less than 50 x 10(9) platelets/l (WHO grade 3 or 4) occurred in 24% of patients. ECCO is a new, active, well-tolerated program for previously untreated patients with small-cell lung cancer. PMID:2155064

  14. Gemcitabine Hydrochloride and Cisplatin With or Without Veliparib or Veliparib Alone in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer

    ClinicalTrials.gov

    2016-07-04

    BRCA1 Mutation Carrier; BRCA2 Mutation Carrier; Metastatic Pancreatic Adenocarcinoma; PALB2 Gene Mutation; Pancreatic Adenocarcinoma; Recurrent Pancreatic Carcinoma; Stage III Pancreatic Cancer; Stage IV Pancreatic Cancer

  15. Development and characterization of polymeric nanoparticulate delivery system for hydrophillic drug: Gemcitabine

    NASA Astrophysics Data System (ADS)

    Khurana, Jatin

    Gemcitabine is a nucleoside analogue, used in various carcinomas such as non small cell lung cancer, pancreatic cancer, ovarian cancer and breast cancer. The major setbacks to the conventional therapy with gemcitabine include its short half-life and highly hydrophilic nature. The objectives of this investigation were to develop and evaluate the physiochemical properties, drug loading and entrapment efficiency, in vitro release, cytotoxicity, and cellular uptake of polymeric nano-particulate formulations containing gemcitabine hydrochloride. The study also entailed development and validation of a high performance liquid chromatography (HPLC) method for the analysis of gemcitabine hydrochloride. A reverse phase HPLC method using a C18 Luna column was developed and validated. Alginate and Poly lactide co glycolide/Poly-epsilon-caprolactone (PLGA:PCL 80:20) nanoparticles were prepared by multiple emulsion-solvent evaporation methodology. An aqueous solution of low viscosity alginate containing gemcitabine was emulsified into 10% solution of dioctyl-sulfosuccinate in dichloro methane (DCM) by sonication. The primary emulsion was then emulsified in 0.5% (w/v) aqueous solution of polyvinyl alcohol (PVA). Calcium chloride solution (60% w/v) was used to cause cross linking of the polymer. For PLGA:PCL system, the polymer mix was dissolved in dichloromethane (DCM) and an aqueous gemcitabine (with and without sodium chloride) was emulsified under ultrasonic conditions (12-watts; 1-min). This primary emulsion was further emulsified in 2% (w/v) PVA under ultrasonic conditions (24-watts; 3-min) to prepare a multiple-emulsion (w/o/w). In both cases DCM, the organic solvent was evaporated (20- hours, magnetic-stirrer) prior to ultracentrifugation (10000-rpm for PLGA:PCL; 25000-rpm for alginate). The pellet obtained was washed thrice with de-ionized water to remove PVA and any free drug and re-centrifuged. The particles were re-suspended in de-ionized water and then lyophilized to

  16. Propofol induces apoptosis and increases gemcitabine sensitivity in pancreatic cancer cells in vitro by inhibition of nuclear factor-κB activity

    PubMed Central

    Du, Qi-Hang; Xu, Yan-Bing; Zhang, Meng-Yuan; Yun, Peng; He, Chang-Yao

    2013-01-01

    AIM: To investigate the effect of propofol on human pancreatic cells and the molecular mechanism of propofol action. METHODS: We used the human pancreatic cancer cell line MIAPaCa-2 for in vitro studies measuring growth inhibition and degree of apoptotic cell death induced by propofol alone, gemcitabine alone, or propofol followed by gemcitabine. All experiments were conducted in triplicate and carried out on three or more separate occasions. Data were means of the three or more independent experiments ± SE. Statistically significant differences were determined by two-tailed unpaired Student’s t test and defined as P < 0.05. RESULTS: Pretreatment of cells with propofol for 24 h followed by gemcitabine resulted in 24%-75% growth inhibition compared with 6%-18% when gemcitabine was used alone. Overall growth inhibition was directly correlated with apoptotic cell death. We also showed that propofol potentiated gemcitabine-induced killing by downregulation of nuclear factor-κB (NF-κB). In contrast, NF-κB was upregulated when pancreatic cancer cells were exposed to gemcitabine alone, suggesting a potential mechanism of acquired chemoresistance. CONCLUSION: Inactivation of the NF-κB signaling pathway by propofol might abrogate gemcitabine-induced activation of NF-κB, resulting in chemosensitization of pancreatic tumors to gemcitabine. PMID:24023491

  17. Enhanced Antitumor Activity of Monophosphate Ester Prodrugs of Gemcitabine: In Vitro and In Vivo Evaluation.

    PubMed

    Qi, Huixin; Lu, Jia; Li, Jiajun; Wang, Meiyu; Xu, Yunting; Wang, Yedong; Zhang, Hongjian

    2016-09-01

    The prodrug strategy has been explored frequently for a number of marked drugs to obtain better pharmaceutical properties and efficacy and safety profiles. For gemcitabine, a nucleoside analog that has been used widely as a chemotherapeutic agent for the treatment of a variety of cancers, the protection of the amino group from extensive deamination and increase of permeability have been used for oral prodrug development. In the present study, several novel and proprietary monophosphate ester prodrugs of gemcitabine representing different "tail" structures were evaluated for their antiproliferation activities in various tumor cell lines. As compared to LY2334737, a prototype oral prodrug of gemcitabine, the monophosphate ester prodrugs exhibited superior in vitro antiproliferation activity. Among those, compound-3 emerged as a promising prodrug candidate. Data revealed that cellular concentrations of compound-3 were correlated well with its antiproliferation activity and its cellular uptake did not involve human equilibrative nucleoside transporter, suggesting a potential to treat gemcitabine resistant tumors. Compound-3 demonstrated equal or better antitumor efficacy after oral administration as compared to intraperitoneally injected gemcitabine. Taken together, compound-3 has the potential for further development as an orally active antitumor agent. PMID:26994559

  18. Antitumor efficacy of combination of interferon-gamma-inducible protein 10 gene with gemcitabine, a study in murine model

    PubMed Central

    Mei, Kai; Wang, Lian; Tian, Ling; Yu, Jingrui; Zhang, Zhixuan; Wei, Yuquan

    2008-01-01

    Background Interferon-γ-inducible protein 10 (IP-10) is a potent inhibitor of tumor angiogenesis. It has been reported that the antiangiogenic therapy combined with chemotherapy has synergistic effects. Methods To elucidate the mechanisms of IP-10 gene combined with a chemotherapy agent, we intramuscularly injected pBLAST-IP-10 expression plasmid combined with gemcitabine into tumor-bearing mice. Results The proliferation of endothelial cells was effectively inhibited by IP-10 combined with gemcitabine in vitro. Treatment with pBLAST-IP-10 twice a week for 4 weeks combined with gemcitabine 10 mg/kg (once a week) resulted in sustained high level of IP-10 protein in serum, inhibition of tumor growth and prolongation of the survival of tumor-bearing mice. Compared with administration of IP-10 plasmid or gemcitabine alone, the angiogenesis in tumors were apparently inhibited, and the numbers of apoptotic cells and lymphocytes in tumor increased in the combination therapy group. Conclusion Our data indicate that the gene therapy of antiangiogenesis by intramuscular delivery of plasmid DNA encoding IP-10 combined with gemcitabine has synergistic effects on tomor by inhibiting the proliferation of endothelail cells, inducing the apoptosis of tumor cells, and recruiting lymphocytes to tumor in murine models. The present findings provided evidence of antitumor effects of genetherapy combined with chemotherapy. PMID:18983688

  19. Long-term outcome of patients with advanced-stage cutaneous T cell lymphoma treated with gemcitabine.

    PubMed

    Pellegrini, Cinzia; Stefoni, Vittorio; Casadei, Beatrice; Maglie, Roberto; Argnani, Lisa; Zinzani, Pier Luigi

    2014-11-01

    The choice of treatment for cutaneous T cell lymphoma (CTCL) is often determined by institutional experience, particularly as there is a paucity of data from phase III trials and a lack of consensus concerning treatment of the advanced stages. Among the several second-line and experimental drugs, gemcitabine could be considered one of the most suitable options for pretreated CTCL. Since it is difficult to find in literature the long-term outcome regarding the efficacy of a single-agent drug in pretreated patients and, in particular, in rare diseases such as CTCL, a retrospective observational study was conducted with the aim of evaluating the long-term outcome of CTCL patients treated with gemcitabine. Twenty-five patients with at least one therapy (range 1-8) performed prior to gemcitabine were found. After gemcitabine treatment, the overall response was 48 % with a 20 % of complete responses. At 15 years, the estimated overall survival is 47 %, progression-free survival 8.8 %, and disease-free survival 40 % (median reached at 2.9 years). All patients received at least three cycles and no grade 3-4 hematological adverse events occurred. At the latest follow-up, two patients are still in continuous complete response. This long-term update on the role of gemcitabine as a single agent in pretreated advanced-stage CTCL confirms this monotherapy as effective and safe. PMID:24908331

  20. Safety and pharmacokinetics of motesanib in combination with gemcitabine for the treatment of patients with solid tumours.

    PubMed

    Price, T J; Lipton, L; McGreivy, J; McCoy, S; Sun, Y-N; Rosenthal, M A

    2008-11-01

    The aim of this open-label phase 1b study was to assess the safety and pharmacokinetics of motesanib in combination with gemcitabine in patients with advanced solid tumours. Eligible patients with histologically or cytologically documented solid tumours or lymphoma were enroled in three sequential, dose-escalating cohorts to receive motesanib 50 mg once daily (QD), 75 mg two times daily (BID), or 125 mg QD in combination with gemcitabine (1000 mg m(-2)). The primary end point was the incidence of dose-limiting toxicities (DLTs). Twenty-six patients were enroled and received motesanib and gemcitabine. No DLTs occurred. The 75 mg BID cohort was discontinued early; therefore, 125 mg QD was the maximum target dose. Sixteen patients (62%) experienced motesanib-related adverse events, most commonly lethargy (n=6), diarrhoea (n=4), fatigue (n=3), headache (n=3), and nausea (n=3). The pharmacokinetics of motesanib and of gemcitabine were not markedly affected after combination therapy. The objective response rate was 4% (1 of 26), and 27% (7 of 26) of patients achieved stable disease. In conclusion, treatment with motesanib plus gemcitabine was well tolerated, with adverse event and pharmacokinetic profiles similar to that observed in monotherapy studies. PMID:18971935

  1. BRCA2 and RAD51 promote double-strand break formation and cell death in response to gemcitabine.

    PubMed

    Jones, Rebecca M; Kotsantis, Panagiotis; Stewart, Grant S; Groth, Petra; Petermann, Eva

    2014-10-01

    Replication inhibitors cause replication fork stalling and double-strand breaks (DSB) that result from processing of stalled forks. During recovery from replication blocks, the homologous recombination (HR) factor RAD51 mediates fork restart and DSB repair. HR defects therefore sensitize cells to replication inhibitors, with clear implications for cancer therapy. Gemcitabine is a potent replication inhibitor used to treat cancers with mutations in HR genes such as BRCA2. Here, we investigate why, paradoxically, mutations in HR genes protect cells from killing by gemcitabine. Using DNA replication and DNA damage assays in mammalian cells, we show that even short gemcitabine treatments cause persistent replication inhibition. BRCA2 and RAD51 are recruited to chromatin early after removal of the drug, actively inhibit replication fork progression, and promote the formation of MUS81- and XPF-dependent DSBs that remain unrepaired. Our data suggest that HR intermediates formed at gemcitabine-stalled forks are converted into DSBs and thus contribute to gemcitabine-induced cell death, which could have implications for the treatment response of HR-deficient tumors. PMID:25053826

  2. Phase II Trial of Gemcitabine and Tanespimycin (17AAG) in Metastatic Pancreatic Cancer: A Mayo Clinic Phase II Consortium Study

    PubMed Central

    Pedersen, Katrina S.; Kim, George P.; Foster, Nathan R.; Wang-Gillam, Andrea; Erlichman, Charles; McWilliams, Robert R.

    2016-01-01

    Objectives Heat Shock Protein 90 (HSP90) is a molecular chaperone that stabilizes many oncogenic proteins. HSP90 inhibitors may sensitize tumors to cytotoxic agents by causing client protein degradation. Gemcitabine, which has modest activity in pancreas cancer, activates Chk1, a client protein of HSP90. This phase II trial was designed to determine whether 17AAG could enhance the clinical activity of gemcitabine through degradation of Chk1 in patients with stage IV pancreatic cancer. Methods A multicenter, prospective study combining gemcitabine and 17AAG enrolled patients with stage IV pancreatic adenocarcinoma, adequate liver and kidney function, ECOG performance status 0-2, and no prior chemotherapy for metastatic disease. The primary goal was to achieve a 60% overall survival at six months. Sixty-six patients were planned for accrual, with an interim analysis after 25 patients enrolled. Results: After a futility analysis to achieve the endpoint, accrual was halted with 21 patients enrolled. No complete or partial responses were seen. 40% of patients were alive at 6 months. Median overall survival was 5.4 months. Tolerability was moderate, with 65% of patients having ≥ grade 3 adverse events (AE), and 15% having grade 4 events. Conclusions The lack of clinical activity suggests that targeting Chk1 by inhibiting HSP90 is not important in pancreatic cancer sensitivity to gemcitabine alone. Further studies of HSP90 targeted agents with gemcitabine alone are not warranted. PMID:25952464

  3. Hypoxia protects HepG2 cells against etoposide-induced apoptosis VIA a HIF-1-independent pathway

    SciTech Connect

    Piret, Jean-Pascal; Cosse, Jean-Philippe; Ninane, Noelle; Raes, Martine; Michiels, Carine . E-mail: carine.michiels@fundp.ac.be

    2006-09-10

    Tumor hypoxia has been described to increase the resistance of cancer cells to radiation therapy and chemotherapy. It also supports the invasiveness and metastatic potential of the tumor. However, few data are available on the transduction pathway set up under hypoxia and leading to this resistance against anti-cancer therapies. HIF-1, the main transcription factor activated by hypoxia, has been recently shown to participate to this process although its role as an anti- or a pro-apoptotic protein is still controversy. In this study, we showed that hypoxia protected HepG2 cells against etoposide-induced apoptosis. The effect of hypoxia on cell death was assayed by measuring different parameters of the apoptotic pathway, like DNA fragmentation, caspase activity and PARP-1 cleavage. The possible implication of HIF-1 in the anti-apoptotic role of hypoxia was investigated using HIF-1{alpha} siRNA. Our results indicated that HIF-1 is not involved in the hypoxia-induced anti-apoptotic pathway. Another transcription factor, AP-1, was studied for its potential role in the hypoxia-induced protection against apoptosis. Specific inhibition of AP-1 decreased the protection effect of hypoxia against etoposide-induced apoptosis. Together, all these data underline that hypoxia could mediate its anti-apoptotic role via different transcription factors depending on the cellular context and pro-apoptotic stimuli.

  4. Physicochemical properties of liposomes as potential anticancer drugs carriers. Interaction of etoposide and cytarabine with the membrane: Spectroscopic studies

    NASA Astrophysics Data System (ADS)

    Pentak, Danuta

    2014-03-01

    The interactions between etoposide, cytarabine and 1,2-dihexadecanoyl-sn-glycerol-3-phosphocholine bilayers were studied using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance (NMR). These techniques have proven to be a very powerful tool in studying the structure and dynamics of phospholipid bilayers. In particular, DSC can provide information on the phase transition temperature and cooperativity of the lipid molecules in the absence and presence of the drug. Vibrational spectroscopy is well suited to the study of drug-lipid interactions, since it allows for an investigation of the conformation of phospholipid molecules at different levels in lipid bilayers and follows structural changes that occur during the gel to liquid-crystalline phase transition. NMR supported the determination of the main phase transition temperatures (TC) of 1,2-dihexadecanoyl-sn-glycerol-3-phosphocholine (DPPC). The main phase transition temperature (TC) determined by 1H NMR is comparable with values obtained by DSC for all studied liposomes. The location of cytarabine and etoposide in liposomes was also determined by NMR. Atomic force microscopy (AFM) images, acquired immediately after sample deposition on a mica surface, revealed the spherical shape of lipid vesicles.

  5. [Cell shrinkage during apoptosis is not obligatory. Apoptosis of U937 cells induced by staurosporine and etoposide].

    PubMed

    Vereninov, A A; Goriachaia, T S; Matveev, V V; Moshkov, A V; Rozanov, Iu M; Sakuta, G A; Shirokova, A V; Iurinskaia, V E

    2004-01-01

    A study was made of apoptotic cell shrinkage, which is generally believed to be a hallmark of apoptosis. The two conventional models of apoptosis were used for examination of changes in cell water balance--one is apoptosis caused in human lymphoma cell line U937 by staurosporine, and the other by etoposide. Intracellular water was determined by measuring buoyant density of cells in continuous Percoll gradient. Apoptosis was recognized by microscopy and flow cytometry. Apoptosis caused by staurosporine (1 microM, 4 h) was found to be associated with a decrease in cell water content by almost 24%. In contrast, no decrease in cell water content was observed in U937 cells incubated with etoposide (50 microM, 4 h), in spite of the number of features suggesting the presence of apoptosis, such as the appearance of apoptotic bodies, chromatin condensation and fragmentation and disappearance of S-phase cells in DNA histogram. It is concluded that definition of apoptosis as "shrinkage-necrosis" (Kerr, 1971) needs correcting: the distinction of apoptotic cells involves the absence of swelling, rather than cell shrinkage. PMID:15473371

  6. Protein flexibility is key to cisplatin crosslinking in calmodulin

    PubMed Central

    Li, Huilin; Wells, Stephen A; Jimenez-Roldan, J Emilio; Römer, Rudolf A; Zhao, Yao; Sadler, Peter J; O'Connor, Peter B

    2012-01-01

    Chemical crosslinking in combination with Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) has significant potential for studying protein structures and protein–protein interactions. Previously, cisplatin has been shown to be a crosslinker and crosslinks multiple methionine (Met) residues in apo-calmodulin (apo-CaM). However, the inter-residue distances obtained from nuclear magnetic resonance structures are inconsistent with the measured distance constraints by crosslinking. Met residues lie too far apart to be crosslinked by cisplatin. Here, by combining FTICR MS with a novel computational flexibility analysis, the flexible nature of the CaM structure is found to be key to cisplatin crosslinking in CaM. It is found that the side chains of Met residues can be brought together by flexible motions in both apo-CaM and calcium-bound CaM (Ca4-CaM). The possibility of cisplatin crosslinking Ca4-CaM is then confirmed by MS data. Therefore, flexibility analysis as a fast and low-cost computational method can be a useful tool for predicting crosslinking pairs in protein crosslinking analysis and facilitating MS data analysis. Finally, flexibility analysis also indicates that the crosslinking of platinum to pairs of Met residues will effectively close the nonpolar groove and thus will likely interfere with the binding of CaM to its protein targets, as was proved by comparing assays for cisplatin-modified/unmodified CaM binding to melittin. Collectively, these results suggest that cisplatin crosslinking of apo-CaM or Ca4-CaM can inhibit the ability of CaM to recognize its target proteins, which may have important implications for understanding the mechanism of tumor resistance to platinum anticancer drugs. PMID:22733664

  7. Infrasound sensitizes human glioblastoma cells to cisplatin-induced apoptosis.

    PubMed

    Rachlin, Kenneth; Moore, Dan H; Yount, Garret

    2013-11-01

    The development of nontoxic agents that can selectively enhance the cytotoxicity of chemotherapy is an important aim in oncology. This study evaluates the ability of infrasound exposure to sensitize glioblastoma cells to cisplatin-induced apoptosis. The infrasound was delivered using a device designed to replicate the unique infrasound emissions measured during external Qigong treatments. Human glioblastoma cell lines harboring wild-type p53 (U87) or mutant p53 (U251, SF210, and SF188) were treated in culture with cisplatin, infrasound emissions, or the combination of the 2 agents. Induction of apoptosis was quantified after 24 hours by flow cytometry following annexin V/propidium iodide staining. Infrasound emissions alone, delivered at moderate levels (~10 mPa) with dynamic frequency content (7-13 Hz), did not induce apoptosis, yet combining infrasound with cisplatin augmented the induction of apoptosis by cisplatin in all the 4 cell lines (P < .05). Increased cellular uptake of the fluorophore calcein associated with infrasound exposure was quantified by fluorescence microscopy as well as flow cytometry, demonstrating increased cell membrane permeability. The 4 cell lines differed in the degree to which infrasound exposure increased calcein uptake, and these differences were predictive of the extent to which infrasound enhanced cisplatin-induced apoptosis. When exposed to specific frequencies, membrane permeabilization also appeared to be differentially responsive for each cell line, suggesting the potential for selective targeting of tissue types using isolated infrasonic frequencies. Additionally, the pressure amplitudes used in this study were several orders of magnitude less than those used in similar studies involving ultrasound and shock waves. The results of this study provide support for using infrasound to enhance the chemotherapeutic effects of cisplatin in a clinical setting. PMID:23165942

  8. Selection of agents for prevention of cisplatin-induced hepatotoxicity.

    PubMed

    Liao, Yingjun; Lu, Xiuqiang; Lu, Chunwei; Li, Gexin; Jin, Yaping; Tang, Hao

    2008-02-01

    The objective of this study was to explore the optimal combination of agents used along with cisplatin for protection of hepatotoxicity. Animal experiment was carried out based on the orthogonal design L(8) (2(7)) setting seven factors with two different levels of each, and eight groups of mice were needed. The agents tested in this study were zinc, selenium, fosfomycin, sodium thiosulfate (STS), N-acetyl-cysteine (NAC), methionine and taurine. Mice were supplemented by gavage with various combinations of agents as designed in the orthogonal table once a day for nine days beginning two days before cisplatin administration. 3.5mg/kg body weight of cisplatin was given intraperitoneally once a day for five days simultaneously. After cessation of cisplatin administration, the agents were supplemented continuously for two days. Activities of alanine aminotransferase (ALT) in serum, levels of glutathione (GSH) and malondialdehyde (MDA) in liver were analyzed after cessation of supplementation. Results showed zinc, fosfomycin and methionine were the effective factors for protection of weight loss; fosfomycin and methionine were the effective factors for prevention of decreased liver ratio; selenium, fosfomycin and STS were the effective factors for prevention of increased ALT activities in serum. On the other hand, methionine was the only effective factor for prevention of decreased GSH levels in liver; zinc, selenium and fosfomycin were the effective factors for prevention of increased MDA levels in liver. Based on the data observed in this study, the optimum combinations of agents were selenium, fosfomycin, methionine and taurine, and zinc, selenium, STS and methionine. In conclusion, each agent used in this study could play a beneficial role for prevention of cisplatin hepatotoxicity, however, none could play the crucial role. The potentiated actions for prevention of cisplatin hepatotoxicity could be achieved via combined use of these agents. PMID:18282716

  9. Hydration of Two Cisplatin Aqua-Derivatives Studied by Quantum Mechanics and Molecular Dynamics Simulations.

    PubMed

    Melchior, Andrea; Tolazzi, Marilena; Martínez, José Manuel; Pappalardo, Rafael R; Sánchez Marcos, Enrique

    2015-04-14

    The hydration of the cisplatin aqua-derivatives, cis-[PtCl(H2O)(NH3)2](+) (w-cisplatin) and cis-[Pt(H2O)2(NH3)2](2+) (w2-cisplatin), has been studied by means of classical molecular dynamics simulations. The new platinum complex-water interaction potential, w-cisplatin-W, has been built on the basis of the already obtained cisplatin-water interaction potential (cisplatin-W) [J. Chem. Theory Comput. 2013 9, 4562]. That potential has been then transferred to the w2-cisplatin-W potential. The w-cisplatin and w2-cisplatin atomic charges were specifically derived from their solute's wave functions. Bulk solvent effects on the complex-water interactions have been included by means of a continuum model. Classical MD simulations with 1 platinum complex and 1000 SPC/E water molecules have been carried out. Angle-solved radial distribution functions and spatial distribution functions have been used to provide detailed pictures of the local hydration structure around the ligands (water, chloride, and ammine) and the axial region. A novel definition of a multisite cavity has been employed to compute the hydration number of complexes in order to provide a consistent definition of their first-hydration shell. Interestingly, the hydration number decreases with the increase of the complex net charge from 27 for cisplatin to 23 and 18 for w-cisplatin and w2-cisplatin, respectively. In parallel to this hydration number behavior, the compactness of the hydration shell increases when going from the neutral complex, i.e. cisplatin, to the doubly charged complex, w2-cisplatin. Quantum mechanics estimation of the hydration energies for the platinum complexes allows the computation of the reaction energy for the first- and second-hydrolysis of cisplatin in water. The agreement with experimental data is satisfactory. PMID:26574384

  10. Cisplatin inhibits MEK1/2

    PubMed Central

    Yamamoto, Tetsu; Tsigelny, Igor F.; Götz, Andreas W.; Howell, Stephen B.

    2015-01-01

    Cisplatin (cDDP) is known to bind to the CXXC motif of proteins containing a ferrodoxin-like fold but little is known about its ability to interact with other Cu-binding proteins. MEK1/2 has recently been identified as a Cu-dependent enzyme that does not contain a CXXC motif. We found that cDDP bound to and inhibited the activity of recombinant MEK1 with an IC50 of 0.28 μM and MEK1/2 in whole cells with an IC50 of 37.4 μM. The inhibition of MEK1/2 was relieved by both Cu+1 and Cu+2 in a concentration-dependent manner. cDDP did not inhibit the upstream pathways responsible for activating MEK1/2, and did not cause an acute depletion of cellular Cu that could account for the reduction in MEK1/2 activity. cDDP was found to bind MEK1/2 in whole cells and the extent of binding was augmented by supplementary Cu and reduced by Cu chelation. Molecular modeling predicts 3 Cu and cDDP binding sites and quantum chemistry calculations indicate that cDDP would be expected to displace Cu from each of these sites. We conclude that, at clinically relevant concentrations, cDDP binds to and inhibits MEK1/2 and that both the binding and inhibitory activity are related to its interaction with Cu bound to MEK1/2. This may provide the basis for useful interactions of cDDP with other drugs that inhibit MAPK pathway signaling. PMID:26155939

  11. Protective effects of subchronic caffeine administration on cisplatin induced urogenital toxicity in male mice.

    PubMed

    Khazaei, M; Bayat, P D; Ghanbari, A; Khazaei, S; Feizian, M; Khodaei, A; Alian, H A S

    2012-09-01

    In Cisplatin treated group, the degeneration intensity of the kidneys the diameter of seminiferous tubules as well as the apoptotic index in testes and kidney were increased. In Caffeine+Cisplatin treated groups, the total body weight, the weight of testes and kidneys and also the histopathological data did not show significant differences. The motility of sperm in cisplatin group reduced but in Caffeine+Cisplatin groups this parameter was increased. These data suggest that caffeine recovers toxicity induced by cisplatin in both kidneys and testes of mice. PMID:23140022

  12. Maitake beta-glucan enhances therapeutic effect and reduces myelosupression and nephrotoxicity of cisplatin in mice.

    PubMed

    Masuda, Yuki; Inoue, Munechika; Miyata, Ayu; Mizuno, Shigeto; Nanba, Hiroaki

    2009-05-01

    Cisplatin is broadly used clinically as an anticancer drug. Despite its significant anticancer activity, cisplatin-induced nephrotoxicity and myelosuppression limit its use. MD-Fraction is glucan purified from maitake (Grifola frondosa), which has beta-1, 6-main chain with beta-1, 3-branches, has been reported to exhibit antitumor and antimetastatic activities by enhancing the immune system. In this study, we demonstrate that MD-Fraction in combination with cisplatin significantly enhanced antitumor and antimetastatic activity compared to cisplatin alone. MD-Fraction reduced decreases in body weight, spleen weight and the number of immunocompetent cells such as macrophages, DCs and NK cells in cisplatin-treated mice. MD-Fraction also induced IL-12p70 production by splenocytes, resulting in increased NK cell activity in cisplatin-treated mice. MD-Fraction significantly increased the mRNA expression of GM-CSF, G-CSF, M-CSF, IFN-gamma, IL-12 p40 in splenocytes and reduced the decrease in the number of CFU-GM colonies in cisplatin-treated bone marrow. These facts suggest that MD-Fraction can reduce cisplatin-induced myelosuppression. Moreover, treatment with MD-Fraction significantly reduced cisplatin-induced nephrotoxicity accompanied by increases in serum creatinine level, necrosis and apoptosis of renal tubular cells. These results suggest that MD-Fraction in combination with cisplatin cannot only enhance antitumor and antimentastatic acitivity, but also reduce cisplatin-induced myelotoxicity and nephrotoxicity. PMID:19249389

  13. Functional mechanotransduction is required for cisplatin-induced hair cell death in the zebrafish lateral line.

    PubMed

    Thomas, Andrew J; Hailey, Dale W; Stawicki, Tamara M; Wu, Patricia; Coffin, Allison B; Rubel, Edwin W; Raible, David W; Simon, Julian A; Ou, Henry C

    2013-03-01

    Cisplatin, one of the most commonly used anticancer drugs, is known to cause inner ear hair cell damage and hearing loss. Despite much investigation into mechanisms of cisplatin-induced hair cell death, little is known about the mechanism whereby cisplatin is selectively toxic to hair cells. Using hair cells of the zebrafish lateral line, we found that chemical inhibition of mechanotransduction with quinine and EGTA protected against cisplatin-induced hair cell death. Furthermore, we found that the zebrafish mutants mariner (myo7aa) and sputnik (cad23) that lack functional mechanotransduction were resistant to cisplatin-induced hair cell death. Using a fluorescent analog of cisplatin, we found that chemical or genetic inhibition of mechanotransduction prevented its uptake. These findings demonstrate that cisplatin-induced hair cell death is dependent on functional mechanotransduction in the zebrafish lateral line. PMID:23467357

  14. Functional mechanotransduction is required for cisplatin-induced hair cell death in the zebrafish lateral line

    PubMed Central

    Thomas, Andrew J.; Hailey, Dale W.; Stawicki, Tamara M.; Wu, Patricia; Coffin, Allison B.; Rubel, Edwin W.; Raible, David W.; Simon, Julian A.; Ou, Henry C.

    2013-01-01

    Cisplatin, one of the most commonly used anti-cancer drugs, is known to cause inner ear hair cell damage and hearing loss. Despite much investigation into mechanisms of cisplatin-induced hair cell death, little is known about the mechanism whereby cisplatin is selectively toxic to hair cells. Using hair cells of the zebrafish lateral line, we found that chemical inhibition of mechanotransduction with quinine and EGTA protected against cisplatin-induced hair cell death. Furthermore, we found that the zebrafish mutants mariner (myo7aa) and sputnik (cad23) that lack functional mechanotransduction were resistant to cisplatin-induced hair cell death. Using a fluorescent analogue of cisplatin, we found that chemical or genetic inhibition of mechanotransduction prevented its uptake. These findings demonstrate that cisplatin-induced hair cell death is dependent on functional mechanotransduction in the zebrafish lateral line. PMID:23467357

  15. Cisplatin-induced Kidney Dysfunction and Perspectives on Improving Treatment Strategies

    PubMed Central

    Oh, Gi-Su; Kim, Hyung-Jin; Shen, AiHua; Lee, Su Bin; Khadka, Dipendra; Pandit, Arpana

    2014-01-01

    Cisplatin is one of the most widely used and highly effective drug for the treatment of various solid tumors; however, it has dose-dependent side effects on the kidney, cochlear, and nerves. Nephrotoxicity is the most well-known and clinically important toxicity. Numerous studies have demonstrated that several mechanisms, including oxidative stress, DNA damage, and inflammatory responses, are closely associated with cisplatin-induced nephrotoxicity. Even though the establishment of cisplatin-induced nephrotoxicity can be alleviated by diuretics and pre-hydration of patients, the prevalence of cisplatin nephrotoxicity is still high, occurring in approximately one-third of patients who have undergone cisplatin therapy. Therefore it is imperative to develop treatments that will ameliorate cisplatin-nephrotoxicity. In this review, we discuss the mechanisms of cisplatin-induced renal toxicity and the new strategies for protecting the kidneys from the toxic effects without lowering the tumoricidal activity. PMID:25606044

  16. Gemcitabine upregulates ABCG2/BCRP and modulates the intracellular pharmacokinetic profiles of bioluminescence in pancreatic cancer cells.

    PubMed

    Sun, Yue; Gu, Mancang; Zhu, Lixin; Liu, Junying; Xiong, Yang; Wei, Yinghui; Li, Fanzhu

    2016-03-01

    A lack of methods capable of exploring real-time intracellular drug deposition has since limited the investigation of gemcitabine-induced multidrug resistance in vitro and in vivo. Specifically, resistance induced by D-luciferin, a substrate of the breast cancer resistance protein (ABCG2/BCRP), has recently attracted clinical attention, but further investigation has been limited. Herein, the intracellular pharmacokinetic behavior of D-luciferin was investigated in pancreatic cancer cell lines in real time by using bioluminescence imaging. To achieve this feat, BxPC3 and Panc1 pancreatic cancer cells overexpressing firefly luciferase were treated with gemcitabine in a dose and time gradient manner in vitro. The intracellular pharmacokinetic profiles of each group were then determined through the acquisition of bioluminescent signal intensity of D-luciferin in cells. Simultaneously, key pharmacokinetic parameters including area under the curve, elimination rate constant (K), and mean resident time were calculated according to the noncompartment model. ABCG2 protein levels following gemcitabine treatment were detected through western blot, and gemcitabine showed no significant effect on luciferase activity over dimethyl sulfoxide (DMSO) as a control (P>0.05). However, gemcitabine significantly increased K values while suppressing area under the curve and mean resident time compared with DMSO (P<0.05) and increased ABCG2 expression over DMSO-treated cells. In addition, gemcitabine increased the elimination rate of the ABCG2 substrate, D-luciferin, and decreased D-luciferin accumulation in BxPC3 and Panc1 cells in a dose-response manner. Advances made herein illustrate the versatility of the in-vitro bioluminescent model and its capability to observe the onset of chemoresistance in real time. PMID:26556627

  17. Cucurbitacin B, a novel in vivo potentiator of gemcitabine with low toxicity in the treatment of pancreatic cancer

    PubMed Central

    Iwanski, Gabriela B; Lee, Dhong H; En-Gal, Shlomit; Doan, Ngan B; Castor, Brandon; Vogt, Marco; Toh, Melvin; Bokemeyer, Carsten; Said, Jonathan W; Thoennissen, Nils H; Koeffler, H Phillip

    2010-01-01

    Background and purpose: Pancreatic cancer is a highly aggressive malignancy, and improvement in systemic therapy is necessary to treat this frequently encountered metastatic disease. The current targeted agents used in combination with gemcitabine improved objective response rates, but with little or no improvements in survival and also increased toxicities in pancreatic cancer patients. Recently, we showed that the triterpenoid cucurbitacin B inhibited tumour growth in pancreatic cancer cells by inhibition of the JAK/STAT pathway, and synergistically increased antiproliferative effects of gemcitabine in vitro. Experimental approach: The anti-tumour effects and toxicities of cucurbitacin B in combination with gemcitabine were tested against human pancreatic cancer cells in a murine xenograft model. Key results: Combined therapy with cucurbitacin B and gemcitabine at relatively low doses (0.5 mg·kg−1 and 25 mg·kg−1 respectively) resulted in highly significant tumour growth inhibition of pancreatic cancer xenografts (up to 79%). Remarkably, this therapy was well tolerated by the animals, as shown by histology of visceral organs, analysis of serum chemistry, full blood counts and bone marrow colony numbers. Western blot analysis of the tumour samples of mice who received both cucurbitacin B and gemcitabine, revealed stronger inhibition of Bcl-XL, Bcl-2 and c-myc, and higher activation of the caspase cascades, than mice treated with either agent alone. Conclusions and implications: Combination of cucurbitacin B and gemcitabine had profound anti-proliferative effects in vivo against xenografts of human pancreatic cancer cells, without any significant signs of toxicity. This promising combination should be examined in therapeutic trials of pancreatic cancer. PMID:20590594

  18. Sensitization of Pancreatic Cancers to Gemcitabine Chemoradiation by WEE1 Kinase Inhibition Depends on Homologous Recombination Repair12

    PubMed Central

    Kausar, Tasneem; Schreiber, Jason S.; Karnak, David; Parsels, Leslie A.; Parsels, Joshua D.; Davis, Mary A.; Zhao, Lili; Maybaum, Jonathan; Lawrence, Theodore S.; Morgan, Meredith A.

    2015-01-01

    To improve the efficacy of chemoradiation therapy for locally advanced pancreatic cancer and begin to establish patient selection criteria, we investigated the combination of the WEE1 inhibitor AZD1775 with gemcitabine-radiation in homologous recombination (HR) repair proficient and deficient pancreatic cancers. Sensitization to gemcitabine-radiation by AZD1775 was assessed in pancreatic cancer cells by clonogenic survival and in patient-derived xenografts by tumor growth. The contributions of HR repair inhibition and G2 checkpoint abrogation to sensitization were assessed by γH2AX, BRCA2 manipulation, and RAD51 focus formation and pHistone H3 flow cytometry, respectively. We found that AZD1775 sensitized to gemcitabine-radiation in BRCA2 wild-type but not BRCA2 mutant pancreatic cancer cells. In all cells, AZD1775 caused inhibition of CDK1 phosphorylation and G2 checkpoint abrogation. However, sensitization by AZD1775 was associated with persistent γH2AX and inhibition of RAD51 focus formation. In HR-proficient (BRCA2 wild-type) or -deficient (BRAC2 null) isogenic cells, AZD1775 sensitized to gemcitabine-radiation in BRCA2 wild-type, but not in BRCA2 null cells, despite significant G2 checkpoint abrogation. In patient-derived pancreatic tumor xenografts, AZD1775 significantly inhibited tumor growth and impaired RAD51 focus formation in response to gemcitabine-radiation. In conclusion, WEE1 inhibition by AZD1775 is an effective strategy for sensitizing pancreatic cancers to gemcitabine chemoradiation. Although this sensitization is accompanied by inhibition of CDK1 phosphorylation and G2 checkpoint abrogation, this mechanism is not sufficient for sensitization. Our findings demonstrate that sensitization to chemoradiation by WEE1 inhibition results from inhibition of HR repair and suggest that patient tumors without underlying HR defects would benefit most from this therapy. PMID:26585231

  19. Preparation and stability of lipid-coated nanocapsules of cisplatin: anionic phospholipid specificity.

    PubMed

    Velinova, Maria J; Staffhorst, Rutger W H M; Mulder, Willem J M; Dries, Arno S; Jansen, Bart A J; de Kruijff, Ben; de Kroon, Anton I P M

    2004-05-27

    Cisplatin nanocapsules represent a novel lipid formulation of the anti-cancer drug cis-diamminedichloroplatinum(II) (cisplatin), in which nanoprecipitates of cisplatin are coated by a phospholipid bilayer consisting of a 1:1 mixture of zwitterionic phosphatidylcholine (PC) and negatively charged phosphatidylserine (PS). Cisplatin nanocapsules are characterized by an unprecedented cisplatin-to-lipid ratio and exhibit increased in vitro cytotoxicity compared to the free drug [Nat. Med. 8, (2002) 81]. In the present study, the stability of the cisplatin nanocapsules was optimized by varying the lipid composition of the bilayer coat and monitoring in vitro cytotoxicity and the release of contents during incubations in water and in mouse serum. The release of cisplatin from the PC/PS (1:1) nanocapsules in water increased with increasing temperature with a t(1/2) of 6.5 h at 37 degrees C. At 4 degrees C, cisplatin was retained in the nanocapsules for well over 8 days. Replacement of PS by either phosphatidylglycerol or phosphatidic acid revealed that nanocapsules prepared of PS were more stable, which was found to be due to the ability of PS to form a stable cisplatin-PS coordination complex. Mouse serum had a strong destabilizing effect on the cisplatin nanocapsules. The PC/PS formulation lost over 80% of cisplatin within minutes after resuspension in serum. Incorporation of poly(ethylene glycol 2000) (PEG)-derivatized phosphatidylethanolamine and cholesterol in the bilayer coat extended the lifetime of the cisplatin nanocapsules in mouse serum to almost an hour. The results demonstrate that specificity in the interaction of cisplatin with anionic phospholipids is an important criterium for the formation and stability of cisplatin nanocapsules. PMID:15157616

  20. High-dose tamoxifen as an enhancer of etoposide cytotoxicity. Clinical effects and in vitro assessment in p-glycoprotein expressing cell lines.

    PubMed Central

    Stuart, N. S.; Philip, P.; Harris, A. L.; Tonkin, K.; Houlbrook, S.; Kirk, J.; Lien, E. A.; Carmichael, J.

    1992-01-01

    Twenty-six patients with relapsed or drug-resistant cancer were treated with a combination of oral etoposide (300 mg day-1 for 3 days) and high-dose oral tamoxifen as a potential modulator of drug resistance (480 or 720 mg day-1 for 6 days beginning 3 days before etoposide). One patient with relapsed high-grade lymphoma and one with adenocarcinoma of unknown primary site has a partial response. Toxicity consisting of nausea, vomiting and subjective dizziness, unsteadiness of gait and malaise occurred during tamoxifen treatment. Serum levels of tamoxifen averaged 3-3.5 microM on day 4 of all courses of treatment at both 480 and 720 mg day-1. N-desmethyltamoxifen levels were lower than tamoxifen during the first course (2 microM) but increased to equal tamoxifen levels during the second course. Didesmethyltamoxifen levels remained below 1 microM. In vitro, both tamoxifen and the standard modulator of multidrug resistance, verapamil, produced minor enhancement of etoposide cytotoxicity in the MCF-7 wt cell line but produced no enhancement with any other cell line. High, intermittent doses of tamoxifen can be given with acceptable toxicity and produce serum levels that have been shown to modulate drug resistance in vitro. In vitro, however, such levels have no significant effect on etoposide cytotoxicity towards a range of wild-type and MDR cell lines. PMID:1358168

  1. The SUMO-targeted ubiquitin ligase RNF4 localizes to etoposide-exposed mitotic chromosomes: implication for a novel DNA damage response during mitosis.

    PubMed

    Saito, Masayuki; Fujimitsu, Yuka; Sasano, Takeshi; Yoshikai, Yushi; Ban-Ishihara, Reiko; Nariai, Yuko; Urano, Takeshi; Saitoh, Hisato

    2014-04-25

    RNF4, a SUMO-targeted ubiquitin ligase (STUbL), localizes to the nucleus and functions in the DNA damage response during interphase of the cell cycle. RNF4 also exists in cells undergoing mitosis, where its regulation and function remain poorly understood. Here we showed that administration of etoposide, an anticancer DNA topoisomerase II poison, to mitotic human cervical cancer HeLa cells induced SUMO-2/3-dependent localization of RNF4 to chromosomes. The FK2 antibody signals, indicative of poly/multi-ubiquitin assembly, were detected on etoposide-exposed mitotic chromosomes, whereas the signals were negligible in cells depleted for RNF4 by RNA interference. This suggests that RNF4 functions as a STUbL in the etoposide-induced damage response during mitosis. Indeed, RNF4-depletion sensitized mitotic HeLa cells to etoposide and increased cells with micronuclei. These results indicate the importance of the RNF4-mediated STUbL pathway during mitosis for the maintenance of chromosome integrity and further implicate RNF4 as a target for topo II poison-based therapy for cancer patients. PMID:24695317

  2. The Effect of Dexpanthenol on Ototoxicity Induced by Cisplatin

    PubMed Central

    Toplu, Yuksel; Sapmaz, Emrah; Parlakpinar, Hakan; Kelles, Mehmet; Kalcioglu, M. Tayyar; Tanbek, Kevser; Kizilay, Ahmet

    2016-01-01

    Objectives This study was aimed to investigate the protective effects of dexpanthenol (Dxp) on against cisplatin-induced ototoxicity. Methods To examine this effect, distortion product otoacoustic emissions (DPOAEs) measurements and serum levels of oxidative and antioxidant status (including malondialdehyde, superoxide dismutase, catalase, glutathione, glutathione peroxidase, total oxidant status, total antioxidant status, and oxidative stress index) were evaluated. Thirty-two adult female Wistar albino rats were randomly divided into 4 equal groups; control (K), cisplatin (C), cisplatin plus Dxp (CD), and Dxp (D). In all groups DPOAEs measurements, between 996 and 10,078 Hz as DPOAEs and input/output functions, were performed on days 0, 1th, 5th, and 12th. Prior to death, the last DPOAEs measurements and blood samples were taken. Results In the C group, statistically significant differences were detected at all frequencies between 0 and 5 days and 0 and 12 days measurements (P<0.05). Serum level of oxidant and antioxidant status were detected statistically significantly changed in this group versus K group (P<0.05). Contrary to the C group, in the CD group hearing ability was seen largely preserved at many frequencies and serum levels of all biochemical parameters were shifted toward normal values, similar to the K group. No significant differences were detected in the either D or K group’s measurements. Conclusion According to these results, Dxp may prevent cisplatin-induced ototoxicity. PMID:26976021

  3. Membrane Transporters as Mediators of Cisplatin Effects and Side Effects

    PubMed Central

    Ciarimboli, Giuliano

    2012-01-01

    Transporters are important mediators of specific cellular uptake and thus, not only for effects, but also for side effects, metabolism, and excretion of many drugs such as cisplatin. Cisplatin is a potent cytostatic drug, whose use is limited by its severe acute and chronic nephro-, oto-, and peripheral neurotoxicity. For this reason, other platinum derivatives, such as carboplatin and oxaliplatin, with less toxicity but still with antitumoral action have been developed. Several transporters, which are expressed on the cell membranes, have been associated with cisplatin transport across the plasma membrane and across the cell: the copper transporter 1 (Ctr1), the copper transporter 2 (Ctr2), the P-type copper-transporting ATPases ATP7A and ATP7B, the organic cation transporter 2 (OCT2), and the multidrug extrusion transporter 1 (MATE1). Some of these transporters are also able to accept other platinum derivatives as substrate. Since membrane transporters display a specific tissue distribution, they can be important molecules that mediate the entry of platinum derivatives in target and also nontarget cells possibly mediating specific effects and side effects of the chemotherapeutic drug. This paper summarizes the literature on toxicities of cisplatin compared to that of carboplatin and oxaliplatin and the interaction of these platinum derivatives with membrane transporters. PMID:24278698

  4. Nebivolol Ameliorates Cisplatin-Induced Nephrotoxicity in Rats.

    PubMed

    Morsy, Mohamed A; Heeba, Gehan H

    2016-06-01

    Treatment with cisplatin is associated with dose-limiting side effects, mainly nephrotoxicity. On the other hand, nebivolol, a β1 -adrenoceptor antagonist, exhibits vasodilatory and antioxidative properties. This study aimed to determine whether nebivolol possesses a protective effect against cisplatin nephrotoxicity and explore many mechanisms underlying this potential effect. Nephrotoxicity was induced in Wistar rats by a single intraperitoneal injection of cisplatin (6 mg/kg) on day 2. Nebivolol (10 mg/kg) was administered orally for 7 consecutive days. Nebivolol showed a nephroprotective effect as demonstrated by the significant reduction in the elevated levels of serum creatinine and urea as well as renal levels of malondialdehyde, nitric oxide products (nitrite/nitrate), inducible nitric oxide synthase, tumour necrosis factor-alpha, caspase-3, angiotensin II and endothelin-1 with a concurrent increase in renal levels of reduced glutathione and endothelial nitric oxide synthase compared to untreated rats. Histopathological examination confirmed the nephroprotective effect of nebivolol. Pre-treatment with Nω -nitro-L-arginine methyl ester, the non-specific nitric oxide synthase inhibitor, partially altered the protection afforded by nebivolol. In conclusion, nebivolol protects rats against cisplatin-induced nephrotoxicity that is most likely through its antioxidant, anti-inflammatory and antiapoptotic effects as well as by abrogation of the augmented angiotensin II and endothelin-1 levels. PMID:26617394

  5. Array analysis for potential biomarker of gemcitabine identification in non-small cell lung cancer cell lines.

    PubMed

    Zhang, Hai-Hong; Zhang, Zhi-Yi; Che, Chun-Li; Mei, Yi-Fang; Shi, Yu-Zhi

    2013-01-01

    Gemcitabine is one of the most widely used drugs for the treatment of advanced Non-small cell lung cancer (NSCLC), but modest objective response rate of patients to gemcitabine makes it necessary to identify novel biomarkers for patients who can benefit from gemcitabine-based therapy and to improve the effect of clinical therapy. In this work, 3 NSCLC cell lines displaying different sensitivities to gemcitabine were applied for mRNA and microRNA (miR) expression chips to figure out the biomarkers for gemcitabine sensitivity. Genes whose expression increased dramatically in sensitive cell lines were mainly enriched in cell adhesion (NRP2, CXCR3, CDK5R1, IL32 and CDH2) and secretory granule (SLC11A1, GP5, CD36 and IGF1), while genes with significantly upregulated expression in resistant cell line were mainly clustered in methylation modification (HIST1H2BF, RAB23 and TP53) and oxidoreductase (TP53I3, CYP27B1 and SOD3). The most intriguing is the activation of Wnt/β-catenin signaling in gemcitabine resistant NSCLC cell lines. The miR-155, miR-10a, miR-30a, miR-24-2* and miR-30c-2* were upregulated in sensitive cell lines, while expression of miR-200c, miR-203, miR-885-5p, miR-195 and miR-25* was increased in resistant cell line. Genes with significantly altered expression and putatively mediated by the expression-changed miRs were mainly enriched in chromatin assembly (MAF, HLF, BCL2, and IGSF3), anti-apoptosis (BCL2, IGF1 and IKBKB), protein kinase (NRP2, PAK7 and CDK5R1) (all the above genes were upregulated in sensitive cells) and small GTPase mediated signal transduction (GNA13, RAP2A, ARHGAP5 and RAB23, down-regulated in sensitive cells). Our results might provide potential biomarkers for gemcitabine sensitivity prediction and putative targets to overcome gemcitabine resistance in NSCLC patients. PMID:24040438

  6. FFCD-1004 Clinical Trial: Impact of Cytidine Deaminase Activity on Clinical Outcome in Gemcitabine-Monotherapy Treated Patients

    PubMed Central

    Serdjebi, Cindy; Gagnière, Johan; Desramé, Jérôme; Fein, Francine; Guimbaud, Rosine; François, Eric; André, Thierry; Seitz, Jean-François; Montérymard, Carole; Arsene, Dominique; Volet, Julien; Abakar-Mahamat, Abakar; Lecomte, Thierry; Guerin-Meyer, Véronique; Legoux, Jean-Louis; Deplanque, Gaël; Guillet, Pierre; Ciccolini, Joseph; Lepage, Côme; Dahan, Laetitia

    2015-01-01

    Purpose Because cytidine deaminase (CDA) is the key enzyme in gemcitabine metabolism, numerous studies have attempted to investigate impact of CDA status (i.e. genotype or phenotype) on clinical outcome. To date, data are still controversial because none of these studies has fully investigated genotype-phenotype CDA status, pharmacokinetics and clinical outcome relationships in gemcitabine-treated patients. Besides, most patients were treated with gemcitabine associated with other drugs, thus adding a confounding factor. We performed a multicenter prospective clinical trial in gemcitabine-treated patients which aimed at investigating the link between CDA deficiency on the occurrence of severe toxicities and on pharmacokinetics, and studying CDA genotype-phenotype relationships. Experimental design One hundred twenty patients with resected pancreatic adenocarcinoma eligible for adjuvant gemcitabine monotherapy were enrolled in this study promoted and managed by the Fédération Francophone de Cancérologie Digestive. Toxicities were graded according to National Cancer Institute’s Common Terminology Criteria for Adverse Events Version 4. They were considered severe for grade ≥ 3, and early when occurring during the first eight weeks of treatment. CDA status was evaluated using a double approach: genotyping for 79A>C and functional testing. Therapeutic drug monitoring of gemcitabine and its metabolite were performed on the first course of gemcitabine. Results Five patients out of 120 (i.e., 4.6%) were found to be CDA deficient (i.e., CDA activity <1.3 U/mg), and only one among them experienced early severe hematological toxicity. There was no statistically significant difference in CDA activity between patients experiencing hematological severe toxicities (28.44%) and patients who tolerated the treatment (71.56%). CDA genetic analysis failed in evidencing an impact in terms of toxicities or in CDA activity. Regarding pharmacokinetics, a wide inter

  7. Contribution of FKBP5 Genetic Variation to Gemcitabine Treatment and Survival in Pancreatic Adenocarcinoma

    PubMed Central

    Ellsworth, Katarzyna A.; Eckloff, Bruce W.; Li, Liang; Moon, Irene; Fridley, Brooke L.; Jenkins, Gregory D.; Carlson, Erin; Brisbin, Abra; Abo, Ryan; Bamlet, William; Petersen, Gloria; Wieben, Eric D.; Wang, Liewei

    2013-01-01

    Purpose FKBP51, (FKBP5), is a negative regulator of Akt. Variability in FKBP5 expression level is a major factor contributing to variation in response to chemotherapeutic agents including gemcitabine, a first line treatment for pancreatic cancer. Genetic variation in FKBP5 could influence its function and, ultimately, treatment response of pancreatic cancer. Experimental Design We set out to comprehensively study the role of genetic variation in FKBP5 identified by Next Generation DNA resequencing on response to gemcitabine treatment of pancreatic cancer by utilizing both tumor and germline DNA samples from 43 pancreatic cancer patients, including 19 paired normal-tumor samples. Next, genotype-phenotype association studies were performed with overall survival as well as with FKBP5 gene expression in tumor using the same samples in which resequencing had been performed, followed by functional genomics studies. Results In-depth resequencing identified 404 FKBP5 single nucleotide polymorphisms (SNPs) in normal and tumor DNA. SNPs with the strongest associations with survival or FKBP5 expression were subjected to functional genomic study. Electromobility shift assay showed that the rs73748206 “A(T)” SNP altered DNA-protein binding patterns, consistent with significantly increased reporter gene activity, possibly through its increased binding to Glucocorticoid Receptor (GR). The effect of rs73748206 was confirmed on the basis of its association with FKBP5 expression by affecting the binding to GR in lymphoblastoid cell lines derived from the same patients for whom DNA was used for resequencing. Conclusion This comprehensive FKBP5 resequencing study provides insights into the role of genetic variation in variation of gemcitabine response. PMID:23936393

  8. Full-Dose Gemcitabine and Concurrent Radiotherapy for Unresectable Pancreatic Cancer

    SciTech Connect

    Murphy, James D.; Adusumilli, Saroja; Griffith, Kent A.; Ray, Michael E.; Zalupski, Mark M.; Lawrence, Theodore S.; Ben-Josef, Edgar . E-mail: edgarb@med.umich.edu

    2007-07-01

    Purpose: Full-dose gemcitabine and concurrent radiotherapy is a promising treatment approach in unresectable pancreatic cancer. This study was conducted to assess the pattern of failure and toxicity associated with the use of conformal treatment volumes, omitting prophylactic lymph node irradiation. Methods and Materials: Seventy-four patients with locally advanced pancreatic cancer were treated between 1997 and 2005 with full-dose (1000 mg/m{sup 2}, Days 1, 8, and 15) gemcitabine and concurrent radiotherapy (36 Gy [median] in 15 daily fractions). The planning target volume (PTV) was limited to the gross tumor volume (GTV) plus 1-cm margin. Patient computed tomography (CT) scans were systematically reviewed to determine the pattern of failure. Kaplan-Meier and Cox-regression models were used to analyze freedom from local progression (FFLP), distant failure, overall survival (OS), and toxicity. Results: With a median follow-up of 10.6 months (20.6 months in living patients), the 1-year and 2-year FFLP rates were 64% and 38%, respectively. Four patients (5%) failed in the peripancreatic lymph nodes (3 in-field and 1 marginal failure). Median OS was 11.2 months. Analyzed as a time-dependent covariate, local failure was a significant predictor of OS (p = 0.0074). Sixteen patients (22%) had significant gastrointestinal (GI) toxicity ({>=} Grade 3). PTV correlated with significant GI toxicity (p = 0.007). Conclusions: Freedom from local progression in unresectable pancreatic cancer is suboptimal. In conjunction with full-dose gemcitabine, the use of conformal fields encompassing only the GTV helps reduce toxicity and does not result in marginal failures. Our findings provide rationale for intensification of local therapy in conjunction with more effective systemic therapy.

  9. Aspirin counteracts cancer stem cell features, desmoplasia and gemcitabine resistance in pancreatic cancer

    PubMed Central

    Zhang, Yiyao; Liu, Li; Fan, Pei; Bauer, Nathalie; Gladkich, Jury; Ryschich, Eduard; Bazhin, Alexandr V.; Giese, Nathalia A.; Strobel, Oliver; Hackert, Thilo; Hinz, Ulf; Gross, Wolfgang; Fortunato, Franco; Herr, Ingrid

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis. An inflammatory microenvironment triggers the pronounced desmoplasia, the selection of cancer stem-like cells (CSCs) and therapy resistance. The anti-inflammatory drug aspirin is suggested to lower the risk for PDA and to improve the treatment, although available results are conflicting and the effect of aspirin to CSC characteristics and desmoplasia in PDA has not yet been investigated. We characterized the influence of aspirin on CSC features, stromal reactions and gemcitabine resistance. Four established and 3 primary PDA cell lines, non-malignant cells, 3 patient tumor-derived CSC-enriched spheroidal cultures and tissues from patients who did or did not receive aspirin before surgery were analyzed using MTT assays, flow cytometry, colony and spheroid formation assays, Western blot analysis, antibody protein arrays, electrophoretic mobility shift assays (EMSAs), immunohistochemistry and in vivo xenotransplantation. Aspirin significantly induced apoptosis and reduced the viability, self-renewal potential, and expression of proteins involved in inflammation and stem cell signaling. Aspirin also reduced the growth and invasion of tumors in vivo, and it significantly prolonged the survival of mice with orthotopic pancreatic xenografts in combination with gemcitabine. This was associated with a decreased expression of markers for progression, inflammation and desmoplasia. These findings were confirmed in tissue samples obtained from patients who had or had not taken aspirin before surgery. Importantly, aspirin sensitized cells that were resistant to gemcitabine and thereby enhanced the therapeutic efficacy. Aspirin showed no obvious toxic effects on normal cells, chick embryos or mice. These results highlight aspirin as an effective, inexpensive and well-tolerated co-treatment to target inflammation, desmoplasia and CSC features PDA. PMID:25846752

  10. CHK1 Inhibition Synergizes with Gemcitabine Initially by Destabilizing the DNA Replication Apparatus.

    PubMed

    Koh, Siang-Boon; Courtin, Aurélie; Boyce, Richard J; Boyle, Robert G; Richards, Frances M; Jodrell, Duncan I

    2015-09-01

    Combining cell-cycle checkpoint kinase inhibitors with the DNA-damaging chemotherapeutic agent gemcitabine offers clinical appeal, with a mechanistic rationale based chiefly on abrogation of gemcitabine-induced G2-M checkpoint activation. However, evidence supporting this mechanistic rationale from chemosensitization studies has not been consistent. Here we report a systematic definition of how pancreatic cancer cells harboring mutant p53 respond to this combination therapy, by combining mathematical models with large-scale quantitative biologic analyses of single cells and cell populations. Notably, we uncovered a dynamic range of mechanistic effects at different ratios of gemcitabine and CHK1 inhibitors. Remarkably, effective synergy was attained even where cells exhibited an apparently functional G2-M surveillance mechanism, as exemplified by a lack of both overt premature CDK1 activation and S-phase mitotic entry. Consistent with these findings, S-G2 duration was extended in treated cells, leading to a definable set of lineage-dependent catastrophic fates. At synergistic drug concentrations, global replication stress was a distinct indicator of chemosensitization as characterized molecularly by an accumulation of S-phase cells with high levels of hyperphosphorylated RPA-loaded single-stranded DNA. In a fraction of these cells, persistent genomic damage was observed, including chromosomal fragmentation with a loss of centromeric regions that prevented proper kinetochore-microtubule attachment. Together, our results suggested a "foot-in-the-door" mechanism for drug synergy where cells were destroyed not by frank G2-M phase abrogation but rather by initiating a cumulative genotoxicity that deregulated DNA synthesis. PMID:26141863

  11. Theranostic reduction-sensitive gemcitabine prodrug micelles for near-infrared imaging and pancreatic cancer therapy

    NASA Astrophysics Data System (ADS)

    Han, Haijie; Wang, Haibo; Chen, Yangjun; Li, Zuhong; Wang, Yin; Jin, Qiao; Ji, Jian

    2015-12-01

    A biodegradable and reduction-cleavable gemcitabine (GEM) polymeric prodrug with in vivo near-infrared (NIR) imaging ability was reported. This theranostic GEM prodrug PEG-b-[PLA-co-PMAC-graft-(IR820-co-GEM)] was synthesized by ring-opening polymerization and ``click'' reaction. The as-prepared reduction-sensitive prodrug could self-assemble into prodrug micelles in aqueous solution confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro drug release studies showed that these prodrug micelles were able to release GEM in an intracellular-mimicking reductive environment. These prodrug micelles could be effectively internalized by BxPC-3 pancreatic cancer cells, which were observed by confocal laser scanning microscopy (CLSM). Meanwhile, a methyl thiazolyl tetrazolium (MTT) assay demonstrated that this prodrug exhibited high cytotoxicity against BxPC-3 cells. The in vivo whole-animal near-infrared (NIR) imaging results showed that these prodrug micelles could be effectively accumulated in tumor tissue and had a longer blood circulation time than IR820-COOH. The endogenous reduction-sensitive gemcitabine prodrug micelles with the in vivo NIR imaging ability might have great potential in image-guided pancreatic cancer therapy.A biodegradable and reduction-cleavable gemcitabine (GEM) polymeric prodrug with in vivo near-infrared (NIR) imaging ability was reported. This theranostic GEM prodrug PEG-b-[PLA-co-PMAC-graft-(IR820-co-GEM)] was synthesized by ring-opening polymerization and ``click'' reaction. The as-prepared reduction-sensitive prodrug could self-assemble into prodrug micelles in aqueous solution confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro drug release studies showed that these prodrug micelles were able to release GEM in an intracellular-mimicking reductive environment. These prodrug micelles could be effectively internalized by BxPC-3 pancreatic cancer cells, which

  12. Radiation Therapy With Full-Dose Gemcitabine and Oxaliplatin for Unresectable Pancreatic Cancer

    SciTech Connect

    Hunter, Klaudia U.; Feng, Felix Y.; Griffith, Kent A.; Francis, Isaac R.; Lawrence, Theodore S.; Desai, Sameer; Murphy, James D.; Zalupski, Mark M.; Ben-Josef, Edgar

    2012-07-01

    Purpose: We completed a Phase I trial of gemcitabine and oxaliplatin with concurrent radiotherapy in patients with previously untreated pancreatic cancer. The results of a subset of patients with unresectable disease who went on to receive planned additional therapy are reported here. Methods and Materials: All patients received two 28-day cycles of gemcitabine (1,000 mg/m{sup 2} on Days 1, 8, and 15) and oxaliplatin (40-85 mg/m{sup 2} on Days 1 and 15, per a dose-escalation schema). Radiation therapy was delivered concurrently with Cycle 1 (27 Gy in 1.8-Gy fractions). At 9 weeks, patients were reassessed for resectability. Those deemed to have unresectable disease were offered a second round of treatment consisting of 2 cycles of gemcitabine and oxaliplatin and 27 Gy of radiation therapy (total, 54 Gy). Radiation was delivered to the gross tumor volume plus 1 cm by use of a three-dimensional conformal technique. We used the Common Terminology Criteria for Adverse Events to assess acute toxicity. Late toxicity was scored per the Radiation Therapy Oncology Group scale. Computed tomography scans were reviewed to determine pattern of failure, local response, and disease progression. Kaplan-Meier methodology and Cox regression models were used to evaluate survival and freedom from failure. Results: Thirty-two patients from the Phase I dose-escalation study had unresectable disease, three of whom had low-volume metastatic disease. Of this group, 16 patients went on to receive additional therapy to complete a total of 4 cycles of chemotherapy and 54 Gy of concurrent radiation. For this subset, 38% had at least a partial tumor response at a median of 3.2 months. Median survival was 11.8 months (range, 4.4-26.3 months). The 1-year freedom from local progression rate was 93.8% (95% confidence interval, 63.2-99.1). Conclusions: Radiation therapy to 54 Gy with concurrent full-dose gemcitabine and oxaliplatin is well tolerated and results in favorable rates of local tumor

  13. Modulation of cisplatin cytotoxicity and cisplatin-induced DNA cross-links in HepG2 cells by regulation of glutathione-related mechanisms.

    PubMed

    Zhang, K; Chew, M; Yang, E B; Wong, K P; Mack, P

    2001-04-01

    Glutathione (GSH), glutathione S-transferase (GST), and glutathione conjugate export pump (GS-X pump) have been shown to participate collectively in the detoxification of many anticancer drugs, including cisplatin. Identification and regulation of the rate-limiting step in the overall system for cisplatin detoxification is of crucial importance for sensitization of human tumor cells to cisplatin. In this study, the GSH content, GST activity, and GS-X pump activity were regulated separately to examine effects of the regulation on cisplatin cytotoxicity and cisplatin-induced DNA interstrand cross-links (ICL) in HepG2 cells. Seventy-percent depletion of GSH by buthionine sulfoximine (BSO) and 50% increase of GSH by monoethyl GSH ester (GSHe) potentiated and decreased cisplatin cytotoxicity, respectively. This was reflected by a significant decrease and increase of their respective IC(50) values by 62 and 107%. Cisplatin-induced ICL was also potentiated by depletion of GSH by BSO and decreased by enrichment of GSH by GSHe, as shown by a 125% increase and a 34% decrease of cross-linked DNA compared with control samples exposed to cisplatin alone (p = 0.008 and 0.03, respectively). On the other hand, inhibition of GST and GS-X pump by ethacrynic acid, quercetin, tannic acid, and indomethacin at concentrations that inhibited activities of GST and GS-X pump by more than 50% had no significant effects on cisplatin cytotoxicity and cisplatin-induced DNA ICL in these cells. The results showed that of the parameters measured, intracellular GSH seems to be the rate-limiting factor, and its regulation would provide a more promising strategy for sensitization of human liver tumor cells to cisplatin. PMID:11259628

  14. Electroacupuncture alleviates cisplatin-induced nausea in rats

    PubMed Central

    Cui, Yingxue; Wang, Linpeng; Shi, Guangxia; Liu, Lu; Pei, Pei; Guo, Jianyou

    2016-01-01

    Objective Acupuncture has been shown to be effective for the treatment of chemotherapy-related nausea and vomiting. The aim of this study was to explore the mechanisms of action underlying the anti-emetic effect of electroacupuncture (EA). Design Forty-eight rats received saline (n=12) or 6 mg/kg cisplatin (n=36) to establish a chemotherapy-induced nausea and vomiting model. EA was performed at CV12 (n=12), bilateral PC6 (n=12), or sham points (n=12) 3 days before and 1–2 days after cisplatin administration (4–5 times in total), at 0.5–1 mA intensity and 2/15 Hz frequency for 10 min. Kaolin intake, food intake and bodyweight change were evaluated as markers of nausea and vomiting severity. Concentrations of serotonin (5-hydroxytryptamine, 5-HT) in the duodenum and c-Fos expression in the nucleus of the solitary tract (NTS) were measured using high performance liquid chromatography and immunohistochemistry, respectively. Results Cisplatin administration led to increased kaolin intake and reduced food intake and bodyweight over the following 2 days. EA at CV12 significantly reversed the cisplatin-induced change in kaolin intake (on days 1 and 2) and food intake and bodyweight (on day 1). EA at CV12 also attenuated the cisplatin-induced increase in 5-HT in the duodenum and suppressed c-Fos expression in the NTS. EA at PC6 influenced kaolin intake (on day 1 only) and c-Fos expression, but had no statistically significant effect on food intake, bodyweight or 5-HT expression. Conclusions This study demonstrated beneficial effects of EA on chemotherapy-induced nausea and vomiting in a rat model. The anti-emetic effect of EA may be mediated through inhibition of 5-HT secretion in the duodenum and activity of the NTS. PMID:26386034

  15. Chemotherapy for acute myeloid leukemias with cytosine arabinoside, daunorubicin, etoposide, and mitoxantrone may cause permanent oligoasthenozoospermia or amenorrhea in middle-aged patients.

    PubMed

    Lemez, P; Urbánek, V

    2005-01-01

    The aim was to follow-up gonadal functions in long-term survivors of acute myeloid leukemias (AML) after intensive chemotherapy based on high-doses of cytosine arabinoside (Ara-C) and anthracyclines in the study UHKT-911. Adult patients were treated with at least 3 cycles of chemotherapy including 1-3 courses of Ara-C 10 x 2000 mg/m2/12 h and daunorubicin (DNR) 2 x 45 mg/m2/d. Spermiologic examinations were performed in 7 men by the classic microscopic method and results were evaluated according to the WHOcriteria. Two patients (42- and 47-year-old) after DNR and Ara-C chemotherapy had nearly normal spermiologic findings. The semen of a 49-year-old patient contained normal numbers of spermatozoa with decreased velocity when examined 1 year after chemotherapy but 4 years later exhibited oligoasthenozoospermia. The patient received 4 cycles of Ara-C and DNR plus one cycle with etoposide 350 mg/m2 and mitoxantrone 30 mg/m2. Semen examination of two patients 55- and 59-year-old showed permanent oligoasthenozoospermia with only sporadic progressively motile spermatozoa which might not be compatible with fertilization by sexual intercourse. They received the same chemotherapy including cumulative doses of etoposide 500 mg/m2 and mitoxantrone 36 mg/m2. Semen of two patients after allogeneic bone marrow transplantation exhibited severe oligoasthenozoospermia with no motile spermatozoa. Permanent amenorrhea developed in two women (42- and 46-year-old) during chemotherapy with DNR, Ara-C, etoposide, and mitoxantrone which was not the case in three women (29-40 years old) treated without etoposide and mitoxantrone. Intensive chemotherapy with high-doses of Ara-C and DNR plus one cycle of etoposide and mitoxantrone may cause permanent gonadal dysfunction in middle-aged patients with AML. PMID:16151584

  16. Altered expression of topoisomerase IIα contributes to cross-resistant to etoposide K562/MX2 cell line by aberrant methylation

    PubMed Central

    Asano, T; Nakamura, K; Fujii, H; Horichi, N; Ohmori, T; Hasegawa, K; Isoe, T; Adachi, M; Otake, N; Fukunaga, Y

    2005-01-01

    KRN 8602 (MX2) is a novel morpholino anthracycline derivative having the chemical structure 3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride. To investigate the mechanisms of resistance to MX2, we established an MX2-resistant phenotype (K562/MX2) of the human myelogeneous leukaemia cell line (K562/P), by continuously exposing a suspension culture to increasing concentrations of MX2. K562/MX2 cells were more resistant to MX2 than the parent cells, and also showed cross-resistance to etoposide and doxorubicin. Topoisomerase (Topo) IIα protein levels in K562/MX2 cells were lower of those in K562/P cells on immunoblot analysis and decreased expression of Topo IIα mRNA was seen in K562/MX2 cells. Topoisomerase II catalytic activity was also reduced in the nuclear extracts from K562/MX2 cells when compared with K562/P cells. Aberrant methylated CpG of Topo IIα gene was observed in K562/MX2 cells when compared with the parent line on methylation-specific restriction enzyme analysis. To overcome the drug resistance to MX2 and etoposide, we investigated treatment with 5-Aza-2′-deoxycytidine (5AZ), which is a demethylating agent, in K562/MX2 cells. 5-Aza-2′-deoxycytidine treatment increased Topo IIα mRNA expression in K562/MX2 cells, but not in K562/P cells, and increased the cytotoxicity of MX2 and etoposide. Methylated CpG was decreased in K562/MX2 cells after 5AZ treatment. We concluded that the mechanism of drug resistance to MX2 and etoposide in K562/MX2 cells might be the combination of decreased expression of Topo IIα gene and increased methylation, and that 5AZ could prove to be a novel treatment for etoposide-resistant cell lines, such as K562/MX2. PMID:15798770

  17. Pilomatrix carcinoma of the scalp with pulmonary metastasis: A case report of a complete response to oral endoxan and etoposide

    PubMed Central

    ARSLAN, DENIZ; GÜNDÜZ, ŞEYDA; AVCI, FATMA; MERDIN, ALPARSLAN; TATLI, ALI MURAT; UYSAL, MÜKREMIN; TURAL, DENIZ; BAŞSORGUN, CUMHUR İBRAHIM; SAVAŞ, BURHAN

    2014-01-01

    Pilomatrix carcinoma is an extremely rare skin tumor derived from basaloid cells in the hair follicles; it often exhibits locally aggressive behavior with a tendency toward local recurrence. The average age of occurrence is 45 years, and there appears to be a male to female incidence ratio of 4:1. Although pilomatrix carcinomas are predominantly identified in the neck and scalp, there are studies in the literature reporting other tumor development sites, including the upper extremities, torso and popliteal fossa. If diagnosed at an early stage, this malignant tumor is generally treated with wide surgical resection. However, for the advanced-stage tumors, there are no standard treatment procedures known to produce good results. The current study presents the case of a 76-year-old male with pilomatrix carcinoma originating from the scalp with metastases to the lung. The patient had a rapid and complete clinical response following an oral combination chemotherapy regimen of cyclophosphamide and etoposide. PMID:24932268

  18. Elemental bioimaging of Cisplatin in Caenorhabditis elegans by LA-ICP-MS

    PubMed Central

    Crone, Barbara; Aschner, Michael; Schwerdtle, Tanja; Karst, Uwe; Bornhorst, Julia

    2015-01-01

    Cis-diamminedichloroplatinum(II) (Cisplatin) is one of the most important and frequently used cytostatic drugs for the treatment of various solid tumors. Herein, a laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) method incorporating a fast and simple sample preparation protocol was developed for the elemental mapping of Cisplatin in the model organism Caenorhabditis elegans (C. elegans). The method allows imaging of the spatially-resolved elemental distribution of platinum in the whole organism with respect to the anatomic structure in L4 stage worms at a lateral resolution of 5 µm. In addition, a dose- and time-dependent Cisplatin uptake was corroborated quantitatively by a total reflection X-ray fluorescence spectroscopy (TXRF) method, and the elemental mapping indicated that Cisplatin is located in the intestine and in the head of the worms. Better understanding of the distribution of Cisplatin in this well-established model organism will be instrumental in deciphering Cisplatin toxicity and pharmacokinetics. Since the cytostatic effect of Cisplatin is based on binding the DNA by forming intra- and interstrand crosslinks, the response of poly(ADP-ribose)metabolism enzyme 1 (pme-1) deletion mutants to Cisplatin was also examined. Loss of pme-1, which is the C. elegans ortholog of human poly(ADP-ribose) polymerase 1 (PARP-1) led to disturbed DNA damage response. With respect to survival and brood size, pme-1 deletion mutants were more sensitive to Cisplatin as compared to wildtype worms, while Cisplatin uptake was indistinguishable. PMID:25996669

  19. Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells

    PubMed Central

    Wu, Hui-Mei; Jiang, Zi-Feng; Ding, Pei-Shan; Shao, Li-Jie; Liu, Rong-Yu

    2015-01-01

    Hypoxia which commonly exists in solid tumors, leads to cancer cells chemoresistance via provoking adaptive responses including autophagy. Therefore, we sought to evaluate the role of autophagy and hypoxia as well as the underlying mechanism in the cisplatin resistance of lung cancer cells. Our study demonstrated that hypoxia significantly protected A549 and SPC-A1 cells from cisplatin-induced cell death in a Hif-1α- and Hif-2α- dependent manner. Moreover, compared with normoxia, cisplatin-induced apoptosis under hypoxia was markedly reduced. However, when autophagy was inhibited by 3-MA or siRNA targeted ATG5, this reduction was effectively attenuated, which means autophagy mediates cisplatin resisitance under hypoxia. In parallel, we showed that hypoxia robustly augmented cisplatin-induced autophagy activation, accompanying by suppressing cisplatin-induced BNIP3 death pathways, which was due to the more efficient autophagic process under hypoxia. Consequently, we proposed that autophagy was a protective mechanism after cisplatin incubation under both normoxia and hypoxia. However, under normoxia, autophagy activation ‘was unable to counteract the stress induced by cisplatin, therefore resulting in cell death, whereas under hypoxia, autophagy induction was augmented that solved the cisplatin-induced stress, allowing the cells to survival. In conclusion, augmented induction of autophagy by hypoxia decreased lung cancer cells susceptibility to cisplatin-induced apoptosis. PMID:26201611

  20. Enhancement of Cisplatin Nephrotoxicity by Morphine and Its Attenuation by the Opioid Antagonist Naltrexone.

    PubMed

    Aminian, Atefeh; Javadi, Shiva; Rahimian, Reza; Dehpour, Ahmad Reza; Asadi Amoli, Fahimeh; Moghaddas, Payman; Ejtemaei Mehr, Shahram

    2016-07-01

    Nephrotoxicity is a major side effect of cisplatin, a widely used chemotherapy agent. Morphine and other opioids are also used extensively in different types of cancer for the clinical management of pain associated with local or metastatic neoplastic lesions. In addition to its analgesic effects, morphine has also been reported to possess potential immunomodulatory and antioxidant properties. Herein, we investigated the effects of morphine in a rat model of cisplatin-induced nephrotoxicity. Following administration of a single dose of cisplatin (5 mg/kg), animals received intraperitoneal injections of morphine (5 mg/kg/day) and/or naltrexone (20 mg/kg/day), an opioid antagonist, for 5 days. Cisplatin-induced nephrotoxicity was detected by a significant increase in plasma urea and creatinine levels in addition to alterations in kidney tissue morphology. Levels of TNF-α and IL-1β were significantly increased in the renal tissue in cisplatin group. Moreover, glutathione (GSH) concentration and superoxide dismutase activity were significantly reduced in renal tissue in cisplatin group compared with control animals. Treatment with morphine aggravated the deleterious effects of cisplatin at clinical, biochemical and histopathological levels; whereas naltrexone diminished the detrimental effects of morphine in animals receiving morphine and cisplatin. Morphine or naltrexone alone had no effect on the mentioned parameters. Our findings indicate that concomitant treatment with morphine might intensify cisplatin-induced renal damage in rats. These findings suggest that morphine and other opioids should be administered cautiously in patients receiving cisplatin chemotherapy. PMID:27424012

  1. Cisplatin Concentrations in Long and Short Duration Infusion: Implications for the Optimal Time of Radiation Delivery

    PubMed Central

    Mathew, Binu Susan; Das, Saikat; Isaiah, Rajesh; John, Subashini; Prabha, Ratna; Fleming, Denise Helen

    2016-01-01

    Introduction Cisplatin has radiosensitizing properties and the best sensitization to radiotherapy occurs with a higher plasma concentration of cisplatin. To our knowledge the optimal time sequence between chemotherapy and administration of radiation therapy, to obtain maximum effect from concurrent chemoradiation is unclear. Aim The aim of this study was to measure the two cisplatin infusion regimens in order to determine the total and free cisplatin post infusion concentration changes over time. These changes may have clinical implications on the optimum time of administration of post infusion radiation therapy. Materials and Methods Two cohorts of patients were recruited and both, total and free plasma concentration of cisplatin following long and short durations of intravenous infusion was determined. Blood samples were collected at 0.5, 1, 1.5, 2, 3 and 5 hours from the start of the infusion in the 1hour infusion group and at 2, 3, 3.5, 4, 6 and 24 hours from the start of the infusion, in the 3 hour infusion group. Total and free cisplatin concentrations were measured using a validated HPLC-UV method. Results The highest concentration of total and free cisplatin was achieved at the end of the infusion in both regimens. Total cisplatin concentration declined 30 minutes after the end of infusion in both the groups. After 1hour of discontinuing cisplatin, the free cisplatin concentration also declined significantly. Conclusion We conclude that radiation should be administered within 30 minutes of completion of the infusion irrespective of the duration of infusion.

  2. Anti-apoptotic effect of clusterin on cisplatin-induced cell death of retinoblastoma cells.

    PubMed

    Song, Hyun Beom; Jun, Hyoung-Oh; Kim, Jin Hyoung; Yu, Young Suk; Kim, Kyu-Won; Min, Bon Hong; Kim, Jeong Hun

    2013-12-01

    Clusterin is a cytoprotective chaperone protein that is known to protect various retinal cells. It was also reported to be overexpressed in several types of malignant tumors, whose chemoresistance correlates with the expression of clusterin. Herein, we investigated the effect of clusterin on cisplatin-induced cell death of retinoblastoma cells. Firstly, evaluation of clusterin expression demonstrated that it was highly expressed in human retinoblastoma tissues and cell lines (SNUOT-Rb1 and Y79) particularly in the area between viable cells around vessels and necrotic zones in the relatively avascular area in human retinoblastoma tissues. Furthermore, the effects of cisplatin on retinoblastoma cells were evaluated. Cisplatin (1 µg/ml) significantly affected cell viability of SNUOT-Rb1 cells by inducing caspase-3-dependent apoptosis. Notably, the cell death due to cisplatin was prevented by 5 µg/ml of clusterin administered 4 h prior to cisplatin treatment by inhibiting cisplatin-induced apoptosis. Furthermore, overexpression of clusterin exerted its anti-apoptotic effect on cisplatin-induced apoptosis, and effectively prevented cisplatin-induced cell death. These data suggest that clusterin, found to be expressed in human retinoblastoma, may exert anti-apoptotic effects on cisplatin-induced apoptosis and prevent cell death. Therefore, clusterin can contribute to cisplatin resistance of retinoblastoma. PMID:24085287

  3. 14-3-3σ regulation of and interaction with YAP1 in acquired gemcitabine resistance via promoting ribonucleotide reductase expression

    PubMed Central

    Qin, Li; Dong, Zizheng; Zhang, Jian-Ting

    2016-01-01

    Gemcitabine is an important anticancer therapeutics approved for treatment of several human cancers including locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). Its clinical effectiveness, however, is hindered by existence of intrinsic and development of acquired resistances. Previously, it was found that 14-3-3σ expression associates with poor clinical outcome of PDAC patients. It was also found that 14-3-3σ expression is up-regulated in gemcitabine resistant PDAC cells and contributes to the acquired gemcitabine resistance. In this study, we investigated the molecular mechanism of 14-3-3σ function in gemcitabine resistance and found that 14-3-3σ up-regulates YAP1 expression and then binds to YAP1 to inhibit gemcitabine-induced caspase 8 activation and apoptosis. 14-3-3σ association with YAP1 up-regulates the expression of ribonucleotide reductase M1 and M2, which may mediate 14-3-3σ/YAP1 function in the acquired gemcitabine resistance. These findings suggest a possible role of YAP1 signaling in gemcitabine resistance. PMID:26894857

  4. Enhanced antitumor efficacy of cisplatin in combination with HemoHIM in tumor-bearing mice

    PubMed Central

    2009-01-01

    Background Although cisplatin is one of the most effective chemotherapeutic agents, cisplatin alone does not achieve a satisfactory therapeutic outcome. Also cisplatin accumulation shows toxicity to normal tissues. In this study, we examined the possibility of HemoHIM both to enhance anticancer effect with cisplatin and to reduce the side effects of cisplatin in melanoma-bearing mice. Methods HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of 3 edible herbs, Angelica Radix, Cnidium Rhizoma and Paeonia Radix. Anticancer effects of HemoHIM with cisplatin were evaluated in melanoma-bearing mice. We used a Cr51-release assay to measure the activity of NK/Tc cell and ELISA to evaluate the production of cytokines. Results In melanoma-bearing mice, cisplatin (4 mg/kg B.W.) reduced the size and weight of the solid tumors, and HemoHIM supplementation with cisplatin enhanced the decrease of both the tumor size (p < 0.1) and weight (p < 0.1). HemoHIM itself did not inhibit melanoma cell growth in vitro, and did not disturb the effects of cisplatin in vitro. However HemoHIM administration enhanced both NK cell and Tc cell activity in mice. Interestingly, HemoHIM increased the proportion of NK cells in the spleen. In melanoma-bearing mice treated with cisplatin, HemoHIM administration also increased the activity of NK cells and Tc cells and the IL-2 and IFN-γ secretion from splenocytes, which seemed to contribute to the enhanced efficacy of cisplatin by HemoHIM. Also, HemoHIM reduced nephrotoxicity as seen by tubular cell of kidney destruction. Conclusion HemoHIM may be a beneficial supplement during cisplatin chemotherapy for enhancing the anti-tumor efficacy and reducing the toxicity of cisplatin. PMID:19292900

  5. Chronic Pancreatitis and Systemic Infl