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Sample records for cisplatin based chemotherapy

  1. Mitochondrial Transcription Factor A and Mitochondrial Genome as Molecular Targets for Cisplatin-Based Cancer Chemotherapy.

    PubMed

    Kohno, Kimitoshi; Wang, Ke-Yong; Takahashi, Mayu; Kurita, Tomoko; Yoshida, Yoichiro; Hirakawa, Masakazu; Harada, Yoshikazu; Kuma, Akihiro; Izumi, Hiroto; Matsumoto, Shinji

    2015-08-20

    Mitochondria are important cellular organelles that function as control centers of the energy supply for highly proliferative cancer cells and regulate apoptosis after cancer chemotherapy. Cisplatin is one of the most important chemotherapeutic agents and a key drug in therapeutic regimens for a broad range of solid tumors. Cisplatin may directly interact with mitochondria, which can induce apoptosis. The direct interactions between cisplatin and mitochondria may account for our understanding of the clinical activity of cisplatin and development of resistance. However, the basis for the roles of mitochondria under treatment with chemotherapy is poorly understood. In this review, we present novel aspects regarding the unique characteristics of the mitochondrial genome in relation to the use of platinum-based chemotherapy and describe our recent work demonstrating the importance of the mitochondrial transcription factor A (mtTFA) expression in cancer cells.

  2. Prometheus' spirit: quality survival in advanced hepatocellular carcinoma after gemcitabine and cisplatin-based chemotherapy.

    PubMed

    Doval, D C; Pande, S B; Sharma, J B; Pavithran, K; Jena, A; Vaid, A K

    2008-10-01

    In advanced virus-induced hepatocellular carcinoma (HCC) associated with cirrhosis, the average survival is four months. We report a 56-year-old man with a large-volume advanced HCC, in whom gemcitabine and cisplatin-based chemotherapy resulted in near-complete regression, and quality survival of 24 months.

  3. The impact of paclitaxel or cisplatin-based chemotherapy on sympathetic skin response: a prospective study.

    PubMed

    Argyriou, A A; Koutras, A; Polychronopoulos, P; Papapetropoulos, S; Iconomou, G; Katsoulas, G; Makatsoris, T; Kalofonos, H P; Chroni, E

    2005-11-01

    The current study aimed to assess the viability of sympathetic sudomotor fibers in cancer patients treated with cisplatin or paclitaxel-based chemotherapy and to ascertain whether this method could contribute to the diagnostic sensitivity of conventional techniques. Sympathetic skin response (SSR) from the hand and sole of 23 cancer patients (nine females and 14 males, mean age 62.4 +/- 10.5 years) was recorded unilaterally before and after chemotherapy with six courses of cumulative cisplatin or paclitaxel containing regimens. Clinical and electrophysiological data were also collected and correlated with the SSR results. Twenty-three healthy subjects served as controls. SSR abnormalities were only present in patients with evidence of peripheral neuropathy assessed by conventional nerve conduction techniques. Three patients had absent SSR in the upper limb whilst six patients had absent SSR both in the upper and lower limbs. In the upper limb, the mean SSR latency was not significantly altered through time (P = 0.086). In the lower limb the mean delay from baseline to follow-up was significantly changed (P = 0.029). In patients, the mean SSR latency was significantly prolonged compared with controls in both upper limb (P = 0.001) and lower limb (P = 0.000). SSR abnormalities were strongly related to sensory conduction abnormalities as detected by conventional techniques (r = 0.39, P = 0.004). Our results showed that SSR does not seem to add to the diagnostic sensitivity of conventional techniques in chemotherapy-induced neuropathy. However, its role in the disclosure of small fibers neuropathy abnormalities is worth considering. Further studies are warranted to address this important issue.

  4. Ototoxicity After Intensity-Modulated Radiation Therapy and Cisplatin-Based Chemotherapy in Children With Medulloblastoma

    SciTech Connect

    Paulino, Arnold C.; Lobo, Mark; Teh, Bin S.; Okcu, M. Fatih; South, Michael; Butler, E. Brian; Su, Jack; Chintagumpala, Murali

    2010-12-01

    Purpose: To report the incidence of Pediatric Oncology Group (POG) Grade 3 or 4 ototoxicity in a cohort of patients treated with craniospinal irradiation (CSI) followed by posterior fossa (PF) and/or tumor bed (TB) boost using intensity-modulated radiation therapy (IMRT). Methods and Materials: From 1998 to 2006, 44 patients with medulloblastoma were treated with CSI followed by IMRT to the PF and/or TB and cisplatin-based chemotherapy. Patients with standard-risk disease were treated with 18 to 23.4 Gy CSI followed by either a (1) PF boost to 36 Gy and TB boost to 54 to 55.8 Gy or (2) TB boost to 55.8 Gy. Patients with high-risk disease received 36 to 39.6 Gy CSI followed by a (1) PF boost to 54 to 55.8 Gy, (2) PF boost to 45 Gy and TB boost to 55.8 Gy, or (3) TB boost to 55.8 Gy. Median audiogram follow-up was 41 months (range, 11-92.4 months). Results: POG Grade Ototoxicity 0, 1, 2, 3. and 4 was found in 29, 32, 11, 13. and 3 ears. respectively, with POG Grade 3 or 4 accounting for 18.2% of cases. There was a statistically significant difference in mean radiation dose (D{sub mean}) cochlea according to degree of ototoxicity, with D{sub mean} cochlea increasing with severity of hearing loss (p = 0.027). Conclusions: Severe ototoxicity was seen in 18.2% of ears in children treated with IMRT boost and cisplatin-based chemotherapy. Increasing dose to the cochlea was associated with increasing severity of hearing loss.

  5. Changes in blood concentrations of trace metals in cancer patients receiving cisplatin-based chemotherapy

    PubMed Central

    Nakamura, Tsutomu; Takahashi, Minoru; Niigata, Riho; Yamashita, Kazuhiko; Kume, Manabu; Hirai, Midori; Yasui, Hiroyuki

    2016-01-01

    The administration of cisplatin (CDDP) may influence trace metal concentrations in body fluids. In order to test this hypothesis, the blood concentrations of trace metals were determined during the present study in eight Japanese esophageal and lung cancer patients receiving CDDP-based chemotherapy. The levels of manganese, iron (Fe), cobalt, copper, zinc (Zn), platinum and lead in the plasma were determined by inductively coupled plasma-mass spectrometry. In addition, the serum levels of Fe, transferrin and ferritin were evaluated. The baseline plasma concentration of Fe in patients with esophageal cancer was significantly lower than that in lung cancer patients (P=0.011), although there were no significant differences identified with respect to the plasma levels of other trace metals. The data obtained from six fasting patients without blood transfusion demonstrated that plasma concentrations of Fe increased 3.5-fold soon after CDDP treatment and returned to baseline levels ~10 days after therapy. The excessive Fe levels in the bloodstream induced changes in serum ferritin and transferrin levels. Furthermore, serum Zn levels increased 1.8-fold in the 1–3 days following CDDP treatment, and serum cystatin C levels transiently increased. These findings indicate that serum Fe and Zn levels may be useful to understanding the physiological responses in the early stages of CDDP-based chemotherapy, which may be associated with systemic inflammation and/or tissue distribution of CDDP. PMID:28105341

  6. Relative Contributions of Radiation and Cisplatin-Based Chemotherapy to Sensorineural Hearing Loss in Head-and-Neck Cancer Patients

    SciTech Connect

    Hitchcock, Ying J. Tward, Jonathan D.; Szabo, Aniko; Bentz, Brandon G.; Shrieve, Dennis C.

    2009-03-01

    Purpose: To investigate the risk of sensorineural hearing loss (SNHL) in patients with head-and-neck cancer and treated with radiation therapy (RT) or concomitant cisplatin-based chemoradiation, the relationship among SNHL and radiation dose to the cochlea, the use of two common cisplatin dose regimens. Methods and Materials: A total of 62 head-and-neck cancer patients treated with curative intent were included in this prospective study. Of the patients, 21 received RT alone, 27 received 40 mg/m{sup 2} weekly cisplatin, 13 received 100 mg/m{sup 2} every 3 weeks during RT, and 1 received RT with weekly epidermal growth factor receptor inhibitor antibody. The effect of chemotherapy and RT dose on hearing was determined using a model that accounted for the age and variability between each ear for each patient. Results: We constructed a model to predict dose-dependent hearing loss for RT or cisplatin-based chemotherapy either alone or in combination. For patients only receiving RT, no significant hearing loss was found at doses to the cochlea of less than 40 Gy. Patients receiving 100 mg/m{sup 2} or 40 mg/m{sup 2} of cisplatin chemotherapy had an estimated +21.5 dB and +9.5 dB hearing loss at 8,000 Hz with low radiation doses (10 Gy), which rose to +38.4 dB and +18.9 dB for high radiation doses (40 Gy). Conclusions: Use of RT alone with doses of less than 40 Gy did not result in clinically significant hearing loss. High-frequency SNHL was profoundly damaged in patients who received concomitant cisplatin when doses of 100 mg/m{sup 2} were used. The threshold cochlear dose for hearing loss with cisplatin-based chemotherapy and RT was predicted to be 10 Gy. The inner ear radiation dose constraints and cisplatin dose intensity should be considered in the treatment of advanced head-and-neck cancer.

  7. Clinical outcomes following neoadjuvant cisplatin-based chemotherapy for bladder cancer in elderly compared with younger patients.

    PubMed

    Chau, C; Wheater, M; Geldart, T; Crabb, S J

    2015-03-01

    Bladder cancer is a disease of the elderly. Older patients might potentially be undertreated due to assumptions about benefit versus risk. Our objective was to determine outcomes in older patients receiving neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC). We hypothesised that appropriately selected elderly patients (≥70 years) with MIBC could have similar clinical outcomes, and be safely treated, with standard neoadjuvant chemotherapy prior to definitive cystectomy or radiotherapy. We utilised a single institution case series analysis of patients with T2-4a N0 M0 transitional cell carcinoma of the bladder treated with cisplatin-based neoadjuvant chemotherapy between 2005 and 2011. Eighty-three patients were eligible. Median age was 68 (range 48-80), 33 patients (40%) were ≥70 years. Overall survival at 3 years was 65.8% (≥70) and 63.2% (<70) (P = 0.653), relapse-free survival at 3 years was 61.6% and 54.8% respectively (P = 0.471). The rates going forward to definitive local therapy (87.9% ≥ 70 and 84.0% < 70) and the pathological complete response rate (31.3% ≥ 70 and 40% < 70) were similar. Disease relapse rate was also similar (63.6% ≥ 70 vs. 60% < 70, P = 0.906). Elderly patients with good functional status and limited comorbidities diagnosed with MIBC receiving standard neoadjuvant chemotherapy followed by cystectomy or radiotherapy can have similar clinical outcomes as their younger counterparts. Prospective studies evaluating the optimum curative management in this elderly population are warranted.

  8. Induction Cisplatin and Fluorouracil-Based Chemotherapy Followed by Concurrent Chemoradiation for Muscle-Invasive Bladder Cancer

    SciTech Connect

    Lin, C.-C.; Hsu, C.-H.; Cheng, Jason C.; Huang, C.-Y.; Tsai, Y.-C.; Hsu, F.-M.; Huang, K.-H.; Cheng, A.-L.; Pu, Y.-S.

    2009-10-01

    Purpose: To evaluate a multimodality bladder-preserving therapy in patients with muscle-invasive bladder cancer. Methods and Materials: Patients with stages T2-4aN0M0 bladder cancer suitable for cystectomy underwent radical transurethral resection and induction chemotherapy, followed by concurrent chemoradiotherapy (CCRT). Patients with a Karnofsky performance status (KPS) <80 or age {>=}70 years underwent Protocol A: induction chemotherapy with three cycles of the cisplatin and 5-fluorouracil (CF) regimen, and CCRT with six doses of weekly cisplatin and 64.8 Gy radiotherapy given with the shrinking-field technique. Patients with KPS {>=}80 and age <70 years underwent Protocol B: induction chemotherapy with three cycles of weekly paclitaxel plus the CF regimen, and CCRT with six doses of weekly paclitaxel and cisplatin plus 64.8 Gy radiotherapy. Interval cystoscopy was employed after induction chemotherapy and when radiotherapy reached 43.2 Gy. Patients without a complete response (CR) were referred for salvage cystectomy. Results: Among 30 patients (median, 66 years) enrolled, 17 and 13 patients underwent Protocol A and B, respectively. After induction chemotherapy, 23 patients achieved CR. Five (17%) of 7 patients without CR underwent salvage cystectomy. Overall, 28 patients (93%) completed the protocol treatment. Of 22 patients who completed CCRT, 1 had recurrence with carcinoma in situ and 3 had distant metastases. After a median follow-up of 47 months, overall and progression-free survival rate for all patients were 77% and 54% at 3 years, respectively. Of 19 surviving patients, 15 (79%) retained functioning bladders. Conclusions: Our protocols may be alternatives to cystectomy for selected patients who wish to preserve the bladder.

  9. Prevention of cisplatin-based chemotherapy-induced delayed nausea and vomiting using triple antiemetic regimens: a mixed treatment comparison

    PubMed Central

    Li, Hongjia; Le, Qiqi; Liu, Shanshan; Zong, Shaoqi; Zheng, Leizhen; Hou, Fenggang

    2016-01-01

    A variety of triple antiemetic regimens are being used to prevent cisplatin-based chemotherapy induced delayed emesis and nausea in cancer patients. We performed a network meta-analysis to compare the efficacies of the different regimens. Electronic searches of the PubMed, Cochrane Library and MEDLINE databases were performed to identify randomized controlled trials, and data were analyzed using JAGS, Stata 14.0 and R project. The primary outcome was a complete response (CR). The secondary outcomes were no vomiting (NV) and no nausea (NN). Among the 398 studies identified, 10 were eligible and included, providing data on nine regimens. In the CR analysis, the absolute rank of netupitant + palonosetron + dexamethasone (NEPA) was 0.8579. In the NV and NN analyses, NEPA's absolute ranks were 0.8631 and 0.7902, respectively. The compliance of patients treated with rolapitant + granisetron + dexamethasone (RGD) was the best due to a low incidence of adverse events, and good compliance was also observed with NEPA. It was difficult to achieve good compliance with aprepitant + granisetron + dexamethasone (AGD). Overall, NEPA was the best regimen, and aprepitant + ondansetron + dexamethasone (AOD) is also worthy of recommendation because of its low cost and good effect. For patients with severe constipation, hiccups, asthenia and/or delayed nausea, RGD is worthy of consideration. PMID:27015550

  10. An Epigenomic Approach to Improving Response to Neoadjuvant Cisplatin Chemotherapy in Bladder Cancer.

    PubMed

    Xylinas, Evanguelos; Hassler, Melanie R; Zhuang, Dazhong; Krzywinski, Martin; Erdem, Zeynep; Robinson, Brian D; Elemento, Olivier; Clozel, Thomas; Shariat, Shahrokh F

    2016-09-02

    Bladder cancer is among the five most common cancers diagnosed in the Western world and causes significant mortality and morbidity rates in affected patients. Therapeutic options to treat the disease in advanced muscle-invasive bladder cancer (MIBC) include cystectomy and chemotherapy. Neoadjuvant cisplatin-based combination chemotherapy is effective in MIBC; however, it has not been widely adopted by the community. One reason is that many patients do not respond to neoadjuvant chemotherapy, and no biomarker currently exists to identify these patients. It is also not clear whether a strategy to sensitize chemoresistant patients may exist. We sought to identify cisplatin-resistance patterns in preclinical models of bladder cancer, and test whether treatment with the epigenetic modifier decitabine is able to sensitize cisplatin-resistant bladder cancer cell lines. Using a screening approach in cisplatin-resistant bladder cancer cell lines, we identified dysregulated genes by RNA sequencing (RNAseq) and DNA methylation assays. DNA methylation analysis of tumors from 18 patients receiving cisplatin-based chemotherapy was used to confirm in vitro results. Cisplatin-resistant bladder cancer cells were treated with decitabine to investigate epigenetic sensitization of resistant cell lines. Our results show that HOXA9 promoter methylation status is associated with response to cisplatin-based chemotherapy in bladder cancer cell lines and in metastatic bladder cancer. Bladder cancer cells resistant to cisplatin chemotherapy can be sensitized to cisplatin by the DNA methylation inhibitor decitabine. Our data suggest that HOXA9 promoter methylation could serve as potential predictive biomarker and decitabine might sensitize resistant tumors in patients receiving cisplatin-based chemotherapy.

  11. Multi-Institutional Assessment of Adverse Health Outcomes Among North American Testicular Cancer Survivors After Modern Cisplatin-Based Chemotherapy.

    PubMed

    Fung, Chunkit; Sesso, Howard D; Williams, Annalynn M; Kerns, Sarah L; Monahan, Patrick; Abu Zaid, Mohammad; Feldman, Darren R; Hamilton, Robert J; Vaughn, David J; Beard, Clair J; Kollmannsberger, Christian K; Cook, Ryan; Althouse, Sandra; Ardeshir-Rouhani-Fard, Shirin; Lipshultz, Steve E; Einhorn, Lawrence H; Fossa, Sophie D; Travis, Lois B

    2017-04-10

    Purpose To provide new information on adverse health outcomes (AHOs) in testicular cancer survivors (TCSs) after four cycles of etoposide and cisplatin (EPX4) or three or four cycles of bleomycin, etoposide, cisplatin (BEPX3/BEPX4). Methods Nine hundred fifty-two TCSs > 1 year postchemotherapy underwent physical examination and completed a questionnaire. Multinomial logistic regression estimated AHOs odds ratios (ORs) in relation to age, cumulative cisplatin and/or bleomycin dose, time since chemotherapy, sociodemographic factors, and health behaviors. Results Median age at evaluation was 37 years; median time since chemotherapy was 4.3 years. Chemotherapy consisted largely of BEPX3 (38.2%), EPX4 (30.9%), and BEPX4 (17.9%). None, one to two, three to four, or five or more AHOs were reported by 20.4%, 42.0%, 25.1%, and 12.5% of TCSs, respectively. Median number after EPX4 or BEPX3 was two (range, zero to nine and zero to 11, respectively; P > .05) and two (range, zero to 10) after BEPX4. When comparing individual AHOs for EPX4 versus BEPX3, Raynaud phenomenon (11.6% v 21.4%; P < .01), peripheral neuropathy (29.2% v 21.4%; P = .02), and obesity (25.5% v 33.0%; P = .04) differed. Larger cumulative bleomycin doses (OR, 1.44 per 90,000 IU) were significantly associated with five or more AHOs. Increasing age was a significant risk factor for one to two, three to four, or five or more AHOs versus zero AHOs (OR, 1.22, 1.50, and 1.87 per 5 years, respectively; P < .01); vigorous physical activity was protective (OR, 0.62, 0.51, and 0.41, respectively; P < .05). Significant risk factors for three to four and five or more AHOs included current (OR, 3.05 and 3.73) or former (OR, 1.61 and 1.76) smoking ( P < .05). Self-reported health was excellent/very good in 59.9% of TCSs but decreased as AHOs increased ( P < .001). Conclusion Numbers of AHOs after EPX4 or BEPX3 appear similar, with median follow-up of 4.3 years. A healthy lifestyle was associated with reduced number of AHOs.

  12. Breast cancer resistance protein (BCRP) and excision repair cross complement-1 (ERCC1) expression in esophageal cancers and response to cisplatin and irinotecan based chemotherapy

    PubMed Central

    Bharthuar, Anubha; Black, Jennifer D.; Levea, Charles; Malhotra, Usha; Mashtare, Terry L.; Iyer, Renuka

    2014-01-01

    Background Esophageal cancer patients face a dismal outcome despite tri-modality management and median survival remains 15-18 months. Breast cancer resistance protein (BCRP) is an ATP-dependent efflux protein associated with chemotherapy resistance. The role of BCRP expression in esophageal cancer and normal esophageal cells is not known. Excision repair cross complement-1 (ERCC1) overexpression has been correlated with poorer response to cisplatin based chemotherapy. We examined the expression of BCRP and ERCC1 in patients with esophageal cancer and correlated it with survival in patients receiving irinotecan and cisplatin based chemotherapy. Methods With IRB approval, 40 cases of esophageal cancer diagnosed from 2004-2008, were stained for BCRP and ERCC1 expression by immunohistochemistry and scored by a pathologist blinded to clinical data. Baseline demographics, therapy given and survival data were collected and correlated with BCRP and ERCC1 expression. Fisher’s exact test was used to determine association between BCRP and ERCC1 expression and demographics. Cox proportional hazards model was used for association of BCRP and ERCC1 with survival. Results On immunohistochemistry, 30/40 cancers (75%) expressed BCRP. Interestingly, down-regulation of BCRP expression in tumor compared with normal cells was seen in 40% of patients. ERCC1 positivity was seen in 15/30 cases (50%). Median overall survival (OS) was 19 months with no difference in survival between BCRP positive and negative patients (P=0.13) or ERCC1 positive and negative patients (P=0.85). Estimated hazard ratio (HR) of death for BRCP positive patients was 2.29 (95% CI: 0.79-6.64) and for ERCC1 positive patients was 1.09 (95% CI: 0.46-2.56). There was no association of BCRP and ERCC1 expression with disease stage, age, gender or histology. For patients who received cisplatin and irinotecan as first line chemotherapy, there was no difference in survival based on BCRP or ERCC1 status. Conclusions BCRP

  13. Randomized Clinical Trial of Weekly vs. Triweekly Cisplatin-Based Chemotherapy Concurrent With Radiotherapy in the Treatment of Locally Advanced Cervical Cancer

    SciTech Connect

    Ryu, Sang-Young; Lee, Won-Moo; Kim, Kidong; Park, Sang-Il; Kim, Beob-Jong; Kim, Moon-Hong; Choi, Seok-Cheol; Cho, Chul-Koo; Nam, Byung-Ho; Lee, Eui-Don

    2011-11-15

    Purpose: To compare compliance, toxicity, and outcome of weekly and triweekly cisplatin administration concurrent with radiotherapy in locally advanced cervical cancer. Methods and Materials: In this open-label, randomized trial, 104 patients with histologically proven Stage IIB-IVA cervical cancer were randomly assigned by a computer-generated procedure to weekly (weekly cisplatin 40 mg/m{sup 2}, six cycles) and triweekly (cisplatin 75 mg/m{sup 2} every 3 weeks, three cycles) chemotherapy arms during concurrent radiotherapy. The difference of compliance and the toxicity profiles between the two arms were investigated, and the overall survival rate was analyzed after 5 years. Results: All patients tolerated both treatments very well, with a high completion rate of scheduled chemotherapy cycles. There was no statistically significant difference in compliance between the two arms (86.3% in the weekly arm, 92.5% in the triweekly arm, p > 0.05). Grade 3-4 neutropenia was more frequent in the weekly arm (39.2%) than in the triweekly arm (22.6%) (p = 0.03). The overall 5-year survival rate was significantly higher in the triweekly arm (88.7%) than in the weekly arm (66.5%) (hazard ratio 0.375; 95% confidence interval 0.154-0.914; p = 0.03). Conclusions: Triweekly cisplatin 75-mg/m{sup 2} chemotherapy concurrent with radiotherapy is more effective and feasible than the conventional weekly cisplatin 40-mg/m{sup 2} regimen and may be a strong candidate for the optimal cisplatin dose and dosing schedule in the treatment of locally advanced cervical cancer.

  14. Human antigen R as a predictive marker for response to gemcitabine-based chemotherapy in advanced cisplatin-resistant urothelial cancer

    PubMed Central

    Miyata, Yasuyoshi; Mitsunari, Kensuke; Akihiro, Asai; Watanabe, Shin-Ichi; Matsuo, Tomohiro; Ohba, Kojiro; Sakai, Hideki

    2017-01-01

    In patients with advanced urothelial cancer (UC), a combination of cisplatin (CDDP) and gemcitabine (GEM) is the most commonly used first-line systematic chemotherapy regimen. Although no standard regime for the treatment of CDDP-resistant UC has been established, GEM-based regimens are frequently used in these patients. In other types of cancer, human antigen R (HuR) status in cancer cells is closely associated with patient response to GEM. The aim of the present study was to establish the predictive potential of HuR expression for disease progression and survival in patients with UC who were treated with GEM-based regimens as a first or second-line chemotherapy. A total of 50 patients with advanced UC were enrolled in the current study. As first-line chemotherapy, methotrexate, vinblastine, epirubicin and CDDP (MVEC) combination therapy and GEM and CDDP combination therapy were administered in 34 (68.0%) and 16 patients (32.0%), respectively. Following progression, 45 patients (90.0%) were treated with combined GEM and paclitaxel therapy, and 5 patients (10.0%) were treated with GEM monotherapy. Cytoplasmic and nuclear HuR expression was evaluated using immunohistochemical techniques. The associations between HuR expression levels and local tumor response and treatment outcomes were analyzed. In first-line chemotherapy, no anticancer effects were observed to be significantly associated with nuclear or cytoplasmic HuR expression. In second-line chemotherapy nuclear HuR expression also exhibited no significant association with anticancer effects; however, the local tumor response was significantly improved if positive cytoplasmic HuR expression was present (P=0.002). Multivariate analyses revealed that cytoplasmic HuR expression levels were a significant predictive marker for longer OS (hazard ratio, 0.22; 95% confidence interval, 0.09–0.56; P=0.001). No significant association was observed between nuclear HuR expression levels and the overall survival. Therefore

  15. Comparison of the Efficacy between Gemcitabine-Cisplatin and Capecitabine-Cisplatin Combination Chemotherapy for Advanced Biliary Tract Cancer

    PubMed Central

    Lee, Jieun; Hong, Tae Ho; Lee, In Seok; You, Young Kyoung; Lee, Myung Ah

    2015-01-01

    Purpose Gemcitabine-cisplatin combination chemotherapy has been regarded as standard regimen for advanced or metastatic biliary tract cancer (BTC), based on the ABC-02 trial. To date, however, no studies have compared the efficacies of gemcitabine-platinum and fluoropyrimidine- platinum combination chemotherapy, even though fluoropyrimidine has been widely used as a backbone agent for gastrointestinal cancer. This study compared the efficacy and toxicities of gemcitabine-cisplatin (GP) and capecitabine-cisplatin (XP) combination chemotherapy for treatment of advanced BTC. Materials and Methods We examined 49 patients treated with GP and 44 patients treated with XP from October 2009 to July 2012. All patients had unresectable BTC. The GP regimen comprised gemcitabine (1,000 mg/m2, intravenously [IV], days 1 and 8) and cisplatin (75 mg/m2, IV, day 1). The XP regimen comprised capecitabine (1,250 mg/m2 twice a day, peroral, days 1-14) and cisplatin (60 mg/m2, IV, day 1, every three weeks). We analyzed the response rate (RR), time to progression (TTP), overall survival (OS), and toxicity. Results The RRs were 27.3% and 6.1% in the XP and GP arms, respectively. XP resulted in longer TTP (5.2 months vs. 3.6 months, p=0.016), but OS was not statistically different (10.7 months vs. 8.6 months, p=0.365). Both regimens resulted in grade 3-4 hematologic toxicities, but febrile neutropenia was not noted. Grade 3-4 asthenia, stomatitis, and hand-foot syndrome occurred more frequently in the XP arm. Conclusion XP resulted in a superior TTP and RR compared to GP for treatment of advanced BTC, with comparable toxicity. Conduct of prospective large, randomized trials to evaluate the possibility of XP as another standard therapy is warranted. PMID:25648099

  16. Ifosfamide, Cisplatin or Carboplatin, and Etoposide (ICE)-based Chemotherapy for Mobilization of Autologous Peripheral Blood Stem Cells in Patients with Lymphomas

    PubMed Central

    Zhou, Ping; Liu, Peng; Zhou, Sheng-Yu; He, Xiao-Hui; Han, Xiao-Hong; Qin, Yan; Yang, Sheng; Zhang, Chang-Gong; Gui, Lin; Yao, Jia-Rui; Zhao, Li-Ya; Zhang, Shu-Xiang; Sun, Yan; Shi, Yuan-Kai

    2015-01-01

    Background: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a promising approach for lymphomas. This study aimed to evaluate the effect of ifosfamide, cisplatin or carboplatin, and etoposide (ICE)-based regimen as a mobilization regimen on relapsed, refractory, or high-risk aggressive lymphoma. Methods: From June 2001 to May 2013, patients with lymphomas who mobilized by ICE-based regimen for ASCT were analyzed in this retrospective study. The results of the autologous peripheral blood stem cells collection, toxicity, engraftment after ICE-based mobilization regimen were analyzed in this study. Furthermore, risk factors for overall survival (OS) and progression free survival (PFS) were evaluated by univariate analysis. Results: The stem cells were mobilized using ICE-based regimen plus rituximab or ICE-based regimen alone in 12 patients and 54 patients, respectively. The results of stem cell mobilization were excellent. Ninety-seven percentages of the patients had the stem cell collection of at least 2.0 × 106 CD34+ cells/kg and 68% had at least 5 × 106 CD34+ cells/kg. Fifty-eight percentage of the patients experienced Grade 4 neutropenia, 20% developed febrile neutropenia, and only 12% had Grade 4 thrombocytopenia. At a median follow-up of 63.8 months, the 5-year PFS and OS were 64.4% and 75.3%, respectively. Conclusion: ICE is a powerful regimen for stem cell mobilization in patients with lymphomas. PMID:26365969

  17. Combined chemotherapy and photodynamic therapy using a nanohybrid based on layered double hydroxides to conquer cisplatin resistance.

    PubMed

    Wang, Zhigang; Ma, Rong; Yan, Li; Chen, Xianfeng; Zhu, Guangyu

    2015-07-25

    A nanohybrid is assembled by ratiometrically co-loading Pt(IV) prodrugs and photosensitizers into layered double hydroxide nanoparticles. The nanohybrid shows synergistic cell-killing effects and is significantly active against the proliferation of cisplatin-resistant human cancer cells with nanomolar IC50 values. Profound mechanistic investigations confirm its action mode of combined chemo- and photodynamic therapy.

  18. 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

  19. Cisplatin-based chemotherapy followed by focal, reduced-dose irradiation for pediatric primary central nervous system germinomas.

    PubMed

    Douglas, James G; Rockhill, Jason K; Olson, James M; Ellenbogen, Richard G; Geyer, J Russell

    2006-01-01

    The objective of this study was to evaluate retrospectively one institution's experience treating pediatric central nervous system (CNS) pure germinomas with platinum-based chemotherapy followed by focal, reduced-dose irradiation. Eight patients were identified with localized, pure CNS germinomas from 1993 to 2004 at the authors' institution. The median age at diagnosis was 13 years (range 7-19). The median follow-up was 40 months (range 8-141). The tumor location was suprasellar in four, the pineal region in three, and the third ventricle in one. Irradiation was started a median of 20 weeks (range 17-22) from diagnosis and consisted of conformal fields to the primary site as determined by the initial diagnostic MR plus a 1.5- to 2-cm margin. Six of the eight patients received a dose of 3,060 cGy; two patients received 3,600 cGy. The 5-year actuarial event free survival was 71% (56-86%, 95% CI). Two patients suffered marginal (at field edge) failures and both were salvaged using reinduction platinum-based chemotherapy followed by cranial spinal irradiation and a boost to the primary tumor. The 5-year actuarial overall survival was 100%. There were no spinal failures. These data suggest that a reduction in both volume and dose (30.6-36 Gy) retains the excellent survival rates for patients with localized, pure germinomas of the CNS. A higher rate of ventricular relapse rate is observed, although salvage of those patients is feasible.

  20. Quantitation of cis-diamminedichloroplatinum II (cisplatin)-DNA-intrastrand adducts in testicular and ovarian cancer patients receiving cisplatin chemotherapy.

    PubMed

    Reed, E; Yuspa, S H; Zwelling, L A; Ozols, R F; Poirier, M C

    1986-02-01

    The antitumor activity of cis-diamminedichloroplatinum II (cisplatin) is believed to be related to its covalent interaction with DNA where a major DNA binding product is an intrastrand N7-bidentate adduct on adjacent deoxyguanosines. A novel immunoassay was used to quantitate this adduct in buffy coat DNA from testicular and ovarian cancer patients undergoing cisplatin therapy. 44 out of 120 samples taken from 45 cisplatin patients had detectable cisplatin-DNA adducts. No adducts were detected in 18 samples of DNA taken from normal controls, patients on other chemotherapy, or patients before treatment. The quantity of measurable adducts increased as a function of cumulative dose of cisplatin. This was observed both during repeated daily infusion of the drug and over long-term, repeated 21-28 d cycles of administration. These results suggested that adduct removal is slow even though the tissue has a relatively rapid turnover. Patients receiving cisplatin for the first time on 56-d cycles, and those given high doses of cisplatin as a "salvage" regimen, did not accumulate adducts as rapidly as patients on first time chemotherapy on 21- or 28-d cycles. Disease response data, evaluated for 33 cisplatin-treated patients, showed a positive correlation between the formation of DNA adducts and response to drug therapy. However, more data will be required to confirm this relationship. These data show that specific immunological probes can readily be applied to quantitate DNA adducts in patients undergoing cancer chemotherapy.

  1. Effect of vinorelbine, ifosfamide, and cisplatin combination chemotherapy in advanced non-small-cell lung cancer.

    PubMed

    Ahn, J B; Ko, W K; Lee, J G; Shim, K Y; Jeung, H C; Park, J O; Yoo, N C; Kim, B S; Kim, S K; Kim, S K; Kim, J H

    2000-12-01

    Cisplatin-based chemotherapy is being tried in the treatment of nonoperable cases of non-small-cell lung cancer (NSCLC). However, the prognosis is unfavorable and to improve survival, clinical studies using various combinations of a variety of drugs as well as experimental material are in progress. We compared the efficacy and toxicities of combination chemotherapy using different doses of vinorelbine and ifosfamide with a constant dose of cisplatin in this study. Patients diagnosed with inoperable stage III or IV NSCLC between June 1997 and December 1998 were included. Cisplatin was administered at a constant dose of 80 mg/m2 on day 5, whereas vinorelbine on days 1 and 5 and ifosfamide on day 5 were administered in one of two different doses. In arm A, vinorelbine 25 mg/m2 and ifosfamide 3.0 g/m2 were administered. In arm B, vinorelbine 20 mg/m2 and ifosfamide 2.5 g/m2 were administered. Also, we reviewed for phase II and III studies that test 1) cisplatin, 2) vinorelbine monotherapy, and 3) vinorelbine/cisplatin/ifosfamide combination chemotherapy for stage IIIb-IV non-SCLC. Summation dose intensity (SDI) was calculated in each published and current study. Twenty patients in arm A and 35 patients in arm B were available for evaluation. There was no difference in patient activity, pathologic diagnosis, and differentiation or stage between the two arms. The median number of cycles was four in both arms. The response rate was 50% in arm A and 30% in arm B. The median survival times for arm A and B were 40 and 42 weeks, respectively, whereas the SDI was 1.94 and 1.7, respectively. More than grade III leukopenia was observed in 28.9% in arm A, which is more frequent than the 17.2% in arm B. There was a significant correlation between the SDIs and response rates and median survival (r2 = 0.629, p = 0.001; r2 = 0.453, p = 0.001, respectively). Although the follow-up period is relatively short, the survival time was similar in both arms. Because a high response rate may

  2. Synergistic Cisplatin/Doxorubicin Combination Chemotherapy for Multidrug-Resistant Cancer via Polymeric Nanogels Targeting Delivery.

    PubMed

    Wu, Haiqiu; Jin, Haojie; Wang, Cun; Zhang, Zihao; Ruan, Haoyu; Sun, Luyan; Yang, Chen; Li, Yongjing; Qin, Wenxin; Wang, Changchun

    2017-03-08

    Combination chemotherapy has been proposed to achieve synergistic effect and minimize drug dose for cancer treatment in clinic application. In this article, the stimuli-responsive polymeric nanogels (<100 nm in size) based on poly(acrylic acid) were designed as codelivery system for doxorubicin and cisplatin to overcome drug resistance. By chelation, electrostatic interaction, and π-π stacking interactions, the nanogels could encapsulate doxorubicin and cisplatin with designed ratio and high capacity. Compared with free drugs, the nanogels could deliver more drugs into MCF-7/ADR cells. Significant accumulation in tumor tissues was observed in the biodistribution experiments. The in vitro antitumor studies demonstrated the superior cell-killing activity of the nanogel drug delivery system with a combination index of 0.84, which indicated the great synergistic effect. All the antitumor experimental data revealed that the combination therapy was effective for the multidrug-resistant MCF-7/ADR tumor with reduced side effects.

  3. Poly(amido)amine (PAMAM) dendrimer-cisplatin complexes for chemotherapy of cisplatin-resistant ovarian cancer cells

    NASA Astrophysics Data System (ADS)

    Yellepeddi, Venkata Kashyap; Vangara, Kiran Kumar; Palakurthi, Srinath

    2013-09-01

    Dendrimer-cisplatin complexes were prepared using PAMAM dendrimers with terminal -NH2 and -COOH groups as well as biotin-conjugated dendrimers. Preformulation parameters of dendrimer-cisplatin complexes were studied using differential scanning calorimetry (DSC) and inductively coupled plasma-mass spectrometry (ICP-MS). Cytotoxicity and mechanism of cytotoxicity of dendrimer-cisplatin complexes was investigated in OVCAR-3, SKOV, A2780 and cisplatin-resistant CP70 human ovarian cancer cell lines. The loading of cisplatin in dendrimers was 11 % (w/w). PAMAM G4 dendrimers with amine surface groups (biotinylated and native) have shown 2.5- to 3.0-fold reduction in IC50 values in ovarian cancer cells when compared with carboxylate surface dendrimers ( p < 0.05). A correlation was observed among cytotoxicity of the complexes, cellular uptake, and platinum-DNA adduct formation. Treatment with dendrimer-cisplatin complexes resulted in a 7.0-fold increase ( p < 0.05) in expression of apoptotic genes ( Bcl2, Bax, p53) and 13.2- to 27.1-fold increase ( p < 0.05) in the activity of caspases 3, 8, and 9 in vitro. Results suggest that PAMAM dendrimers can be used as potential carrier for cisplatin chemotherapy of ovarian cancer.

  4. Albumin-to-Alkaline Phosphatase Ratio: A Novel Prognostic Index of Overall Survival in Cisplatin-based Chemotherapy-treated Patients with Metastatic Nasopharyngeal Carcinoma

    PubMed Central

    Nie, Man; Sun, Peng; Chen, Cui; Bi, Xiwen; Wang, Yu; Yang, Hang; Liu, Panpan; Li, Zhiming; Xia, Yi; Jiang, Wenqi

    2017-01-01

    The Albumin-to-Alkaline Phosphatase Ratio (AAPR) has been recently revealed as a prognostic index for hepatocellular carcinoma, whereas its role in metastatic nasopharyngeal cancer (NPC) remains unclear. The aim of this study was to evaluate the clinical value of AAPR in patients with metastatic NPC. We retrospectively reviewed 209 metastatic NPC patients treated with cisplatin-based regimens. Survival data were calculated using the Kaplan-Meier method and were compared using the log-rank test. Univariate and multivariate survival analyses were conducted using the Cox proportional hazards regression methodology. The optimal cutoff level of AAPR for assessing overall survival (OS) was 0.447, which was determined by R software. An AAPR less than 0.447 was significantly associated with a higher lactate dehydrogenase (LDH) level (273 vs. 185 U/L, P = 0.004), a higher EBV DNA viral load (5.59×105 vs. 3.49×104 copies/ml, P = 0.001), and more liver and bone metastases (P = 0.005 and P = 0.001, respectively). Additionally, patients with an AAPR < 0.447 had a shorter overall survival and progression-free survival (hazard ratio: 3.269, 95% confidence interval: 1.710-6.248; HR: 2.295, 95% confidence interval: 1.217-4.331, respectively) than those with an AAPR ≥ 0.447. Our study suggested that the AAPR might be a novel prognostic factor in metastatic NPC patients treated with cisplatin-based regimens. However, a prospective study to validate its prognostic value is needed, and the mechanisms underlying the low AAPR and poor survival in metastatic NPC need to be further investigated. PMID:28382143

  5. Two cases of cisplatin-induced permanent renal failure following neoadjuvant chemotherapy for esophageal cancer

    PubMed Central

    Sasaki, Tomohiko; Motoyama, Satoru; Komatsuda, Atsushi; Shibata, Hiroyuki; Sato, Yusuke; Yoshino, Kei; Wakita, Akiyuki; Saito, Hajime; Anbai, Akira; Jin, Mario; Minamiya, Yoshihiro

    2016-01-01

    Introduction We experienced two esophageal cancer patients who developed severe acute renal failure after neoadjuvant chemotherapy with cisplatin and 5-fluorourasil. Presentation of case After administration of cisplatin, their serum creatinine increased gradually until they required hemodialysis and their renal failure was permanent. In both cases, renal biopsy examination indicated partial recovery of the proximal tubule, but renal function did not recover. After these events, one patient underwent definitive radiotherapy and the other underwent esophagectomy for their esophageal cancers, while continuing dialysis. Both patients are alive without cancer recurrence. Discussion In these two cases of cisplatin-induced renal failure, renal biopsy examination showed only slight disorder of proximal tubules and tendency to recover. Conclusion Although cisplatin-related nephrotoxicity is a well-recognized complication, there have been few reports of renal failure requiring hemodialysis in cancer patients. In this report, we present their clinical courses and the pathological findings of cisplatin-related renal failure. PMID:26851395

  6. On the Discovery, Biological Effects, and Use of Cisplatin and Metallocenes in Anticancer Chemotherapy

    PubMed Central

    Gómez-Ruiz, Santiago; Maksimović-Ivanić, Danijela; Mijatović, Sanja; Kaluđerović, Goran N.

    2012-01-01

    The purpose of this paper is to summarize mode of action of cisplatin on the tumor cells, a brief outlook on the metallocene compounds as antitumor drugs as well as the future tendencies for the use of the latter in anticancer chemotherapy. Molecular mechanisms of cisplatin interaction with DNA, DNA repair mechanisms, and cellular proteins are discussed. Molecular background of the sensitivity and resistance to cisplatin, as well as its influence on the efficacy of the antitumor immune response was evaluated. Furthermore, herein are summarized some metallocenes (titanocene, vanadocene, molybdocene, ferrocene, and zirconocene) with high antitumor activity. PMID:22844263

  7. Is Gemcitabine and Cisplatin Induction Chemotherapy Superior in Locoregionally Advanced Nasopharyngeal Carcinoma?

    PubMed Central

    Zheng, Wei; Qiu, Sufang; Huang, Lingling; Pan, Jianji

    2015-01-01

    Objective: To investigate the outcome of locoregionally advanced nasopharyngeal carcinoma (NPC) treated with induction chemotherapy followed by chemoradiotherapy. Methods: Between June 2005 and October 2007, 604 patients with locoregionally advanced NPC were analyzed, of whom 399 and 205 were treated with conventional radiotherapy and intensity-modulated radiotherapy (IMRT) respectively. Meanwhile, 153 patients received concurrent chemotherapy, and 520 were given induction chemotherapy. Results: With a median follow-up time of 65 months, the 3-, and 5-year overall survival (OS), locoregional free survival (LRFS), and distant-metastasis free survival (DMFS) rates were 82.5% vs. 72.6%, 90.6% vs. 87.1%, and 82.5% vs. 81.2%, respectively. Induction chemotherapy was not an independent prognostic factor for OS (P=0.193) or LRFS, but there was a positive tendency for DMFS (P=0.088). GP regimen (gemcitabine + cisplatin) was an independent prognostic factor for OS (P = 0.038) and it had a trend toward improved DMFS (P = 0.109). TP regimen (taxol + cisplatin) was only a significant prognostic factor for DMFS (P =0.038). Conclusions: Adding induction chemotherapy had no survival benefit, but GP regimen benefited overall survival and had a trend toward improved DMFS. GP regimen may be superior to TP/FP regimen (fluorouracil + cisplatin) in treating locoregionally advanced NPC. PMID:26430402

  8. [A case of small cell carcinoma in the urinary bladder responding to gemcitabine/cisplatin combination therapy as neoadjuvant chemotherapy].

    PubMed

    Shirato, Akitomi; Shimamoto, Kenji; Ozawa, Akira; Tanji, Nozomu; Yokoyama, Masayoshi

    2006-12-01

    We report a case of primary small cell carcinoma of the urinary bladder. A 79-year-old man with the chief complaints of macrohematuria and pollakisuria was admitted to our hospital. Cystoscopy and computed tomography (CT) revealed a non-papillary broad-based bladder tumor. Histological diagnosis was small cell carcinoma of the urinary bladder, and he underwent 3 courses of neoadjuvant chemotherapy including gemcitabine and cisplatin with a preoperative diagnosis of cT3bN0M0. After the chemotherapy, cystoscopy and CT showed complete remission. Total cystectomy with ileal conduit was performed following 3 courses of chemotherapy. Microscopic examination revealed that the small cell carcinoma had disappeared and the converted squamous cell carcinoma remained only in a small part of the specimens. The patient was carefully followed for 10 months after operation, with no tumor recurrence.

  9. Induction Chemotherapy with Cisplatin and 5-Fluorouracil in Advanced Head and Neck Cancers: A Short Term Response Evaluation

    PubMed Central

    Rao, Raghavendra; Shenoy, Vijendra; Hegde, Mahesh Chandra; Prasad, Vishnu; Prasad, Krishna

    2015-01-01

    Background Considering the uprising number of Head and neck cancer in the state with limited options of medical and surgical treatment, the focus of this study involved on chemotherapy in advanced Head and neck cancers. The aim of this study was to evaluate the efficacy and toxicity of combination of Cisplatin and 5-Fluorouracil (PF) as induction chemotherapy in patients in locally advanced squamous cell cancer of head and neck. Materials and Methods Forty four patients with previously untreated stage III -IV advanced and inoperable cases were included in this prospective study. Induction chemotherapy consisted of 3 cycles of Cisplatin 100mg/mt2 as infusion on day 1, 5-Fluorouracil of 750mg/mt2 on day 2, 5-Fluorouracil of 1000mg/mt2 as infusion on day 3 in an inpatient basis. Cycles were repeated with an interval of 21 days. Patients were evaluated within a period of 3 weeks at the end of completion of third cycle of chemotherapy. Post chemotherapy local therapy was individualized based on the response, site and stage of the tumour. Results Out of 44 eligible and evaluable patients, major dominance was noted in male group constituting 68%. After induction chemotherapy 58.8% of stage III experienced stable response, & 44% had partial response. In stage IV, 44% showed a stable response and 33.3% had partial response. But in comparison to primary tumour response and nodal response, which had a significant clinical response, the overall response of malignancy with respect to stage and site specificity was clinically insignificant. Moderate adverse reaction was noted in 47.6% and 42.1% had mild reactions. Majority of patients experienced grade 3 adverse events, of which anaemia in females and leucopenia in males pre-dominated. Conclusion With the use of cisplatin and 5-FU as induction chemotherapy agents in advanced and inoperable squamous cell carcinoma of head and neck, a distinct benefit was seen in stabilizing the tumour from progression. But achieving a significant

  10. Pediatric and Young Adult Nasopharyngeal Carcinoma Patients Treated With Preradiation Cisplatin and Docetaxel Chemotherapy

    SciTech Connect

    Varan, Ali Ozyar, Enis; Corapcioglu, Funda; Koeksal, Yavuz; Aydin, Burca; Yazici, Nalan; Akyuez, Canan; Bueyuekpamukcu, Muenevver

    2009-03-15

    Purpose: To evaluate treatment results for pediatric and young adult (aged <21 years) patients with nonmetastatic nasopharyngeal carcinoma treated with neoadjuvant cisplatin + docetaxel and radiotherapy. Methods and Materials: Ten patients with nasopharyngeal carcinoma who received diagnoses between 2004 and 2007 were treated with four cycles of cisplatin 100 mg/m{sup 2} + docetaxel 75 mg/m{sup 2} on Day 1 with premedication every 3 weeks. All patients were treated with fractionated external beam radiotherapy after chemotherapy to a median dose of 59.4 Gy (range, 54-59.4 Gy) to the primary disease and 40 Gy to the supraclavicular field with the clavicles shielded. Five children were monitored with serum EBV DNA quantification at diagnosis, after each cycle of chemotherapy, before radiotherapy, and at follow-up. Results: The median age of the patients was 14 years (range, 9-20 years), with a male:female ratio of 6:4. Stage distribution was as follows: 2 patients had Stage IIb disease, 2 had Stage III, 4 had Stage IVa, and 2 had Stage IVb disease. After cisplatin+docetaxel chemotherapy 1 patient had a complete response, 5 had a partial response, 3 had stable disease, and 1 had disease progression. The 2-year overall survival rate in our series was 90% and the event-free survival rate was 70%. No major chemotherapy toxicity was observed. The EBV DNA titers were higher in 2 of the 5 monitored patients at the time of diagnosis. Conclusion: As neoadjuvant chemotherapy before radiotherapy, the cisplatin+docetaxel combination is safe for use in the treatment of childhood nasopharyngeal carcinoma.

  11. Seizure following chemotherapy (paclitaxel and cisplatin) in a patient of carcinoma cervix

    PubMed Central

    Dana, Rohitashwa; Spartacus, R. K.; Mutha, Shweta; Bhat, Prashanth

    2016-01-01

    Cisplatin and paclitaxel both can cause peripheral neurotoxicity as an adverse effect; however, central nervous system neurotoxicity in the form of seizures is rare. We report a case of a 36-year-old female patient of metastatic carcinoma cervix, who developed seizure shortly after cisplatin infusion. Her laboratory investigations were within normal limits. Computed tomography scan and magnetic resonance imaging of the brain did not reveal brain primary metastasis or meningeal carcinomatosis. She had no complaints of fever, no signs and symptoms of infection, and no history of seizure nor was she on any medication predisposing to such an event. Excluding several causes, seizure was thought to be most likely related to the chemotherapy and cisplatin was the more likely agent in view of observed temporal relationship with the adverse event. PMID:28066118

  12. Seizure following chemotherapy (paclitaxel and cisplatin) in a patient of carcinoma cervix.

    PubMed

    Dana, Rohitashwa; Spartacus, R K; Mutha, Shweta; Bhat, Prashanth

    2016-01-01

    Cisplatin and paclitaxel both can cause peripheral neurotoxicity as an adverse effect; however, central nervous system neurotoxicity in the form of seizures is rare. We report a case of a 36-year-old female patient of metastatic carcinoma cervix, who developed seizure shortly after cisplatin infusion. Her laboratory investigations were within normal limits. Computed tomography scan and magnetic resonance imaging of the brain did not reveal brain primary metastasis or meningeal carcinomatosis. She had no complaints of fever, no signs and symptoms of infection, and no history of seizure nor was she on any medication predisposing to such an event. Excluding several causes, seizure was thought to be most likely related to the chemotherapy and cisplatin was the more likely agent in view of observed temporal relationship with the adverse event.

  13. First-line chemotherapy with liposomal doxorubicin plus cisplatin for patients with advanced malignant pleural mesothelioma: phase II trial

    PubMed Central

    Arrieta, Ó; Medina, L A; Estrada-Lobato, E; Hernández-Pedro, N; Villanueva-Rodríguez, G; Martínez-Barrera, L; Macedo, E O; López-Rodríguez, V; Motola-Kuba, D; Corona-Cruz, J F

    2012-01-01

    Background: Chemotherapy based on platinum is the standard treatment for unresectable malignant pleural mesothelioma (MPM). Liposomal doxorubicin (LD) consists of pegylated phospholipid vesicles that encapsulate doxorubicin-enhancing liposome deposition in the tumour. We evaluated the toxicity profile and anti-tumour activity of cisplatin plus LD in untreated patients with MPM, as well as 99mTc-LD distribution in MPM lesions after chemotherapy administration. Methods: A total of 38 patients with non-resectable MPM received LD 40 mg m−2 and cisplatin 60 mg m−2 every 21 days. Gamma camera images of 99mTc-LD were acquired to evaluate LD accumulation in measurable tumour tissue. The study was registered in Clinical Trials (NCT00886028). Results: In all, 72% of patients were stage III and 28% were stage IV. Eighty four percent and 16% have high and low risk acording EORTC respectively. The median time to progression was 4.6 months (95% confidence interval (95% CI: 3.4–5.9 months), and median overall survival (OS) was 19.6 months (15.2–37.2 months). Patients that responded to chemotherapy treatment had better survival than patients who did not. Functional physical scales, dysnea, cough, and chest/arm pain demonstrated improvement. The accumulation ratio of LD in tumour and soft tissues vs liver was 0.78±0.16 and 0.29±0.09, respectively. After 1 h of administration, LD uptake in tumour tissue was higher than in soft tissue (P< 0.001). Conclusion: The combination of LD and cisplatin results in an active therapeutic regimen for unresectable MPM, with an acceptable toxicity profile and improvement in quality of life. 99mTc-LD showed higher levels of tumour uptake as compared with surrounding tissues. PMID:22353806

  14. Postoperative chemotherapy in gastric cancer, consisting of etoposide, doxorubicin and cisplatin, followed by radiotherapy with concomitant cisplatin: A feasibility study

    PubMed Central

    SHULMAN, KATERINA; HAIM, NISSIM; WOLLNER, MIRA; BERNSTEIN, ZVI; ABDAH-BORTNYAK, ROXYLANA; BAR-SELA, GIL

    2012-01-01

    The prognosis following surgical treatment of gastric carcinoma (GC) or gastroesophageal junction (GEJ) adenocarcinoma remains poor. Although adjuvant chemo-radiotherapy with 5-fluorouracil has been shown to be beneficial, a high rate of distant failure has been reported. Thus, the toxicity profile and efficacy of an intensified chemo-radiotherapy regimen following complete or near-complete resection of GC was evaluated. Patients who underwent surgery for GC were eligible for evaluation. Treatment consisted of four cycles of modified EAP: etoposide 100 mg/m2, days 1–3; cisplatin 27 mg/m2, days 1–3; and adriamycin 40 mg/m2, day 1; every 21 days, followed by a course of radiotherapy (45 Gy; 1.8 Gy/fr) combined with weekly cisplatin 40 mg/m2. In total, 40 patients were included in the analysis. Median follow-up was 34 months from the onset of chemotherapy. Microscopic stage IV disease and/or R1 resection were found in 11 patients. For these patients, the median progression-free survival was 6.5 months, and overall survival 9.5 months, compared to 25 and 54 months, respectively, for the remaining 29 patients. In the latter subgroup, longer disease-free survival was associated with average dose intensity of >90% for the four cycles of EAP. The predominant grade 3–4 toxicities during EAP-chemotherapy were hematological adverse events. Nevertheless, the rate of severe non-hematologic toxicity reached 60%. There was one toxicity-related mortality. During the chemo-radiotherapy course, 39% of patients experienced grade 3–4 non-hematologic toxicities. It was concluded that the high toxicity rate of this regimen does not justify further evaluation of this postoperative protocol. Chemo-radiotherapy for R1 or pathological microscopic M1 patients does not appear to be justified. PMID:22783410

  15. Clinical Significance of Early Changes in Circulating Tumor Cells from Patients Receiving First-Line Cisplatin-Based Chemotherapy for Metastatic Urothelial Carcinoma1

    PubMed Central

    Fina, Emanuela; Necchi, Andrea; Giannatempo, Patrizia; Colecchia, Maurizio; Raggi, Daniele; Daidone, Maria Grazia; Cappelletti, Vera

    2016-01-01

    Background: The therapeutic paradigm of metastatic urothelial carcinoma (UC) is rapidly shifting and new biomarkers are needed to enhance patient selection. Objective: Early identification of dynamic predictors of outcome may be a key to optimize the sequence of effective therapies in metastatic UC patients. Methods: Blood samples from patients receiving first-line MVAC chemotherapy were collected at baseline (T0) and after 2 cycles (T2). Samples were processed by immunomagnetic beads (AdnaTest ProstateCancerSelect kit) and the expression of EPCAM, MUC1 and ERBB2 was studied using multiplex-PCR. Circulating tumor cell (CTC) positivity and cutoffs, obtained by receiver operator characteristic (ROC) curve analysis in healthy donors, were: ≥1 positive marker among EPCAM (≥0.40 ng/μl), MUC1 (≥0.10 ng/μl) and ERBB2 (≥0.20 ng/μl). CTC variation (T0/T2) was split in favorable (+/–, –/–, –/+) and unfavorable groups (+/+). Cox regression analyses evaluated associations with clinical factors. Results: In this pilot study to assess a new CTC detection method, among 31 evaluable patients, 17 (54.8%) were CTC-positive at T0. No association was found between CTC and objective response to MVAC. CTC dynamic changes better predicted 3-year progression-free (PFS) and overall survival (OS) compared to CTC status assessed at single time points. Unfavorable trend was univariably detrimental on 3-year PFS (10% vs. 49.2%, p = 0.006) and OS (20% vs. 63.5%, p = 0.017). Significance was maintained after controlling for liver metastases (p = 0.031 and p = 0.025 for PFS and OS) and MSKCC score (p = 0.014 and 0.025). Conclusions: Newly described early CTC changes during chemotherapy might be useful to improve our prognostic ability. Pending validation, these results could fulfill the promise to help accelerating therapeutic sequences. PMID:28035320

  16. MCL-1 is the key target of adjuvant chemotherapy to reverse the cisplatin-resistance in NSCLC.

    PubMed

    Ma, Jun; Zhao, Zhenxian; Wu, Kaiming; Xu, Zhe; Liu, Kuanzhi

    2016-08-10

    Cisplatin is one of the most effective chemotherapeutic agents for the treatment of lung cancer. However, the acquired resistance occurred in cancer cells limits the clinical application of cisplatin. MCL-1, which is an important member in the pro-survival Bcl-2 family, plays a critical role in multidrug resistance (MDR). The aim of the present study is to investigate the value of Pan-Bcl-2 inhibitor as sensitizer for the chemotherapy of cisplatin-resistant non-small cell lung cancer (NSCLC) cells. We found the obatoclax but not the ABT-737 significantly decreased the IC50 (half maximal inhibitory concentration) of cisplatin in cisplatin-resistant NSCLC cells. Furthermore, we demonstrated that the mechanism of obatoclax-promoted cell death induced by cisplatin was dependent on the inhibition of MCL-1, which couldn't be inhibited by ABT-737 but is the target of obatoclax. Moreover, inhibition of MCL-1 recovered the function of NOXA and BAK in cisplatin-resistant NSCLC cells, leading to the promotion of mitochondrial apoptosis induced by cisplatin. Interestingly, our date indicated the obatoclax also reversed the cross-resistance in cisplatin-resistant NSCLC cells. Therefore, we demonstrated that the targeted therapy with MCL-1 inhibitors, such as obatoclax, may represent a novel strategy for cancer therapy.

  17. Transarterial Infusion Chemotherapy Using Cisplatin-Lipiodol Suspension With or Without Embolization for Unresectable Hepatocellular Carcinoma

    SciTech Connect

    Kawaoka, Tomokazu; Aikata, Hiroshi Takaki, Shintaro; Katamura, Yoshio; Hiramatsu, Akira; Waki, Koji; Takahashi, Shoichi; Hieda, Masashi; Toyota, Naoyuki; Ito, Katsuhide; Chayama, Kazuaki

    2009-07-15

    We evaluate the long-term prognosis and prognostic factors in patients treated with transarterial infusion chemotherapy using cisplatin-lipiodol (CDDP/LPD) suspension with or without embolization for unresectable hepatocellular carcinoma (HCC). Study subjects were 107 patients with HCC treated with repeated transarterial infusion chemotherapy alone using CDDP/LPD (adjusted as CDDP 10mg/LPD 1ml). The median number of transarterial infusion procedures was two (range, one to nine), the mean dose of CDDP per transarterial infusion chemotherapy session was 30 mg (range, 5.0-67.5 mg), and the median total dose of transarterial infusion chemotherapy per patient was 60 mg (range, 10-390 mg). Survival rates were 86% at 1 year, 40% at 3 years, 20% at 5 years, and 16% at 7 years. For patients with >90% LPD accumulation after the first transarterial infusion chemotherapy, rates were 98% at 1 year, 60% at 3 years, and 22% at 5 years. Multivariate analysis identified >90% LPD accumulation after the first transarterial infusion chemotherapy (p = 0.001), absence of portal vein tumor thrombosis (PVTT; p < 0.001), and Child-Pugh class A (p = 0.012) as independent determinants of survival. Anaphylactic shock was observed in two patients, at the fifth transarterial infusion chemotherapy session in one and the ninth in the other. In conclusion, transarterial infusion chemotherapy with CDDP/LPD appears to be a useful treatment option for patients with unresectable HCC without PVTT and in Child-Pugh class A. LPD accumulation after the first transarterial infusion chemotherapy is an important prognostic factor. Careful consideration should be given to the possibility of anaphylactic shock upon repeat infusion with CDDP/LPD.

  18. A Phase II Tolerability Study of Cisplatin Plus Docetaxel as Adjuvant Chemotherapy for Resected Non-small Cell Lung Cancer

    PubMed Central

    Azzoli, Christopher G.; Krug, Lee M.; Miller, Vincent A.; Rizvi, Naiyer A.; Kris, Mark G.; Dunne, Megan; Farmer, Amy; Pizzo, Barbara; Tyson, Leslie; Seeger, Teresa; Coleman, Barbara; Moore, Erin; Lastinger, Lauren; Venkatraman, Ennapadam; Rudin, Charles M.

    2013-01-01

    Introduction We undertook this phase II study to measure postoperative drug delivery and toxicity of cisplatin plus docetaxel in patients with resected stage I-III non-small cell lung cancer. Methods The primary endpoint was amount of cisplatin delivered over a planned four cycles of adjuvant chemotherapy. Statistical design required a cohort to close if the regimen proved unlikely to improve cisplatin delivery compared with published phase III data. The first cohort was treated with docetaxel 35 mg/m2 intravenously (IV) on days 1, 8, and 15, and cisplatin 80 mg/m2 IV on day 15, every 4 weeks for four planned cycles. A second cohort was treated with docetaxel 75 mg/m2 IV plus cisplatin 80 mg/m2 IV on day 1 every 3 weeks for four planned cycles. Results Sixteen patients were treated with weekly docetaxel and cisplatin every 4 weeks, with five of 16 (31%) unable to complete three cycles. Subsequently, 11 patients were treated with docetaxel and cisplatin every 3 weeks, with six of 11 (55%) unable to complete three cycles. Among the 11 patients who failed to complete three cycles, the reasons for stopping included one or more of the following: fatigue (n = 8), nausea (n = 4), febrile neutropenia (n = 1), hypotension (n = 1), and nephrotoxicity (n = 1). Conclusions The combination of cisplatin at 80 mg/m2 with docetaxel 35 mg/m2 weekly or 75 mg/m2 every 3 weeks is no better tolerated than older chemotherapy regimens. The most common reason to stop chemotherapy was intolerable fatigue. These results suggest that the most common dose-limiting toxicities are attributable to the cisplatin, given similar problems were encountered whether the docetaxel was delivered as a single dose every 3 weeks or as a lower weekly dose. PMID:17607120

  19. Capecitabine and cisplatin (XP) combination systemic chemotherapy in heavily pre-treated HER2 negative metastatic breast cancer

    PubMed Central

    Lee, Jieun; Kim, Hyun Ho; Ro, Sang Mi; Yang, Ji Hyun

    2017-01-01

    Purpose/Objective(s) After taxane and anthracycline failure, no standard chemotherapy regimen is established in metastatic breast cancer (MBC). Capecitabine and cisplatin (XP) combination shows promising results in gastrointestinal cancer, but there are relatively scarce data in MBC. We reviewed the clinical outcome of XP regimen in anthracycline and taxane resistant, heavily pretreated MBC patients. Materials/Methods Between Jan. 2010 to Feb. 2016, 48 HER2 negative MBC patients who failed anthracycline and taxane based chemotherapy were enrolled. In 43.8% of patients, more than 4 regimens were administrated before XP. Thirty-four patients (70.8%) were hormone receptor (HR) positive MBC. Patients were treated with XP (capecitabine [2000mg/m2 per oral; day 1–14] plus cisplatin [60mg/m2 IV; day 1], every 3 weeks) regimen. Results Median progression-free survival (PFS) in total population was 4.33 months (range 1.1~33.57 months). HR positive patients showed trends for superior PFS compared to triple negative breast cancer (TNBC), without statistical significance (6.53 vs. 3.83 months, P = 0.168). In HR positive group, patients receiving 3 or less lines of chemotherapy showed superior PFS compared to others (10.1 vs. 3.0 months, P = 0.039). In multivariate analysis, HR positive patients receiving 3 or less lines of regimens still showed superior PFS (HR = 2.624, 95% CI; 1.071~6.43, P = 0.032). Most common toxicity was grade 3–4 neutropenia, without treatment-related deaths. Conclusions XP combination regimen showed clinical benefit with tolerable toxicity in heavily pretreated patients, including HR positive patients. After anthracycline and taxane failure, early administration of XP regimen in selected patients may have improve clinical outcome in breast cancer. PMID:28234911

  20. Mesoporous Silica Nanoparticles Loaded with Cisplatin and Phthalocyanine for Combination Chemotherapy and Photodynamic Therapy in vitro

    PubMed Central

    Vivero-Escoto, Juan L.; Elnagheeb, Maram

    2015-01-01

    Mesoporous silica nanoparticles (MSNs) have been synthesized and loaded with both aluminum chloride phthalocyanine (AlClPc) and cisplatin as combinatorial therapeutics for treating cancer. The structural and photophysical properties of the MSN materials were characterized by different spectroscopic and microscopic techniques. Intracellular uptake and cytotoxicity were evaluated in human cervical cancer (HeLa) cells by confocal laser scanning microscopy (CLSM) and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assays, respectively. The CLSM experiments showed that the MSN materials can be readily internalized in HeLa cells. The cytotoxic experiments demonstrated that, after light exposure, the combination of both AlClPc and cisplatin compounds in the same MSN platform potentiate the toxic effect against HeLa cells in comparison to the control AlClPc-MSN and cisplatin-MSN materials. These results show the potential of using MSN platforms as nanocarriers for combination photodynamic and chemotherapies to treat cancer. PMID:28347122

  1. Radiation enhanced efficiency of combined electromagnetic hyperthermia and chemotherapy of lung carcinoma using cisplatin functionalized magnetic nanoparticles.

    PubMed

    Babincová, M; Kontrisova, K; Durdík, S; Bergemann, C; Sourivong, P

    2014-02-01

    The effect of trimodality treatment consisting of hyperthermia, cisplatin and radiation was investigated in two non-small lung carcinoma cell lines with different sensitivities to cisplatin. Hyperthermia treatment was performed using heat released via Neél and Brown relaxation of magnetic nanoparticles in an alternating magnetic field. Radiation with dose 1.5 Gy was performed after 15 min electromagnetic hyperthermia and cisplatin treatment. Electromagnetic hyperthermia enhanced cisplatin-induced radiosensitization in both the cisplatin-sensitive H460 (viability 11.2 +/- 1.8 %) and cisplatin-resistant A549 (viability 14.5 +/- 2.3 %) lung carcinoma cell line. Proposed nanotechnology based trimodality cancer treatment may have therefore important clinical applications.

  2. MALDI-LTQ-Orbitrap mass spectrometry imaging for lipidomic analysis in kidney under cisplatin chemotherapy.

    PubMed

    Moreno-Gordaliza, Estefanía; Esteban-Fernández, Diego; Lázaro, Alberto; Humanes, Blanca; Aboulmagd, Sarah; Tejedor, Alberto; Linscheid, Michael W; Gómez-Gómez, M Milagros

    2017-03-01

    Imaging techniques for mapping molecular distributions in tissue sections can reveal valuable information on biomolecules involved in relevant biochemical processes. A method has been developed for comprehensive, reproducible and sensitive lipid imaging by matrix-assisted laser/desorption ionization-LTQ-Orbitrap mass spectrometry in kidney sections, showing the benefits of exact mass determination. Matrix deposition parameters for positive and negative lipid ion imaging using different matrices such as 2,5-dihydroxybenzoic acid (DHB), 9-aminoacridine (9-AA) or α-cyano-4-hydroxycinnamic acid (CHCA) have been optimized for the broadest detection and identification of renal lipids. The combination of 9-AA and DHB was found as the most suitable for negative and positive ion mode lipid imaging, respectively. Lipid mapping and related identification strategies and limitations have also been discussed. Production of 100-µm resolution images was proved to be enough for discerning lipid distribution in kidney substructures. Imaging reproducibility was assessed on parallel kidney slices with time. This method has been applied to the lipidomics analysis on kidney sections from rats treated with the antitumor drug cisplatin and compared to healthy control rats. Up to 66 different renal lipids out of 450 extracted ion images (mainly phospholipid species, in addition to sulfatides and cholesterol sulfate) have been found and identified showing a modified distribution pattern due to cisplatin-induced nephrotoxicity. These lipid species reflect either topographic, signaling or structural processes in damaged kidney and could potentially be used for nephrotoxicity assessment or as therapeutic targets. This is, to our knowledge, the first imaging lipidomics study for nephrotoxicity assessment of cisplatin chemotherapy.

  3. Comparing two lower-dose cisplatin programs for radio-chemotherapy of locally advanced head-and-neck cancers.

    PubMed

    Rades, Dirk; Seidl, Daniel; Janssen, Stefan; Strojan, Primoz; Karner, Katarina; Bajrovic, Amira; Hakim, Samer G; Wollenberg, Barbara; Schild, Steven E

    2017-02-01

    Radio-chemotherapy is a common treatment for locally advanced squamous cell head-and-neck cancers (LA-SCCHN). Cisplatin (100 mg/m(2)) every 3 weeks is very common but associated with considerable toxicity. Therefore, cisplatin programs with lower daily doses were introduced. There is a lack of studies comparing lower-dose programs. In this study, 85 patients receiving radio-chemotherapy with 20 mg/m(2) cisplatin on 5 days every 4 weeks (group A) were retrospectively compared to 85 patients receiving radio-chemotherapy with 30-40 mg/m(2) cisplatin weekly (group B). Groups were matched for nine factors including age, gender, performance score, tumor site, T-/N-category, surgery, hemoglobin before radio-chemotherapy, and radiation technique. One- and 3-year loco-regional control rates were 83 and 69 % in group A versus 74 and 63 % in group B (p = 0.12). One- and 3-year survival rates were 93 % and 73 % in group A versus 91 and 49 % in group B (p = 0.011). On multivariate analysis, survival was significantly better for group A (HR 1.17; p = 0.002). In groups A and B, 12 and 28 % of patients, respectively, did not receive a cumulative cisplatin dose ≥180 mg/m(2) (p = 0.016). Toxicity rates were not significantly different. On subgroup analyses, group A patients had better loco-regional control (p = 0.040) and survival (p = 0.005) than group B patients after definitive radio-chemotherapy. In patients receiving adjuvant radio-chemotherapy, outcomes were not significantly different. Thus, 20 mg/m(2) cisplatin on 5 days every 4 weeks resulted in better loco-regional control and survival in patients receiving definitive radio-chemotherapy and may be preferable for these patients. Confirmation of these results in a randomized trial is warranted.

  4. [A case of pineoblastoma successfully treated with surgery, combined chemotherapy of cisplatin and etoposide, and radiotherapy].

    PubMed

    Akiyama, Y; Akiyama, Y; Kumai, J; Nishikawa, M

    1995-10-01

    A 5-year-old girl was admitted to another clinic because of vomiting and convulsions. She was brought to our clinic after a ventriculoperitoneal shunt was inserted. CT scan on admission in our clinic showed a tumor in the pineal region with tumoral hemorrhage. Tumor markers such as HCG, AFP, CEA, P-LAP were within normal range. A biopsy of the tumor was performed and the histological diagnosis was pineoblastoma. Her recovery was excellent and disseminated metastasis was not recognized. A subtotal removal of the tumor was performed through the occipital transtentorial approach. She had no neurological deficits after surgery. She then received two 5-day cycles of chemotherapy, consisting of intravenous administration of 20 mg/m2/day cisplatin and 60 mg/m2/day etoposide, and craniospinal radiotherapy. After these therapies, the tumor responded and disappeared completely. Follow-up radiographic investigations also demonstrated no abnormal evidence except for brain atrophy. She is attending a primary school without any problems. Pineoblastoma is quite rare and remarkably malignant. Hence, aggressive therapies including surgery, radiotherapy and chemotherapy is indicated for this tumor.

  5. Primary Concurrent Chemoradiation in Head and Neck Cancers with Weekly Cisplatin Chemotherapy: Analysis of Compliance, Toxicity and Survival.

    PubMed

    Iqbal, Muhammad Shahid; Chaw, Cheng; Kovarik, Josef; Aslam, Shahzeena; Jackson, Aaron; Kelly, John; Dobrowsky, Werner; Kelly, Charles

    2017-04-01

    Introduction Concurrent chemoradiation is the standard of care in inoperable locally advanced squamous cell head and neck cancers. The most widely accepted schedule of concomitant cisplatin is 100mg/m(2) given on a 3 weekly basis but the optimal regime is unknown. Objective The objective of this study is to assess the tolerability, compliance, and clinical outcomes of weekly cisplatin (40mg/m(2)). Methods During the period of January 2007-December 2009, we analyzed retrospectively 122 patients with histologically proven squamous cell carcinoma of head and neck (nasopharynx, oropharynx, larynx, hypopharynx, and oral cavity) treated with definitive chemoradiation. All patients received 63 Gy in 30 daily fractions with concomitant weekly cisplatin 40mg/m(2). We assessed treatment toxicities and patient compliance. We estimated overall survival using the Kaplan-Meier method. Results Sixty-eight percent of patients managed to complete all six cycles of chemotherapy while 87% of patients completed at least 5 cycles of weekly cisplatin. Incidence of grade 3/4 toxicity was as follows: mucositis 33%, dermatitis 41%, dysphagia 15%, mouth/neck pain 17%, neutropenia 2%, and renal impairment 3%. 53% patients required at least one hospital admission for symptom control. The 5-year overall survival rate was 60%. Conclusion Concurrent chemoradiotherapy using weekly cisplatin at 40mg/m(2) per week is an effective, well tolerated regimen allowing most patients to receive at least 5 cycles of chemotherapy. However, a phase III randomized control trial comparing the standard dose of 100mg/m(2) cisplatin tri-weekly with a weekly regimen is needed to establish the long term clinical outcome.

  6. Primary Concurrent Chemoradiation in Head and Neck Cancers with Weekly Cisplatin Chemotherapy: Analysis of Compliance, Toxicity and Survival

    PubMed Central

    Iqbal, Muhammad Shahid; Chaw, Cheng; Kovarik, Josef; Aslam, Shahzeena; Jackson, Aaron; Kelly, John; Dobrowsky, Werner; Kelly, Charles

    2016-01-01

    Introduction Concurrent chemoradiation is the standard of care in inoperable locally advanced squamous cell head and neck cancers. The most widely accepted schedule of concomitant cisplatin is 100mg/m2 given on a 3 weekly basis but the optimal regime is unknown. Objective The objective of this study is to assess the tolerability, compliance, and clinical outcomes of weekly cisplatin (40mg/m2). Methods During the period of January 2007–December 2009, we analyzed retrospectively 122 patients with histologically proven squamous cell carcinoma of head and neck (nasopharynx, oropharynx, larynx, hypopharynx, and oral cavity) treated with definitive chemoradiation. All patients received 63 Gy in 30 daily fractions with concomitant weekly cisplatin 40mg/m2. We assessed treatment toxicities and patient compliance. We estimated overall survival using the Kaplan-Meier method. Results Sixty-eight percent of patients managed to complete all six cycles of chemotherapy while 87% of patients completed at least 5 cycles of weekly cisplatin. Incidence of grade 3/4 toxicity was as follows: mucositis 33%, dermatitis 41%, dysphagia 15%, mouth/neck pain 17%, neutropenia 2%, and renal impairment 3%. 53% patients required at least one hospital admission for symptom control. The 5-year overall survival rate was 60%. Conclusion Concurrent chemoradiotherapy using weekly cisplatin at 40mg/m2 per week is an effective, well tolerated regimen allowing most patients to receive at least 5 cycles of chemotherapy. However, a phase III randomized control trial comparing the standard dose of 100mg/m2 cisplatin tri-weekly with a weekly regimen is needed to establish the long term clinical outcome.

  7. Hyperthermic intraperitoneal chemotherapy with cisplatin and paclitaxel in advanced ovarian cancer: a multicenter prospective observational study

    PubMed Central

    Coccolini, Federico; Campanati, Luca; Catena, Fausto; Ceni, Valentina; Jimenez Cruz, Jorge; Lotti, Marco; Magnone, Stefano; Napoli, Josephine; Rossetti, Diego; De Iaco, Pierandrea; Frigerio, Luigi; Pinna, Antonio; Runnebaum, Ingo; Ansaloni, Luca

    2015-01-01

    Objective Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been recently reported with favorable oncological outcomes as treatment of advanced epithelial ovarian cancer (EOC). The aim of this study was to demonstrate the feasibility of CRS+HIPEC with cisplatin and paclitaxel for the treatment of advanced EOC. Methods This is a prospective observational study of 54 patients, from April 2007 to October 2013, with primary or recurrent peritoneal carcinomatosis due to EOC. The mean age was 54.51±9.34. Thirty patients (59%) had primary EOC, and 24 patients (41%) had recurrent disease. Results Mean peritoneal cancer index was 10.11 (range, 0 to 28), complete cytoreduction (CC0) was achieved for 47 patients (87%), CC1 for seven patients (13%). Patients with suboptimal cytoreduction (CC2 and CC3) were not included in the study. The mean stay in intensive care unit was 4.73±5.51 days and the mean hospitalization time was 24.0±10.03 days. We did not observe any intraoperative death. Seven patients (13%) required additional operations. Three patients (5.6%) died within 30 days from the procedure. Severe complications were seen in 19 patients (35.2%). During the follow-up period, disease recurred in 33 patients (61.1%); the median disease-free survival time was 12.46 months and the median overall survival time was 32.91 months. Conclusion CRS+HIPEC with cisplatin and paclitaxel for advanced EOC is feasible with acceptable morbidity and mortality. Additional follow-up and further studies are needed to determine the effects of HIPEC on long term survival. PMID:25376916

  8. Cisplatin triggers platelet activation.

    PubMed

    Togna, G I; Togna, A R; Franconi, M; Caprino, L

    2000-09-01

    Clinical observations suggest that anticancer drugs could contribute to the thrombotic complications of malignancy in treated patients. Thrombotic microangiopathy, myocardial infarction, and cerebrovascular thrombotic events have been reported for cisplatin, a drug widely used in the treatment of many solid tumours. The aim of this study is to explore in vitro cisplatin effect on human platelet reactivity in order to define the potentially active role of platelets in the pathogenesis of cisplatin-induced thrombotic complications. Our results demonstrate that cisplatin increases human platelet reactivity (onset of platelet aggregation wave and thromboxane production) to non-aggregating concentrations of the agonists involving arachidonic acid metabolism. Direct or indirect activation of platelet phospholipase A(2) appears to be implicated. This finding contributes to a better understanding of the pathogenesis of thrombotic complications occurring during cisplatin-based chemotherapy.

  9. Phase II trial of biweekly docetaxel, cisplatin, and 5-fluorouracil chemotherapy for advanced esophageal squamous cell carcinoma.

    PubMed

    Tanaka, Yoshihiro; Yoshida, Kazuhiro; Yamada, Atsuko; Tanahashi, Toshiyuki; Okumura, Naoki; Matsuhashi, Nobuhisa; Yamaguchi, Kazuya; Miyazaki, Tatsuhiko

    2016-06-01

    The prognosis of esophageal cancer patients is still unsatisfactory. Although a docetaxel, cisplatin, and 5-Fu (DCF) regimen has been reported, it is often difficult to accomplish because of severe toxicity. Therefore, we developed a new biweekly DCF (Bi-DCF) regimen and previously reported the recommended dose in a phase I dose-escalation study. We then performed a phase II study of Bi-DCF for advanced esophageal squamous cell carcinoma (SCC). Patients with clinical stage II/III were eligible. Patients received 2 courses of chemotherapy: docetaxel 35 mg/m(2) with cisplatin 40 mg/m(2) on days 1 and 15 and 400 mg/m(2) 5-fluorouracil on days 1-5 and 15-19 every 4 weeks. After completion of the chemotherapy, patients received esophagectomy. The primary endpoint was the completion rate of protocol treatment. Thirty-two patients were enrolled. The completion rate of protocol treatment (completion of two courses of preoperative chemotherapy and R0 surgery) was 100 %. During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (31.3 %). No treatment-related death was observed, and the incidence of operative morbidity was tolerable. The overall response rate after the chemotherapy was 90.3 %. This Bi-DCF regimen was well tolerated and highly active. This trial was registered with the University Hospital Medical Information Network (No. UMIN 000014625).

  10. [Cisplatin and vinca alkaloid combination chemotherapy of advanced non-small-cell lung cancer in the aged].

    PubMed

    Teramoto, S; Nagase, T; Fukuchi, Y; Ishida, K; Yamaoka, M; Matsuse, T; Jo, C; Orimo, H

    1990-11-01

    Fifteen patients aged over 65 years of age with advanced non-small-cl lung cancer (mean age = 70.7, stage IIIb: IV = 4:11) were treated with combination chemotherapy consisting of Cisplatin (50 or 80 mg/m2) and a vinca-alkaloid (Vindesine 3 mg/m2 or Etoposide 80 mg/m2). The effectiveness and side effects of this cisplatin therapy in different combinations of vinca-alkaloid regimens (Vindesine vs Etoposide) were examined. The mean dose of Cisplatin in the Etoposide combination group (75.2 mg/m2) was significantly higher than that in the Vindesine combination group (54.3 mg/m2) (p less than 0.01). A notable reduction the tumor size was observed in 25% of the Etoposide group, only. The 6-month survival rate and one-year survival rate were respectively 85.7%, 57.1% in the Vindesine + Cisplatin group, and 87.5%, 50% in the Etoposide + Cisplatin group. The common side effects were nausea, vomiting, anorexia, and alopecia. These symptoms were either alleviated by antiemetic drugs or followed by spontaneous recovery. Leucopenia, anemia and thrombocytopenia were found in both groups, and there was no difference in the time course of myelosuppression between the two groups. The extent of nephrotoxicity was assessed by creatinine clearance rate. Its decrease in the Vindesine group (60.1----38.9 ml/min) was higher than that in the Etoposide group (64.9----48.9 ml/min), while there was no significant change in BUN, serum creatinine and urine NAG between the two groups. There were no cases in which chemotherapy schedules had to be interrupted due to myelosuppression and nephrotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

  11. A safe and effective dose of cisplatin in hepatic arterial infusion chemotherapy for hepatocellular carcinoma

    PubMed Central

    Osaki, Akihiko; Suda, Takeshi; Kamimura, Kenya; Tsuchiya, Atsunori; Tamura, Yasushi; Takamura, Masaaki; Igarashi, Masato; Kawai, Hirokazu; Yamagiwa, Satoshi; Aoyagi, Yutaka

    2013-01-01

    Cisplatin (CDDP) is an anticancer agent that is commonly used in hepatic arterial infusion (HAI) chemotherapy for hepatocellular carcinoma (HCC). This study aimed to clarify the safe and effective dose of CDDP in HAI for HCC. The hypervascular area was measured in 42 HCCs before and after HAI with CDDP. Serum platinum concentration was quantified in the peripheral and/or middle hepatic veins by atomic absorption spectrometry. The relation between the HCC response and CDDP dose was statistically analyzed. The multiple HCC nodules in an individual case generally demonstrated the same response to CDDP. The free-platinum concentration stayed relatively constant in the hepatic vein during HAI followed by a rapid decline, while total-platinum gradually increased then slowly disappeared over several days. After CDDP-HAI, 15 HCCs shrunk and 27 HCCs grew. The reduction rate in the shrunken nodules was tended to be correlated with CDDP dose after standardization with the target liver volume. On the other hand, the growth rate of the enlarged HCCs was significantly correlated with CDDP dose after normalization with creatinine clearance. These data support a recommendation of CDDP-HAI infusion where the amount of CDDP (mg) administered is less than patient creatinine clearance (mL/min/1.73 m2) upon an assumption of HCC doubling time of 90 days, and the targeted liver is smaller than 200 times the CDDP dose (mg). A further analysis is required to define appropriate injection speeds. PMID:24133631

  12. A phase I study of combination S-1 plus cisplatin chemotherapy with concurrent thoracic radiation for locally advanced non-small cell lung cancer.

    PubMed

    Chikamori, Kenichi; Kishino, Daizo; Takigawa, Nagio; Hotta, Katsuyuki; Nogami, Naoyuki; Kamei, Haruhito; Kuyama, Shoichi; Gemba, Kenichi; Takemoto, Mitsuhiro; Kanazawa, Susumu; Ueoka, Hiroshi; Segawa, Yoshihiko; Takata, Saburo; Tabata, Masahiro; Kiura, Katsuyuki; Tanimoto, Mitsune

    2009-07-01

    A combination of S-1, a newly developed oral 5-fluorouracil derivative, and cisplatin is reported to show anti-tumour activity against advanced non-small cell lung cancer (NSCLC). Because S-1 shows synergistic effects with radiation, we conducted a phase I study to evaluate the maximum tolerated doses (MTDs), recommended doses (RDs), and dose-limiting toxicities (DLTs) of cisplatin and S-1 when combined with concurrent thoracic radiation (total dose of 60 Gy with 2 Gy per daily fraction) in patients with locally advanced NSCLC. Chemotherapy consisted of two 4-week cycles of cisplatin administered on days 1 and 8, and S-1 administered on days 1-14. S-1/cisplatin dosages (mg/m(2)/day) were escalated as follows: 60/30, 60/40, 70/40, 80/40 and 80/50. Twenty-two previously untreated patients were enrolled. The MTDs and RDs for S-1/cisplatin were 80/50 and 80/40, respectively. DLTs included febrile neutropaenia, thrombocytopaenia, bacterial pneumonia and delayed second cycle of chemotherapy. No patient experienced radiation pneumonitis>grade 2 and only one patient experienced grade 3 radiation oesophagitis. The overall response rate was 86.4% with a median survival time of 24.4 months. These results indicate that combination cisplatin-S-1 chemotherapy with concurrent thoracic radiation would be a feasible treatment option and a phase II study is currently under way.

  13. Effect of Concurrent High-Dose Cisplatin Chemotherapy and Conformal Radiotherapy on Cervical Esophageal Cancer Survival

    SciTech Connect

    Huang Shaohui; Lockwood, Gina; Brierley, James; Cummings, Bernard; Kim, John; Wong, Rebecca; Bayley, Andrew; Ringash, Jolie

    2008-07-01

    Purpose: To determine whether a change in treatment policy to conformal, elective nodal radiotherapy and concurrent high-dose cisplatin improved survival for cervical esophageal cancer patients. Methods and Materials: All cervical esophageal cancer patients treated between 1997 and 2005 were restaged (1983 American Joint Committee on Cancer criteria). Patients treated before 2001 (previous cohort [PC]) were compared with those treated from 2001 onward (recent cohort [RC]). The PC institutional chemoradiotherapy protocol was 54 Gy in 20 fractions within 4 weeks, with 5-fluorouracil (1,000 mg/m{sup 2}) on Days 1-4 and either mitomycin C (10 mg/m{sup 2}) or cisplatin (75 mg/m{sup 2}) on Day 1. The RC institutional chemoradiotherapy protocol was conformal radiotherapy, 70 Gy in 35 fractions within 7 weeks, to the primary tumor and elective nodes, with high-dose cisplatin (100 mg/m{sup 2}) on Days 1, 22, and 43. Results: The median follow-up was 3.1 years (PC, 8.1 and RC, 2.3). Of 71 patients (25 women and 46 men), 21 of 29 in the PC and 29 of 42 in the RC were treated curatively (curative subgroup, n = 50). Between the two groups, no differences in overall survival or locoregional relapse-free survival were seen. The overall survival rate at 2 and 5 years was 35% (range, 24-47%) and 21% (range, 12-32%) in the whole group and 46% (range 32-60%) and 28% (range, 15-42%) in the curative group, respectively. In the curative group, no statistically significant prognostic factors were found. Trends toward better locoregional relapse-free survival were seen in women (2-year rate, 73% vs. for men, 36%; p = 0.08) and in patients aged >64 years (2-year rate, 68% vs. age {<=}64 years, 34%; p = 0.10). Conclusion: No survival improvement could be demonstrated after changing the treatment policy to high-dose cisplatin-based, conventionally fractionated conformal chemoradiotherapy. Female gender and older age might predict for better outcomes.

  14. Evaluating the Effect of Zingiber Officinalis on Nausea and Vomiting in Patients Receiving Cisplatin Based Regimens

    PubMed Central

    Fahimi, Fanak; Khodadad, Kian; Amini, Somayeh; Naghibi, Farzaneh; Salamzadeh, Jamshid; Baniasadi, Shadi

    2011-01-01

    Ginger, the rhizome of Zingiber officinalis, has long been used as herbal medicine for its antiemetic effect. For evaluating the effect of zingiber officinalis on nausea and vomiting (N and V) in patients receiving cisplatin based regimens, a randomized double-blind placebo-controlled cross-over clinical trial was carried out in patients receiving cisplatin in combination with other chemotherapeutic agents. The patients were randomly assigned to receive ginger capsules (rhizome of zingiber officinalis) or placebo in their first cycle of the study. All patients received standard antiemetics for chemotherapy induced nausea and vomiting (CINV). The patients were crossed-over to receive ginger or placebo in their next cycle of chemotherapy. Among 36 eligible patients who received both cycles of treatment, there were no difference in prevalence, severity, and duration of both acute and delayed N and V. Addition of ginger to the standard antiemetic regimen has shown no advantage in reducing acute and delayed N and V in patients with cisplatin-based regimen in this study. PMID:24250368

  15. Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy.

    PubMed

    Ross, Colin J D; Katzov-Eckert, Hagit; Dubé, Marie-Pierre; Brooks, Beth; Rassekh, S Rod; Barhdadi, Amina; Feroz-Zada, Yassamin; Visscher, Henk; Brown, Andrew M K; Rieder, Michael J; Rogers, Paul C; Phillips, Michael S; Carleton, Bruce C; Hayden, Michael R

    2009-12-01

    Cisplatin is a widely used and effective chemotherapeutic agent, although its use is restricted by the high incidence of irreversible ototoxicity associated with it. In children, cisplatin ototoxicity is a serious and pervasive problem, affecting more than 60% of those receiving cisplatin and compromising language and cognitive development. Candidate gene studies have previously reported associations of cisplatin ototoxicity with genetic variants in the genes encoding glutathione S-transferases and megalin. We report association analyses for 220 drug-metabolism genes in genetic susceptibility to cisplatin-induced hearing loss in children. We genotyped 1,949 SNPs in these candidate genes in an initial cohort of 54 children treated in pediatric oncology units, with replication in a second cohort of 112 children recruited through a national surveillance network for adverse drug reactions in Canada. We identified genetic variants in TPMT (rs12201199, P value = 0.00022, OR = 17.0, 95% CI 2.3-125.9) and COMT (rs9332377, P value = 0.00018, OR = 5.5, 95% CI 1.9-15.9) associated with cisplatin-induced hearing loss in children.

  16. Doxorubicin-cisplatin chemotherapy for high-grade nonosteogenic sarcoma of bone. Comparison of treatment and control groups

    PubMed Central

    Waddell, Andrea E.; Davis, Aileen M.; Ahn, Henry; Wunder, Jay S.; Blackstein, Martin E.; Bell, Robert S.

    1999-01-01

    Objective To evaluate the role of chemotherapy with a combination of doxorubicin (adriamycin) and cisplatin in high-grade, nonosteogenic, non-Ewing’s sarcoma (non-OSA) of bone. Design A case series comparison with a literature-derived control group. Setting A university-affiliated tertiary care centre. Patients Thirty patients with a diagnosis of non-OSA. Of these, 8 had low-grade disease (grade 1 or 2) and 22 had high-grade disease (grade 3). Eleven of the 22 with high-grade disease had malignant fibrous histiocytoma. Seventeen patients with nonmetastatic high-grade non-OSA were compared with a literature cohort of 37 patients who met the eligibility criteria of nonmetastatic, high-grade non-OSA treated with surgery, with or without radiotherapy. The mean follow-up was 25.2 months. Interventions Eight patients with low-grade tumour underwent surgery alone; 22 patients with high-grade tumour underwent surgery and 6 courses of adriamycin (75 mg/m2 every 3 weeks) and cisplatin (100 mg/m2 every 3 weeks). Main outcome measures Disease-free survival and overall survival in those with high-grade tumours treated with or without chemotherapy. Results Of 8 patients who had low-grade tumours and underwent surgery alone, 3 had systemic relapse. Of the 22 having high-grade tumours, 4 did not receive chemotherapy because of age and comorbid conditions. Of the other 18, 13 received 3 courses of chemotherapy preoperatively and 3 courses postoperatively, 4 received all 6 courses postoperatively and 1 received all chemotherapy preoperatively to treat metastatic disease. In the 17-patient cohort used for comparison with the literature control group, disease-free survival was 57% at a mean follow-up of 25.6 months and overall survival was 57% at a mean follow-up of 30.1 months. In the control group, disease-free survival was 16% at a mean follow-up of 20.9 months and overall survival was 26% at a mean follow-up of 29.9 months. These differences are significant: p = 0.0000, χ2 = 41

  17. Inoperable nonmetastatic squamous cell carcinoma of the esophagus managed by concomitant chemotherapy (5-fluorouracil and cisplatin) and radiation therapy

    SciTech Connect

    Seitz, J.F.; Giovannini, M.; Padaut-Cesana, J.; Fuentes, P.; Giudicelli, R.; Gauthier, A.P.; Carcassonne, Y. )

    1990-07-15

    Thirty-five patients with nonmetastatic squamous cell carcinoma of the esophagus were treated with chemotherapy (5-fluorouracil, cisplatin) and concomitant split-course radiation therapy. All of the patients presented with dysphagia. Treatment consisted of two courses of chemotherapy with 5-FU (1 g/m2/day in continuous infusion for 5 days (days 1 to 5 and days 29 to 33) ) and cisplatin (70 mg/m2 intravenous bolus at days 2 and 30). Radiation therapy was concomitant in two courses delivering 20 Gy in 5 days (days 1 to 5 and days 29 to 33). On the first day of treatment, endoscopic peroral dilation or Nd-YAG laser therapy was usually carried out. At the end of the treatment, all of the patients were capable of oral nutrition. Histoendoscopic confirmation was made 8 weeks after the beginning of the therapy. Twenty-five of the 35 patients had a complete response with negative biopsy findings. There was only one serious complication (fatal myelosuppression) in the only patient who received more than two courses of chemotherapy. Sixteen patients died and 19 were still alive at 3 to 42 months after the beginning of treatment. Overall median survival for the 35 patients is 17 months. Actuarial survival was 55 +/- 18% at 1 year and 41 +/- 21% at 2 years. The median survival of the Stage I and II patients is 28 months. These results confirm that concomitant chemoradiotherapy is capable of producing a very high histoendoscopic complete response rate and improved 1-year and 2-year survival. The use of concentrated split-course radiotherapy enabled the authors to reduce the total length of the treatment to two periods of 5 days, with results that are similar to previous studies using classic radiotherapy for a 5-week to 7-week period.

  18. ERCC1 Expression in Metastatic Triple Negative Breast Cancer Patients Treated with Platinum-Based Chemotherapy

    PubMed

    EL Baiomy, Mohamed Ali; El Kashef, Wagdi F

    2017-02-01

    Background: Possible targeted therapies for metastatic triple negative breast cancer (TNBC) include cytotoxic chemotherapy that causes interstrand breaks (platinum-based drugs). The excision repair cross-complementation 1 (ERCC1) enzyme plays an essential role in the nucleotide excision repair pathway, removing platinum-induced DNA adducts and contributing to cisplatin resistance. Detecting ERCC1 overexpression is important in considering treatment options for metastatic TNBC, including individualized approaches to therapy, and may facilitate improved responses or reduction of unnecessary toxicity. We hypothesized that assigning cisplatin based on pretreatment ERCC1 expression would improve response and survival. This study was conducted to assess the impact of ERCC1 expression on PFS, OS and response rates in metastatic triple negative breast cancer patients treated with platinum-based chemotherapy. Methods: From June 2012 to November 2013, 52 metastatic triple negative breast cancer patients were enrolled. ERCC1 protein expression was detected from pretreatment biopsies by Immunohistochemistry. All patients received cisplatin plus paclitaxel. The primary end point was the impact of ERCC1 expression on PFS and OS. Results: 34 patients (65.4%) showed positive ERCC1 expression while 18 (34.6%) proved negative. Positive ERCC1 expression was associated with short PFS (median, 5 months vs. 7 months; P = 0.043), short OS (median, 9 months vs. 11 months; P = 0.033) and poor response to cisplatin based chemotherapy (P = 0.046). Conclusions: This prospective study further validated ERCC1 as a reliable biomarker for customized chemotherapy in metastatic triple negative breast cancer patients. High expression of ERCC1 was thereby fond to be significantly associated with poor outcome in patients treated with platinum based chemotherapy.

  19. Comparison of Four Cisplatin-Based Radiochemotherapy Regimens for Nonmetastatic Stage III/IV Squamous Cell Carcinoma of the Head and Neck;Head-and-neck cancer; Cisplatin-based radiochemotherapy; Toxicity; Treatment outcomes

    SciTech Connect

    Rades, Dirk; Kronemann, Stefanie; Meyners, Thekla; Bohlen, Guenther; Tribius, Silke; Kazic, Nadja; Schroeder, Ursula; Hakim, Samer G.; Schild, Steven E.; Dunst, Juergen

    2011-07-15

    Purpose: To compare the outcomes of four cisplatin-based radiochemotherapy regimens in 311 patients with Stage III/IV squamous cell carcinoma of the head and neck. Methods and Materials: Concurrent chemotherapy consisted of three courses of cisplatin 100 mg/m{sup 2} on Day 1 (Group A, n = 74), two courses of cisplatin 20 mg/m{sup 2} on Days 1-5 plus 5-fluorouracil 1,000 mg/m{sup 2} on Days 1-5 (Group B, n = 49), two courses of cisplatin 20 mg/m{sup 2} on Days 1-5 plus 5-fluorouracil 600 mg/m{sup 2} on Days 1-5 (Group C, n = 102), or two courses of cisplatin 20 mg/m{sup 2} on Days 1-5 (Group D, n = 86). The groups were retrospectively compared for toxicity and outcomes, and 11 additional factors were evaluated for outcomes. Results: No significant difference was observed among the groups regarding radiation-related acute oral mucositis and radiation-related late toxicities. Acute Grade 3 skin toxicity was significantly more frequent in Group B than in the patients of the other three groups (p = .013). The chemotherapy-related Grade 3 nausea/vomiting rate was 24% for Group A, 8% for Group B, 9% for Group C, and 6% for Group D (p = .003). The corresponding Grade 3 nephrotoxicity rates were 8%, 1%, 2%, and 1% (p = .019). The corresponding Grade 3-4 hematologic toxicity rates were 35%, 41%, 19%, and 21% (p = .027). Chemotherapy could be completed in 50%, 59%, 74%, and 83% of the Group A, B, C, and D patients, respectively (p = .002). Toxicity-related radiotherapy breaks occurred in 39%, 43%, 21%, and 15% of Groups A, B, C, and D, respectively (p = .005). The 3-year locoregional control rate was 67%, 72%, 60%, and 59% for Groups A, B, C, and D, respectively (p = .48). The corresponding 3-year metastasis-free survival rates were 67%, 74%, 63%, and 79% (p = .31), and the corresponding 3-year survival rates were 60%, 63%, 50%, and 71% (p = .056). On multivariate analysis, Karnofsky performance status, histologic grade, T/N category, preradiotherapy hemoglobin level

  20. Role of the DNA Base Excision Repair Protein, APE1 in Cisplatin, Oxaliplatin, or Carboplatin Induced Sensory Neuropathy

    PubMed Central

    Kelley, Mark R.; Jiang, Yanlin; Guo, Chunlu; Reed, April; Meng, Hongdi; Vasko, Michael R.

    2014-01-01

    Although chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of platinum drugs, the mechanisms of this toxicity remain unknown. Previous work in our laboratory suggests that cisplatin-induced CIPN is secondary to DNA damage which is susceptible to base excision repair (BER). To further examine this hypothesis, we studied the effects of cisplatin, oxaliplatin, and carboplatin on cell survival, DNA damage, ROS production, and functional endpoints in rat sensory neurons in culture in the absence or presence of reduced expression of the BER protein AP endonuclease/redox factor-1 (APE1). Using an in situ model of peptidergic sensory neuron function, we examined the effects of the platinum drugs on hind limb capsaicin-evoked vasodilatation. Exposing sensory neurons in culture to the three platinum drugs caused a concentration-dependent increase in apoptosis and cell death, although the concentrations of carboplatin were 10 fold higher than cisplatin. As previously observed with cisplatin, oxaliplatin and carboplatin also increased DNA damage as indicated by an increase in phospho-H2AX and reduced the capsaicin-evoked release of CGRP from neuronal cultures. Both cisplatin and oxaliplatin increased the production of ROS as well as 8-oxoguanine DNA adduct levels, whereas carboplatin did not. Reducing levels of APE1 in neuronal cultures augmented the cisplatin and oxaliplatin induced toxicity, but did not alter the effects of carboplatin. Using an in vivo model, systemic injection of cisplatin (3 mg/kg), oxaliplatin (3 mg/kg), or carboplatin (30 mg/kg) once a week for three weeks caused a decrease in capsaicin-evoked vasodilatation, which was delayed in onset. The effects of cisplatin on capsaicin-evoked vasodilatation were attenuated by chronic administration of E3330, a redox inhibitor of APE1 that serendipitously enhances APE1 DNA repair activity in sensory neurons. These outcomes support the importance of the BER pathway, and particularly APE

  1. Chemotherapy

    MedlinePlus

    ... the cancer cells. This is called palliative chemotherapy. Chemotherapy for conditions other than cancer Some chemotherapy drugs ... you'll receive. Side effects that occur during chemotherapy treatment Common side effects of chemotherapy drugs include: ...

  2. [Second-line chemotherapy with gemcitabine and cisplatin for urothelial cancer previously treated with or resistant to M-VAC therapy].

    PubMed

    Honda, Masahito; Hatano, Koji; Satoh, Mototaka; Tsujimoto, Yuichi; Takada, Tsuyoshi; Matsumiya, Kiyomi; Fujioka, Hideki

    2006-09-01

    We evaluated the efficacy of gemcitabine-cisplatin (GC) therapy as a second line chemotherapy for recurrent urothelial cancer previously treated with or resistant to methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) therapy. Four patients who had recurrent cancer after adjuvant M-VAC therapy and five patients with resistant lesions to M-VAC were treated by GC. Of the nine patients, three completely responded to GC and three obtained partial response. These complete responders were cancer-free for 34, 32 and 24 months. In one partial responder, the metastatic masses have been decreasing in size for 12 months after completion of GC therapy. Our findings suggested that GC would be useful as a second line chemotherapy for urothelial cancer previously treated with M-VAC.

  3. Sensitization of cisplatin therapy by a naphthalimide based organoselenium compound through modulation of antioxidant enzymes and p53 mediated apoptosis.

    PubMed

    Ghosh, P; Singha Roy, S; Basu, A; Bhattacharjee, A; Bhattacharya, S

    2015-04-01

    The widely used anti-cancer drug cisplatin imparts various toxic manifestations in the host, with nephrotoxicity being the most severe one. The trace element selenium shows antioxidant activity in both human and animals. The present study was designed to assess the chemoprotecting and chemoenhancing efficacy of a naphthalimide based organoselenium compound 2-(5-selenocyanato-pentyl)-benzo[de]isoquinoline 1,3-dione during cisplatin chemotherapy in mice bearing Ehrlich ascites carcinoma cells. Cisplatin (5 mg/kg b.w.) was administered intraperitoneally and the organoselenium compound (3 mg/kg b.w.) was given by oral gavage in concomitant and pretreatment schedule. The effects of the test compound was evaluated by assaying biochemical, hematological, histological, genotoxicity parameters and by investigating induction of apoptosis in tumor cells, and calculating tumor growth response in the host. The organoselenium compound significantly prevented cisplatin induced generation of reactive oxygen species (ROS), reactive nitrogen species, and onset of lipid peroxidation in the kidney tissue of the experimental mice. In addition, the test compound was also substantially restored cisplatin induced depleted activities of the renal antioxidant enzymes and reduced glutathione level; prevented the serum blood urea nitrogen level, creatinine level, chromosomal aberration, DNA damage, histological alterations of kidney, and normalized the hematological profile of the tumor bearing mice. Furthermore, the organoselenium compound alone or during combination therapy induced apoptosis in tumor cells through mitochondria mediated and DNA damage mediated pathway and ultimately increased the life span of the tumor bearing host. Hence, the results showed that the test compound not only reduced the toxicity of cisplatin but also enhanced its anti-tumor efficacy.

  4. Sorafenib plus hepatic arterial infusion chemotherapy with cisplatin versus sorafenib for advanced hepatocellular carcinoma: randomized phase II trial

    PubMed Central

    Ikeda, M.; Shimizu, S.; Sato, T.; Morimoto, M.; Kojima, Y.; Inaba, Y.; Hagihara, A.; Kudo, M.; Nakamori, S.; Kaneko, S.; Sugimoto, R.; Tahara, T.; Ohmura, T.; Yasui, K.; Sato, K.; Ishii, H.; Furuse, J.; Okusaka, T.

    2016-01-01

    Background Sorafenib (Sor) is acknowledged as a standard therapy for advanced hepatocellular carcinoma (HCC). This trial was conducted to evaluate the effect of addition of hepatic arterial infusion chemotherapy with cisplatin (SorCDDP) to Sor for the treatment of advanced HCC. Patients and methods We conducted a multicenter open-labeled randomized phase II trial in chemo-naïve patients with advanced HCC with Child-Pugh scores of 5–7. Eligible patients were randomly assigned 2:1 to receive SorCDDP (sorafenib: 400 mg bid; cisplatin: 65 mg/m2, day 1, every 4–6 weeks) or Sor (400 mg bid). The primary end point was overall survival. Results A total of 108 patients were randomized (Sor, n = 42; SorCDDP, n = 66). The median survival in the Sor and SorCDDP arms were 8.7 and 10.6 months, respectively [stratified hazard ratio (95% confidence interval), 0.60 (0.38–0.96), P = 0.031]. The median time to progression and the response rate were, respectively, 2.8 months and 7.3% in the Sor arm and 3.1 months and 21.7% in the SorCDDP arm. The adverse events were more frequent in the SorCDDP arm than in the Sor arm, but well-tolerated. Conclusion SorCDDP yielded favorable overall survival when compared with Sor in patients with advanced HCC. Clinical Trial registration UMIN-CTR (http://www.umin.ac.jp/ctr/index-j.htm), identification number: UMIN000005703. PMID:27573564

  5. Concomitant chemobrachyradiotherapy with ifosfamide and cisplatin followed by consolidation chemotherapy in locally advanced squamous cell carcinoma of the uterine cervix: Results of a phase II study

    SciTech Connect

    Vrdoljak, Eduard . E-mail: eduard.vrdoljak@st.hinet.hr; Prskalo, Tomislav; Omrcen, Tomislav; Situm, Kristina; Boraska, Tihana; Frleta Ilic, Nives; Jankovic, Stjepan; Hamm, Wolfgang

    2005-03-01

    Purpose: To evaluate the efficacy and toxicity of ifosfamide and cisplatin administered concomitantly with low-dose-rate brachytherapy followed by consolidation chemotherapy in the treatment of locally advanced squamous cell cervical carcinoma (LASCC). Methods and materials: Forty-four patients with biopsy-proven LASCC were enrolled. FIGO Stages IB2 bulky to IVA were entered into this study. Patients were assigned to receive external radiotherapy (50 Gy in 25 fractions); then ifosfamide 2 g/m{sup 2} plus cisplatin 75 mg/m{sup 2} was applied during two low-dose-rate brachytherapy applications, and 4 cycles of consolidation chemotherapy with the same drug combination were given after completion of radiotherapy. The planned dose to point A was 85 Gy. Results: All patients received both courses of concomitant chemobrachytherapy and at least 1 cycle of consolidation chemotherapy. The average duration of radiation was 45.1 days. The clinical complete response rate was 100%. Grade 3 and 4 leukopenia occurred in 25% and 11% of the cycles, respectively. After a median follow-up of 34 months (range, 20-54 months), the recurrence-free and the overall survival rates were 84% and 91%, respectively. Major delayed local complications occurred in 7 cases (16%). Conclusions: These results indicate that concomitant chemobrachyradiotherapy with ifosfamide and cisplatin is a feasible combination for patients with LASCC of the cervix uteri. A randomized trial is planned.

  6. Cisplatin resistance and opportunities for precision medicine.

    PubMed

    Amable, Lauren

    2016-04-01

    Cisplatin is one of the most commonly used chemotherapy drugs, treating a wide range of cancer types. Unfortunately, many cancers initially respond to platinum treatment but when the tumor returns, drug resistance frequently occurs. Resistance to cisplatin is attributed to three molecular mechanisms: increased DNA repair, altered cellular accumulation, and increased drug inactivation. The use of precision medicine to make informed decisions on a patient's cisplatin resistance status and predicting the tumor response would allow the clinician to tailor the chemotherapy program based on the biology of the disease. In this review, key biomarkers of each molecular mechanism will be discussed along with the current clinical research. Additionally, known polymorphisms for each biomarker will be discussed in relation to their influence on cisplatin resistance.

  7. A Phase II Study of Bevacizumab in Combination With Definitive Radiotherapy and Cisplatin Chemotherapy in Untreated Patients With Locally Advanced Cervical Carcinoma: Preliminary Results of RTOG 0417

    SciTech Connect

    Schefter, Tracey E.; Winter, Kathryn; Kwon, Janice S.; Stuhr, Kelly; Balaraj, Khalid; Yaremko, Brian P.; Small, William; Gaffney, David K.

    2012-07-15

    Purpose: Concurrent cisplatin-based chemoradiotherapy (CRT) is the standard treatment for locally advanced cervical cancer. RTOG 0417 was a Phase II study exploring the safety and efficacy of the addition of bevacizumab to standard CRT. Methods and Materials: Eligible patients with bulky tumors (Stage IB-IIIB) were treated with once-weekly cisplatin (40 mg/m{sup 2}) chemotherapy and standard pelvic radiotherapy and brachytherapy. Bevacizumab was administered at 10 mg/kg intravenously every 2 weeks for three cycles. Treatment-related serious adverse event (SAE) and other adverse event (AE) rates within the first 90 days from treatment start were determined. Treatment-related SAEs were defined as any Grade {>=}4 vaginal bleeding or thrombotic event or Grade {>=}3 arterial event, gastrointestinal (GI) bleeding, or bowel/bladder perforation, or any Grade 5 treatment-related death. Treatment-related AEs included all SAEs and Grade 3 or 4 GI toxicity persisting for >2 weeks despite medical intervention, Grade 4 neutropenia or leukopenia persisting for >7 days, febrile neutropenia, Grade 3 or 4 other hematologic toxicity, and Grade 3 or 4 GI, renal, cardiac, pulmonary, hepatic, or neurologic AEs. All AEs were scored using the National Cancer Institute Common Terminology Criteria (CTCAE) v 3.0 (MedDRA version 6.0). Results: A total of 60 patients from 28 institutions were enrolled between 2006 and 2009, and of these, 49 patients were evaluable. The median follow-up was 12.4 months (range, 4.6-31.4 months).The median age was 45 years (range, 22-80 years). Most patients had FIGO Stage IIB (63%) and were of Zubrod performance status of 0 (67%). 80% of cases were squamous. There were no treatment-related SAEs. There were 15 (31%) protocol-specified treatment-related AEs within 90 days of treatment start; the most common were hematologic (12/15; 80%). 18 (37%) occurred during treatment or follow-up at any time. 37 of the 49 patients (76%) had cisplatin and bevacizumab

  8. Chemotherapy

    MedlinePlus

    Cancer chemotherapy; Cancer drug therapy; Cytotoxic chemotherapy ... Philadelphia, PA: Elsevier Saunders; 2016:chap 179. National Cancer Institute. Chemotherapy and you: support for people who have cancer. ...

  9. Intra-Arterial Infusion Chemotherapy Using Cisplatin With Radiotherapy for Stage III Squamous Cell Carcinoma of the Cervix

    SciTech Connect

    Kaneyasu, Yuko Nagai, Nobutaka; Nagata, Yasushi; Hashimoto, Yasutoshi; Yuki, Shintaro; Murakami, Yuji; Kenjo, Masahiro; Kakizawa, Hideaki; Toyota, Naoyuki; Fujiwara, Hisaya; Kudo, Yoshiki; Ito, Katsuhide

    2009-10-01

    Purpose: To examine the effectiveness of concomitant intra-arterial infusion chemotherapy (IAIC) using cisplatin (CDDP) with radiotherapy for Stage III squamous cell carcinoma of the cervix. Materials and Methods: We analyzed 29 cases of Stage III squamous cell carcinoma of the uterine cervix treated with radiotherapy and IAIC of CDDP from 1991 to 2006. External-beam therapy was given to the whole pelvis using four opposing parallel fields with an 18-MV linear accelerator unit. A central shield was used after 30-40 Gy with external whole-pelvic irradiation, and the total dose was 50 Gy. High-dose-rate brachytherapy was given with {sup 192}Ir microSelectron. The dose at Point A was 6 Gy per fraction, 2 fractions per week, and the total number of fractions was either 3 or 4. Two or three courses of IAIC were given concomitantly with CDDP 120 mg or carboplatin 300 mg. Results: We confirmed excellent medicine distribution directly by using computed tomographic angiography. The 5-year overall survival rate for Stage III patients was 62%, the cause-specific survival rate was 70%, and the local relapse-free survival rate was 89%. Local recurrence, distant metastasis, and occurrences of both were 7%, 38%, and 3%, respectively. The incidence of severe acute hematologic adverse reactions (Grade {>=}3) was 27% for all patients; however, all recovered without interruption of radiotherapy. Severe nonhematologic effects (Grade {>=}3) were 3%, including nausea and ileus. Only 1 patient's radiotherapy was interrupted for a period of 1 week because of ileus. Severe late complication rates (Grade {>=}3) for the bladder, rectum, and intestine were 3%, 3%, and 10%, respectively. Conclusion: A combination of IAIC and systemic chemotherapy should be considered to improve the prognosis of patients with Stage III squamous cell carcinoma of the cervix.

  10. Developing a Highly Stable PLGA-mPEG Nanoparticle Loaded with Cisplatin for Chemotherapy of Ovarian Cancer

    PubMed Central

    Cheng, Lihua; Jin, Chengmeng; Lv, Wen; Ding, Qiuping; Han, Xu

    2011-01-01

    Background Cisplatin is a potent anticancer drug, but its clinical application has been limited due to its undesirable physicochemical characteristics and severe side effects. Better drug formulations for cisplatin are highly desired. Methodology/Principal Findings Herein, we have developed a nanoparticle formulation for cisplatin with high encapsulation efficiency and reduced toxicity by using cisplatin-crosslinked carboxymethyl cellulose (CMC) core nanoparticles made from poly(lactide-co-glycolide)-monomethoxy-poly(polyethylene glycol) copolymers (PLGA-mPEG). The nanoparticles have an average diameter of approximately 80 nm measured by transmission electron microscope (TEM). The encapsulation efficiency of cisplatin in the nanoparticles is up to 72%. Meanwhile, we have also observed a controlled release of cisplatin in a sustained manner and dose-dependent treatment efficacy of cisplatin-loaded nanoparticles against IGROV1-CP cells. Moreover, the median lethal dose (LD50) of the cisplatin-loaded nanoparticles was more than 100 mg/kg by intravenous administration, which was much higher than that of free cisplatin. Conclusion This developed cisplatin-loaded nanoparticle is a promising formulation for the delivery of cisplatin, which will be an effective therapeutic regimen of ovarian cancer without severe side effects and cumulative toxicity. PMID:21966528

  11. Duration of cisplatin excretion in breast milk.

    PubMed

    Hays, Karen E; Ryu, Rachel J; Swisher, Elizabeth M; Reed, Eddie; McManus, Terry; Rybeck, Blanche; Petros, William P; Hebert, Mary F

    2013-11-01

    Cisplatin, a platinum-based chemotherapy agent, is commonly used in treating cancers that may affect women of childbearing age, including cervical cancer, triple-negative breast cancer, and pediatric tumors in adolescents. The authors found that platinum was undetectable in breast milk at 66 hours and beyond following a 70-mg dose of intravenous cisplatin. Relative infant dose of platinum was calculated to be between 0.29% and 0.40% of the maternal dose corrected for body weight. This case demonstrates minimal exposure to platinum via breast milk, following a single 70-mg intravenous dose of cisplatin.

  12. Feasibility Study of Moderately Accelerated Intensity-Modulated Radiotherapy Plus Concurrent Weekly Cisplatin After Induction Chemotherapy in Locally Advanced Head-and Neck Cancer

    SciTech Connect

    Morganti, Alessio G.; Mignogna, Samantha; Deodato, Francesco; Massaccesi, Mariangela; Cilla, Savino; Calista, Franco; Serafini, Giovanni; Digesu, Cinzia; Macchia, Gabriella; Picardi, Vincenzo; Caravatta, Luciana; Di Lullo, Liberato; Giglio, Gianfranco; Sallustio, Giuseppina; Piermattei, Angelo

    2011-03-15

    Purpose: To evaluate the feasibility and efficacy of moderately accelerated intensity-modulated radiation therapy (IMRT) along with weekly cisplatin, after induction chemotherapy, in patients with locally advanced unresectable head and neck cancer (HNC). Methods and Materials: Patients with Stage III or IV locally advanced HNC, without progressive disease after three courses of induction chemotherapy, received concurrent chemo-IMRT (weekly cisplatin 30 mg/m{sup 2} plus simultaneous integrated boost IMRT). A total of 67.5 Gy in 30 fractions were delivered to primary tumor and involved nodes, 60 Gy in 30 fractions to high-risk nodal areas, and 55.5 Gy in 30 fractions to low-risk nodal areas. Results: In all, 36 patients (median age, 56 years) with International Union Against Cancer (UICC) Stage III (n = 5) and IV (n = 31) were included. Of the 36 patients, 17 had received CF (cisplatin and 5-fluorouracil (CF) and 19 had received docetaxel cisplatin and 5-fluorouracil (DCF). During concurrent chemoradiation, 11 of 36 patients (30.5%) experienced Grade III mucositis (CF, 47%; DCF, 15%; p < 0.04). Grade III pharyngeal-esophageal toxicity was observed in 5 of 19 patients (26.3%; CF, 0.0%; DCF, 26.3%; p = 0.02). Two patients died of complications (5.5%). After chemoradiation, the complete response rate was 63.8%. Two-year local control was 88.7%. Two-year progression free survival and overall survival were 74.5% and 60.9%, respectively. Conclusions: In our experience, a moderately accelerated chemo-IMRT was feasible after induction chemotherapy. However, a noteworthy early death rate of 5.5% was observed. Intensive supportive care strategies should be defined to better manage radiation-induced toxic effects. Longer follow-up is required to determine the incidence of late radiation toxicities and tumor control rates.

  13. Adjuvant chemotherapy in patients with completely resected non-small cell lung cancer

    PubMed Central

    2014-01-01

    Adjuvant chemotherapy has been established as a standard for patients with completely resected non-small cell lung cancer (NSCLC). Adjuvant chemotherapy increased the 5-year survival rates by 4% to 15% within randomized trials and, based on a meta-analysis of five cisplatin-based trials, by 5.4%. Adjuvant chemotherapy consists of a cisplatin-based doublet, preferentially cisplatin plus vinorelbine. Future improvements in outcome of adjuvant therapy are expected by customized chemotherapy and the integration of targeted therapies or immunotherapy. PMID:25806316

  14. Stages III and IV Squamous Cell Carcinoma of the Mouth: Three-Year Experience with Superselective Intraarterial Chemotherapy Using Cisplatin Prior to Definitive Treatment

    SciTech Connect

    Hirai, Toshinori; Korogi, Yukunori; Hamatake, Satoshi; Nishimura, Ryuichi; Baba, Yuji; Takahashi, Mutsumasa; Uji, Yasuyoshi; Taen, Akira

    1999-05-15

    Purpose: This study was designed to assess the 3-year experience with superselective intraarterial chemotherapy prior to definitive treatment for stages III and IV squamous cell carcinomas of the mouth. Methods: Twenty-two patients prospectively received superselective intraarterial chemotherapy using relatively low-dose cisplatin via a transfemoral approach. The locations of the tumors were the tongue (n= 12), gingiva (n= 5), buccal mucosa (n= 2), hard palate (n= 1), floor of the mouth (n= 1), and lip (n= 1). After intraarterial chemotherapy, 21 patients underwent surgery (n= 14), radiation therapy (n= 6), or both (n= 1). The survival rate of 25 patients who underwent surgery with/without radiation therapy until 1992 at Kumamoto University Hospital was also evaluated as a historical control. The survival curve was calculated with the Kaplan-Meier method, and the statistical difference between survival curves was determined with the generalized Wilcoxon test. Results: The overall response rate was 95% [complete response (tumor completely resolved), 24%; partial response (tumor reduction {>=}50%), 71%]. Fifty-two intraarterial infusions were performed without any catheter-related complications. Mild and transient local toxicity such as edema or mucositis of the infused area was relatively common. One patient died of renal failure from cisplatin. After a median follow-up of 20 months (range 2-41 months), the estimated 3-year survival rate for patients who underwent intraarterial chemotherapy plus surgery was 91%. The survival of the patients who underwent intraarterial chemotherapy plus surgery tended to be longer than that of the historical control. Conclusions: Early tumor reduction without delay of subsequent treatments can be obtained by intraarterial chemotherapy while minimizing complications and possibly improving survival. Further investigations of long-term survival with larger series need to be performed.

  15. [The effect of combination chemotherapy to adapted to chronotherapy with 5-fluorouracil, leucovorin, mitomycin C and cisplatin in patients with gastric or colorectal cancer].

    PubMed

    Kamoshita, N; Yokomori, T; Iesato, H; Ohya, T; Nagaoka, H; Okabe, T; Kato, Y; Takeyoshi, I; Ohwada, S; Morishita, Y

    2000-05-01

    We performed combination chemotherapy adapted to chronotherapy with 5-fluorouracil, leucovorin, mitomycin C and cisplatin in 11 patients with gastric cancer and 7 with colorectal cancer. Treatment consisted of a 5-day course of continuous arterial or intravenous infusion of 5-FU (500 mg/body/day), arterial or intravenous infusion of leucovorin (20 mg/body/day) at 6:00 p.m. on days 1-5, arterial or intravenous infusion of mitomycin C (2 mg/body) at 9:00 a. m. on day 5, and arterial or intravenous infusion of cisplatin (20-80 mg/body) at 6:00 p.m. on day 5. The effective rate against gastric cancer was 73%; however, the effective rate against colorectal cancer was 29%. During and after this therapy, there was only a little appetite loss, nausea and stomatitis.

  16. miR-125b-5p enhances chemotherapy sensitivity to cisplatin by down-regulating Bcl2 in gallbladder cancer

    PubMed Central

    Yang, Dong; Zhan, Ming; Chen, Tao; Chen, Wei; Zhang, Yunhe; Xu, Sunwang; Yan, Jinchun; Huang, Qihong; Wang, Jian

    2017-01-01

    Gallbladder cancer represents the most common malignancy of the biliary tract and is highly lethal with less than 5% overall 5-year survival rate. Chemotherapy remains the major treatment for late-stage patients. However, insensitivity to these chemotherapeutic agents including cisplatin is common. MicroRNAs (miRNAs) have been shown as modulators of drug resistance in many cancer types. We used genome-wide gene expression analysis in clinical samples to identify miR-125b-5p down-regulated in gallbladder cancer. miR-125b-5p up-regulation promoted cell death in gallbladder cancer cells in the presence of cisplatin. In contrast, knockdown of miR-125b-5p reduced cell death in gallbladder cancer cells treated with cisplatin. Up-regulation of miR-125b-5p significantly decreased tumor growth in combination with cisplatin in a mouse model. We identified Bcl2 as a direct target of miR-125b-5p which mediates the function of miR-125b-5p in gallbladder cancer. In clinical samples, miR-125b-5p was down-regulated in gallbladder cancer whereas Bcl2 was up-regulated and their expression was inversely correlated. Moreover, low miR-125b-5p expression or high expression of Bcl2 is correlated with poor prognosis in gallbladder cancer. Taken together, our findings indicate that miR-125b-5p is a potent chemotherapy sensitizer and may function as a new biomarker for the prognosis of gallbladder cancer patients. PMID:28256505

  17. Syndrome of inappropriate antidiuretic hormone secretion following irinotecan-cisplatin administration as a treatment for recurrent ovarian clear cell carcinoma.

    PubMed

    Kwon, Do Youn; Han, Gwan Hee; Ulak, Roshani; Ki, Kyung Do; Lee, Jong Min; Lee, Seon Kyung

    2017-01-01

    Syndrome of inappropriate antidiuretic hormone secretion (SIADH) has various causes including central nervous system disorders, pulmonary and endocrine diseases, paraneoplastic syndromes, and use of certain drugs. SIADH induced by chemotherapy with irinotecan-cisplatin is not a common complication. Here, we review a case of SIADH after treatment with irinotecan-cisplatin. A 45-year-old woman received adjuvant chemotherapy (paclitaxel-carboplatin) for ovarian clear cell carcinoma, but the cancer recurred within 9 months of chemotherapy. Subsequently, a second line of combination chemotherapy containing irinotecan-cisplatin was initiated. However, 5 days after chemotherapy administration, her general condition began to deteriorate; her hematological tests revealed hyponatremia. Therefore, it is imperative to consider the possibility of SIADH in patients being treated with irinotecan-cisplatin-based chemotherapy. Proper monitoring of serum sodium levels and assessment of clinical symptoms should be performed in such patients for early diagnosis and prompt management.

  18. Pharmacokinetics of concomitant cisplatin and paclitaxel administered by hyperthermic intraperitoneal chemotherapy to patients with peritoneal carcinomatosis from epithelial ovarian cancer

    PubMed Central

    Ansaloni, L; Coccolini, F; Morosi, L; Ballerini, A; Ceresoli, M; Grosso, G; Bertoli, P; Busci, L M; Lotti, M; Cambria, F; Pisano, M; Rossetti, D; Frigerio, L; D'Incalci, M; Zucchetti, M

    2015-01-01

    Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) is advised as a treatment option for epithelial ovarian cancer (EOC) with peritoneal carcinomatosis. This study was designed to define the pharmacokinetics of cisplatin (CDDP) and paclitaxel (PTX) administered together during HIPEC. Methods: Thirteen women with EOC underwent cytoreductive surgery (CRS) and HIPEC, with CDDP and PTX. Blood, peritoneal perfusate and tissue samples were harvested to determine drug exposure by high-performance liquid chromatography and matrix-assisted laser desorption ionization imaging mass spectrometry (IMS). Results: The mean maximum concentrations of CDDP and PTX in perfusate were, respectively, 24.8±10.4 μg ml−1 and 69.8±14.3 μg ml−1; in plasma were 1.87±0.4 μg ml−1 and 0.055±0.009 μg ml−1. The mean concentrations of CDDP and PTX in peritoneum at the end of HIPEC were 23.3±8.0 μg g−1 and 30.1±18.3 μg−1g−1, respectively. The penetration of PTX into the peritoneal wall, determined by IMS, was about 0.5 mm. Grade 3–4 surgical complications were recorded in four patients, five patients presented grade 3 and two patients presented grade 4 hematological complications. Conclusions: HIPEC with CDDP and PTX after CRS is feasible with acceptable morbidity and has a favorable pharmacokinetic profile: high drug concentrations are achieved in peritoneal tissue with low systemic exposure. Larger studies are needed to demonstrate its efficacy in patients with microscopic postsurgical residual tumours in the peritoneal cavity. PMID:25461804

  19. [Combination chemotherapy with bleomycin, vinca alkaloid and cisplatin (BVP) for advanced urothelial cancer].

    PubMed

    Sekine, H; Fukui, I; Yamada, T; Takeuchi, S; Tachibana, Y; Yokokawa, M

    1984-08-01

    Since October 1979, 18 patients with metastatic urothelial cancer have been treated with combination chemotherapy of bleomycin (5-10 mg/day administered on days 1 to 7), vinca alkaloid (vinblastine 5-10 mg/day or vincristine 1 mg/sqm on days 8 and 9) and CDDP (60 mg/sqm on day 10). CR was achieved in 3 of the 18 patients and PR in 6 patients. Over-all, the response rate was 50%. Among 3 patients who achieved CR, 2 patients are still free of disease for 31 months and for 28 months, and the other is alive with cancer for 26 months. The 2-year survival rate was 58% in responders (CR + PR) and 0% in nonresponders. (p less than 0.005). In many cases, the response was observed after the first or second course of BVP therapy, and there was a relatively good response in patients with lymphnode metastasis alone. The treatment was tolerated well and common toxic effects were nausea, vomiting of moderate to severe degree (100%), myelosuppression (50%) and mild nephrotoxicity (22%). As to the choice of vinca alkaloids, vincristine seemed to be the treatment of choice because it was less toxic than vinblastine and was almost equally effective.

  20. Neuropeptide Y protects kidney against cisplatin-induced nephrotoxicity by regulating p53-dependent apoptosis pathway.

    PubMed

    Kim, Namoh; Min, Woo-Kie; Park, Min Hee; Lee, Jong Kil; Jin, Hee Kyung; Bae, Jae-Sung

    2016-05-01

    Cisplatin is a platinum-based chemotherapeutic drug for treating various types of cancers. However, the use of cisplatin is limited by its negative effect on normal tissues, particularly nephrotoxicity. Various mechanisms such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and apoptosis are involved in the adverse effect induced by cisplatin treatment. Several studies have suggested that neuropeptide Y (NPY) is involved in neuroprotection as well as restoration of bone marrow dysfunction from chemotherapy induced nerve injury. However, the role of NPY in chemotherapy- induced nephrotoxicity has not been studied. Here, we show that NPY rescues renal dysfunction by reducing the expression of pro-apoptotic proteins in cisplatin induced nephrotoxicity through Y1 receptor, suggesting that NPY can protect kidney against cisplatin nephrotoxicity as a possible useful agent to prevent and treat cisplatin-induced nephrotoxicity. [BMB Reports 2016; 49(5): 288-292].

  1. An Adsorptive Transfer Technique Coupled with Brdicka Reaction to Reveal the Importance of Metallothionein in Chemotherapy with Platinum Based Cytostatics

    PubMed Central

    Krizkova, Sona; Fabrik, Ivo; Huska, Dalibor; Adam, Vojtech; Babula, Petr; Hrabeta, Jan; Eckschlager, Tomas; Pochop, Pavel; Darsova, Denisa; Kukacka, Jiri; Prusa, Richard; Trnkova, Libuse; Kizek, Rene

    2010-01-01

    The drugs based on platinum metals represent one of the oldest, but also one of the most effective groups of chemotherapeutic agents. Thanks to many clinical studies it is known that resistance of tumor cells to drugs is a frequent cause of chemotherapy failure. With regard to platinum based drugs, multidrug resistance can also be connected with increased expression of low-molecular weight protein metallothionein (MT). This study aimed at investigating the interactions of MT with cisplatin or carboplatin, using the adsorptive transfer technique coupled with differential pulse voltammetry Brdicka reaction (AdTS DPV Brdicka reaction), and a comparison of in vitro results with results obtained in vivo. The results obtained from the in vitro study show a strong affinity between platinum based drugs and MT. Further, we analyzed extracts of neuroblastoma cell lines treated with cisplatin or carboplatin. It is clear that neuroblastoma UKF-NB-4 cisplatin-resistant and cisplatin-sensitive cell lines unlikely respond to the presence of the platinum-based cytostatics cisplatin and carboplatin. Finally, we determined the level of MT in samples from rabbits treated with carboplatin and patients with retinoblastoma treated with the same drug. PMID:21614176

  2. [A case of cardiac tamponade due to malignant pericarditis with lung adenocarcinoma, effectively treated with pericardial drainage and pemetrexed plus cisplatin chemotherapy].

    PubMed

    Yoshida, Kazufumi; Teramoto, Shinji

    2015-01-01

    A 68-year-old man was diagnosed with non small cell lung cancer in May 2013. Although the patient was negative for EGFR mutation, he wished to undergo treatment with gefitinib and erlotinib as first-line therapy. However, one year later, he was admitted to our hospital because of cardiac tamponade due to malignant pericarditis. He received pericardial drainage, after which his condition was stabilized. He was diagnosed with lung adenocarcinoma by cytology of pericardial effusion and treated with pemetrexed plus cisplatin as second-line therapy. Thereafter, the malignant effusion was decreased and the primary lesion was regressed. He received six courses of chemotherapy, however, brain metastases and bone metastases appeared. The brain metastases were controlled with gamma knife radiosurgery and he received carboptatin-paclitaxel plus bevacizumab as third-line therapy. The patient is currently receiving chemotherapy without any recurrence of malignant pericarditis or cardiac tamponade.

  3. Feasibility and Efficacy of Induction Docetaxel, Cisplatin, and 5-Fluorouracil Chemotherapy Combined With Cisplatin Concurrent Chemoradiotherapy for Nonmetastatic Stage IV Head-and-Neck Squamous Cell Carcinomas

    SciTech Connect

    Prestwich, Robin J.; Oeksuez, Didem Colpan; Dyker, Karen; Coyle, Catherine; Sen, Mehmet

    2011-11-15

    Purpose: To report the experience of treating selected fit patients with locally advanced head-and-neck squamous cell carcinoma with three cycles of induction TPF (docetaxel 75 mg/m{sup 2}, cisplatin 75 mg/m{sup 2}, 5-fluorouracil 750 mg/m{sup 2}, Days 2-5) followed by concurrent three-weekly bolus cisplatin 100 mg/m{sup 2} chemoradiotherapy. Methods and Materials: Between March 2006 and February 2010, 66 patients with nonmetastatic Stage IV head-and-neck squamous cell carcinoma were treated in a single institution with three cycles of induction TPF, followed by radical radiotherapy with concurrent cisplatin 100 mg/m{sup 2}. Results: Median age was 54 years (range, 33-69 years). Median follow-up was 21 months (range, 4-55 months). During TPF, Grade 3 toxicity occurred in 18 patients (27%), dose modifications in 10 (15%), delays in 3 (5%), and unplanned admissions in 6 (9%); a clinical tumor response was documented in 60 patients (91%). Median time from the final cycle of TPF to commencing radiotherapy was 22 days. Sixty-two patients (94%) received radical radiotherapy, and all completed treatment with no delays {>=}3 days. One, two, and three cycles of concurrent cisplatin were delivered to 18 patients (29%), 38 patients (61%), and 3 patients (5%), respectively. Ninety-two percent of patients received enteral feeding; median weight loss during treatment was 7%. Forty-two patients (68%) had unplanned admissions with no on-treatment deaths. Three unrelated deaths occurred after treatment. At 1 year after treatment, 21% of patients without disease progression remained gastrostomy dependent. Of 58 assessable patients, 50 (86%) achieved a complete response after treatment. One- and 2-year progression-free survival, cause-specific survival, and overall survival were 88%, 92%, and 86% and 80%, 85%, and 80%, respectively. Conclusion: The combination of induction TPF with concurrent cisplatin chemoradiotherapy in patients with locally advanced head and neck squamous cell

  4. Genetic Determinants of Cisplatin Resistance in Patients With Advanced Germ Cell Tumors.

    PubMed

    Bagrodia, Aditya; Lee, Byron H; Lee, William; Cha, Eugene K; Sfakianos, John P; Iyer, Gopa; Pietzak, Eugene J; Gao, Sizhi Paul; Zabor, Emily C; Ostrovnaya, Irina; Kaffenberger, Samuel D; Syed, Aijazuddin; Arcila, Maria E; Chaganti, Raju S; Kundra, Ritika; Eng, Jana; Hreiki, Joseph; Vacic, Vladimir; Arora, Kanika; Oschwald, Dayna M; Berger, Michael F; Bajorin, Dean F; Bains, Manjit S; Schultz, Nikolaus; Reuter, Victor E; Sheinfeld, Joel; Bosl, George J; Al-Ahmadie, Hikmat A; Solit, David B; Feldman, Darren R

    2016-11-20

    Purpose Owing to its exquisite chemotherapy sensitivity, most patients with metastatic germ cell tumors (GCTs) are cured with cisplatin-based chemotherapy. However, up to 30% of patients with advanced GCT exhibit cisplatin resistance, which requires intensive salvage treatment, and have a 50% risk of cancer-related death. To identify a genetic basis for cisplatin resistance, we performed whole-exome and targeted sequencing of cisplatin-sensitive and cisplatin-resistant GCTs. Methods Men with GCT who received a cisplatin-containing chemotherapy regimen and had available tumor tissue were eligible to participate in this study. Whole-exome sequencing or targeted exon-capture-based sequencing was performed on 180 tumors. Patients were categorized as cisplatin sensitive or cisplatin resistant by using a combination of postchemotherapy parameters, including serum tumor marker levels, radiology, and pathology at surgical resection of residual disease. Results TP53 alterations were present exclusively in cisplatin-resistant tumors and were particularly prevalent among primary mediastinal nonseminomas (72%). TP53 pathway alterations including MDM2 amplifications were more common among patients with adverse clinical features, categorized as poor risk according to the International Germ Cell Cancer Collaborative Group (IGCCCG) model. Despite this association, TP53 and MDM2 alterations predicted adverse prognosis independent of the IGCCCG model. Actionable alterations, including novel RAC1 mutations, were detected in 55% of cisplatin-resistant GCTs. Conclusion In GCT, TP53 and MDM2 alterations were associated with cisplatin resistance and inferior outcomes, independent of the IGCCCG model. The finding of frequent TP53 alterations among mediastinal primary nonseminomas may explain the more frequent chemoresistance observed with this tumor subtype. A substantial portion of cisplatin-resistant GCTs harbor actionable alterations, which might respond to targeted therapies. Genomic

  5. Cisplatin intrastrand adducts sensitize DNA to base damage by hydrated electrons.

    PubMed

    Behmand, B; Wagner, J R; Sanche, L; Hunting, D J

    2014-05-08

    The oligonucleotide TTTTTGTGTTT with or without a cisplatin adduct was reacted with hydrated electrons generated by ionizing radiation. Hydroxyl radicals were quenched with ethylenediaminetetraacetic acid (EDTA), and the solutions were bubbled with wet nitrogen to eliminate oxygen, a scavenger of hydrated electrons. Prior to irradiation, the structure of the initial cisplatin adduct was identified by mass spectrometry as G-cisplatin-G. Radiation damage to DNA bases was quantified by high-performance liquid chromatography (HPLC), after enzymatic digestion of the TTTTTGTGTTT-cisplatin complex to deoxyribonucleosides. The masses of the platinum adducts following digestion and separation by HPLC were measured by mass spectrometry. Our results demonstrate that hydrated electrons induce damage to thymines as well as detachment of the cisplatin moiety from both guanines in the oligonucleotide. This detachment regenerates both unmodified guanine and damaged guanine, in equimolar amounts. At 1000 Gy, a net average of 2.5 thymines and 1 guanine are damaged for each platinum lost from the oligonucleotide. Given the extensive base damage that occurs for each cisplatin adduct lost, it is clear that, prior to undergoing detachment, these adducts must catalyze several cycles of reactions of hydrated electrons with DNA bases. It is likely that a single reaction leads to the loss of the cisplatin adduct and the damage observed on the guanine base; however, the damage to the thymine bases must require the continued presence of the cisplatin adduct, acting as a catalyst. To our knowledge, this is the first time that platinum-DNA adducts have been shown to have catalytic activity. We propose two pathways for the interaction of hydrated electrons with TTTTTGTGTTT-cisplatin: (1) the hydrated electron is initially captured by a thymine base and transferred by base to base electron hopping to the guanine site, where the cisplatin moiety detaches from the oligonucleotide via dissociative

  6. Chemotherapy

    Cancer.gov

    Chemotherapy is a type of cancer treatment that uses drugs to kill cancer cells. Learn how chemotherapy works against cancer, why it causes side effects, and how it is used with other cancer treatments.

  7. Cisplatin induces stemness in ovarian cancer

    PubMed Central

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

    2016-01-01

    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

  8. NHERF1 Enhances Cisplatin Sensitivity in Human Cervical Cancer Cells

    PubMed Central

    Tao, Tao; Yang, Xiaomei; Qin, Qiong; Shi, Wen; Wang, Qiqi; Yang, Ying; He, Junqi

    2017-01-01

    Cervical cancer is one of the most common female malignancies, and cisplatin-based chemotherapy is routinely utilized in locally advanced cervical cancer patients. However, resistance has been the major limitation. In this study, we found that Na+/H+ Exchanger Regulatory Factor 1 (NHERF1) was downregulated in cisplatin-resistant cells. Analysis based on a cervical cancer dataset from The Cancer Genome Atlas (TCGA) showed association of NHERF1 expression with disease-free survival of patients received cisplatin treatment. NHERF1 overexpression inhibited proliferation and enhanced apoptosis in cisplatin-resistant HeLa cells, whereas NHERF1 knockdown had inverse effects. While parental HeLa cells were more resistant to cisplatin after NHERF1 knockdown, NHERF1 overexpression in CaSki cells promoted cisplatin sensitivity. Overexpression and knockdown studies also showed that NHERF1 significantly inhibited AKT and extracellular signal–regulated kinase (ERK) signaling pathways in cisplatin-resistant cells. Taken together, our results provide the first evidence that NHERF1 can sensitize cisplatin-refractory cervical cancer cells. This study may help to increase understanding of the molecular mechanisms underlying cisplatin resistance in tumors. PMID:28085111

  9. Chemotherapy

    MedlinePlus

    ... to Know Central Venous Catheters Track Your Chemotherapy Side Effects [PDF] Common Concerns About Chemotherapy Get information about common concerns people have when getting chemotherapy, and learn more about related topics. Is It Safe to Keep My Pet While I’m Being Treated for ... Drug Use ...

  10. Comparison of Ifosfamide, Carboplatin and Etoposide versus Etoposide, Steroid, and Cytarabine Cisplatin as Salvage Chemotherapy in Patients with Refractory or Relapsed Hodgkin's lymphoma

    PubMed Central

    Mehrzad, Valiollah; Ashrafi, Farzaneh; Farrashi, Ali Reza; Pourmarjani, Reyhaneh; Dehghani, Mehdi; Shahsanaei, Armindokht

    2017-01-01

    Background: Refractory or relapsed Hodgkin's disease (HD) occurs in 10-50% of patients. The treatment of choice for these patients is high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). Response to salvage chemotherapy (SCT) partial remission (PR) is necessary before HDCT with ASCT. However, its applicability is restricted mostly to patients responding to salvage chemotherapy. Optimal salvage regimen for these patients is unclear. In this study, our aim was to compare the efficacy profiles of ifosfamide, carboplatin, and etoposide (ICE) and etoposide-steroid-cytarabine-cisplatin (ESHAP) (cytosine arabinoside, cisplatin, and dexamethasone) regimens in the salvage treatment of relapsed or refractory HD. Materials and Methods: In this retrospective analysis, 114 patients with primary refractory or relapsed HD who received ICE or ESHAP salvage regimen were included. Results: Of 114 patients, 47 (41.2%) were females and the median age was 31.5 years. Response could be evaluated in 114 patients. Of 114 patients, 38 (33%) achieved complete remission (CR) and 21 (18.4%) achieved PR, leading to an overall response rate (ORR: CR + PR) of 51.4%. In the evaluable ICE group (n = 41), rates of CR, PR, and ORR were 21.9%, 17.1%, and 39% and in the ESHAP group (n = 73), rates of CR, PR, and ORR were 39.7%, 19.2%, and 58.9% (for ORR, P = 0.04), respectively. Conclusion: In patients with relapsed or refractory HD, treatment with ESHAP seems to have higher rates of response than ICE regimen does.

  11. [Neoadjuvant, inductive or adjuvant chemotherapy of bladder cancer].

    PubMed

    Ohlmann, C-H; De Santis, M

    2013-11-01

    Perioperative chemotherapy is a standard treatment for patients with muscle-invasive bladder carcinoma undergoing radical cystectomy; however, direct comparisons of neoadjuvant and adjuvant chemotherapy are lacking. Evidence-based data and implementation into daily clinical practice favor neoadjuvant chemotherapy; nevertheless, neoadjuvant chemotherapy is still underused in daily practice compared to adjuvant chemotherapy. If neoadjuvant chemotherapy has not been used and patients are fit enough to receive cisplatin, adjuvant chemotherapy should be considered in patients with pT3-pT4 and/or lymph node metastases.

  12. Amphiphilic oligomer-based micelles as cisplatin nanocarriers for cancer therapy

    NASA Astrophysics Data System (ADS)

    Qi, Xiuxiu; Li, Najun; Gu, Hongwei; Xu, Yujie; Xu, Ying; Jiao, Yang; Xu, Qingfeng; Li, Hua; Lu, Jianmei

    2013-09-01

    Polymeric micelles (~10 nm) have been prepared from the amphiphilic oligomer comprising oligomeric polystyrene as the hydrophobic inner core and half of EDTA (-N(CH2COOH)2) as the hydrophilic outermost shell. After chelating cisplatin with -N(CH2COOH)2 in water, polymeric micelles containing Pt on the spherical surface have been easily obtained. Since the chelate group is introduced into the amphiphilic oligomer as the terminal group by a RAFT agent, the chelation of cisplatin with PS(COOH)2 is almost stoichiometric. The drug carrier based on PS(COOH)2 showed a high loading efficiency (>70%) towards cisplatin. The release of the therapeutic Pt from the cisplatin-loaded composites (PS(COOH)2-Pt) triggered under weak acidic conditions resulted in good Pt-release and accumulation in tumor cells. Both in vitro and in vivo, the chelated cisplatin inhibited Sk-Br3 cancer more effectively than the intact cisplatin does. Furthermore, neither PS(COOH)2 nor PS(COOH)2-Pt showed obvious systematic toxicity.Polymeric micelles (~10 nm) have been prepared from the amphiphilic oligomer comprising oligomeric polystyrene as the hydrophobic inner core and half of EDTA (-N(CH2COOH)2) as the hydrophilic outermost shell. After chelating cisplatin with -N(CH2COOH)2 in water, polymeric micelles containing Pt on the spherical surface have been easily obtained. Since the chelate group is introduced into the amphiphilic oligomer as the terminal group by a RAFT agent, the chelation of cisplatin with PS(COOH)2 is almost stoichiometric. The drug carrier based on PS(COOH)2 showed a high loading efficiency (>70%) towards cisplatin. The release of the therapeutic Pt from the cisplatin-loaded composites (PS(COOH)2-Pt) triggered under weak acidic conditions resulted in good Pt-release and accumulation in tumor cells. Both in vitro and in vivo, the chelated cisplatin inhibited Sk-Br3 cancer more effectively than the intact cisplatin does. Furthermore, neither PS(COOH)2 nor PS(COOH)2-Pt showed obvious

  13. Platinum-based Chemotherapy in Primary Advanced Seminoma—a Retrospective Analysis: Treatment Results at the Northern Israel Oncology Center (1989–2010)

    PubMed Central

    Stein, Moshe E.; Drumea, Karen; Charas, Tomer; Gershuny, Anthony; Ben-Yosef, Rahamim

    2014-01-01

    Objective: Over the past 30 years, great strides have been made in the treatment of disseminated testicular tumors. Despite the low number of patients and the rarity of studies concerning primary advanced seminoma, the efficacy of chemotherapy is clear, mainly 3–4-cisplatin-based chemotherapy. Aiming to contribute to the understanding and implementation of proper chemotherapeutic management in advanced seminoma patients, we retrospectively summarized our experience with 26 patients who were referred for platinum-based chemotherapy, post-orchiectomy to the Northern Israel Oncology Center between 1989 and 2010. Response rate, side effects, and long-term outcome were investigated. Methods: Before chemotherapy, meticulous staging was done, including tumor markers (B-human chorionic gonadotropin (B-HCG), alpha-fetoprotein (AFP), and lactic dehydrogenase (LDH)), and abdominal and pelvic computerized tomography (CT) scans were carried out. Results: All 26 treated patients achieved complete remission, clinically and symptomatically, with normalization of their CT scans. At a median follow-up of 120 months (range, 24–268 months) all patients are alive, without evidence of recurrent disease. One patient whose disease recurred twice achieved a third complete remission following salvage treatment with high-dose chemotherapy and autologous peripheral stem cell transplantation. Another patient, who preferred surveillance, relapsed abdominally after 9 months but achieved long-standing complete remission with cisplatin-based chemotherapy. Both these patients are alive with no evidence of disease. Three patients recovered uneventfully from bleomycin-induced pneumonitis. Conclusions: Advanced seminoma is a highly curable disease using platinum-based chemotherapy. Our study confirms the efficacy and safety of cisplatin-based chemotherapy in the treatment of advanced seminoma. PMID:24498512

  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. Syndrome of inappropriate antidiuretic hormone secretion following irinotecan-cisplatin administration as a treatment for recurrent ovarian clear cell carcinoma

    PubMed Central

    Kwon, Do Youn; Han, Gwan Hee; Ulak, Roshani; Lee, Jong Min; Lee, Seon Kyung

    2017-01-01

    Syndrome of inappropriate antidiuretic hormone secretion (SIADH) has various causes including central nervous system disorders, pulmonary and endocrine diseases, paraneoplastic syndromes, and use of certain drugs. SIADH induced by chemotherapy with irinotecan-cisplatin is not a common complication. Here, we review a case of SIADH after treatment with irinotecan-cisplatin. A 45-year-old woman received adjuvant chemotherapy (paclitaxel-carboplatin) for ovarian clear cell carcinoma, but the cancer recurred within 9 months of chemotherapy. Subsequently, a second line of combination chemotherapy containing irinotecan-cisplatin was initiated. However, 5 days after chemotherapy administration, her general condition began to deteriorate; her hematological tests revealed hyponatremia. Therefore, it is imperative to consider the possibility of SIADH in patients being treated with irinotecan-cisplatin–based chemotherapy. Proper monitoring of serum sodium levels and assessment of clinical symptoms should be performed in such patients for early diagnosis and prompt management. PMID:28217682

  16. Systemic cisplatin exposure during infancy and adolescence causes impaired cognitive function in adulthood.

    PubMed

    John, Tami; Lomeli, Naomi; Bota, Daniela A

    2017-02-15

    Cancer survivors diagnosed during infancy and adolescence may be at risk for chemotherapy-related cognitive impairments (CRCI), however the effects of pediatric chemotherapy treatment on adulthood cognitive function are not well understood. Impairments in memory, attention and executive function affect 15-50% of childhood leukemia survivors related to methotrexate exposure. Systemic cisplatin is used to treat a variety of childhood and adult cancers, yet the risk and extent of cognitive impairment due to platinum-based chemotherapy in pediatric patients is unknown. Systemic cisplatin penetrates the CNS, induces hippocampal synaptic damage, and leads to neuronal and neural stem/progenitor cell (NSC) loss. Survivors of non-leukemic cancers may be at risk for significant cognitive impairment related to cisplatin-driven neurotoxicity. We sought to examine the long-term effects of systemic cisplatin administration on cognitive function when administered during infancy and adolescence in a rat model. We performed cognitive testing in adult rats exposed to systemic cisplatin during either infancy or adolescence. Rats treated as adolescents showed significantly poor retrieval of a novel object as compared to controls. Further, cisplatin-treated infants and adolescents showed poor contextual discrimination as compared to controls, and an impaired response to cued fear conditioning. Ultimately, systemic cisplatin exposure resulted in more profound impairments in cognitive function in rats treated during adolescence than in those treated during infancy. Further, exposure to cisplatin during adolescence affected both hippocampus and amygdala dependent cognitive function, suggesting a more global cognitive dysfunction at this age.

  17. Systemic cisplatin exposure during infancy and adolescence causes impaired cognitive function in adulthood

    PubMed Central

    Lomeli, Naomi; Bota, Daniela A.

    2017-01-01

    Cancer survivors diagnosed during infancy and adolescence may be at risk for chemotherapy-related cognitive impairments (CRCI), however the effects of pediatric chemotherapy treatment on adulthood cognitive function are not well understood. Impairments in memory, attention and executive function affect 15–50% of childhood leukemia survivors related to methotrexate exposure. Systemic cisplatin is used to treat a variety of childhood and adult cancers, yet the risk and extent of cognitive impairment due to platinum-based chemotherapy in pediatric patients is unknown. Systemic cisplatin penetrates the CNS, induces hippocampal synaptic damage, and leads to neuronal and neural stem/progenitor cell (NSC) loss. Survivors of non-leukemic cancers may be at risk for significant cognitive impairment related to cisplatin-driven neurotoxicity. We sought to examine the long-term effects of systemic cisplatin administration on cognitive function when administered during infancy and adolescence in a rat model. We performed cognitive testing in adult rats exposed to systemic cisplatin during either infancy or adolescence. Rats treated as adolescents showed significantly poor retrieval of a novel object as compared to controls. Further, cisplatin-treated infants and adolescents showed poor contextual discrimination as compared to controls, and an impaired response to cued fear conditioning. Ultimately, systemic cisplatin exposure resulted in more profound impairments in cognitive function in rats treated during adolescence than in those treated during infancy. Further, exposure to cisplatin during adolescence affected both hippocampus and amygdala dependent cognitive function, suggesting a more global cognitive dysfunction at this age. PMID:27851909

  18. Dose responsive effects of cisplatin in L02 cells using NMR-based metabolomics.

    PubMed

    Liu, Shu; Wang, Wei; Zhou, Xueyi; Gu, Runhuan; Ding, Zongli

    2014-01-01

    Cisplatin is an effective chemotherapeutic agent for the treatment of various cancers, such as bladder cancer, epithelial ovarian cancer, cervical cancer, and so on. However, cisplatin can cause various side effects. In this study, the dose-responsive effects of cisplatin were investigated in an in vitro model of human liver cells (L02) using NMR-based metabolomics. The inverted U-shaped curve of cell proliferation confirmed the hormetic effects of cisplatin (from 1 nM to 1 mM) in L02 cells. However, the metabolite changes revealed both U-shaped (ethanol, lactate, aspartate, choline, etc.) and inverted U-shaped (glutamate, glutamine, 4-aminobutyrate, myo-inositol, etc.) curves induced by three typical concentrations of cisplatin which covered the inverted U-shaped curve as indicated by the cell proliferation assay. These findings suggested that a macroscopic hormesis phenomenon on the cell proliferation could be reflected by both stimulated and inhibited metabolites and corresponding metabolic pathways to cisplatin treatments. Therefore, a global analysis using metabolomics may give a broader view into the dose-response relationship than using a single endpoint at molecular levels.

  19. Inhibition of PKCδ reduces cisplatin-induced nephrotoxicity without blocking chemotherapeutic efficacy in mouse models of cancer

    PubMed Central

    Pabla, Navjotsingh; Dong, Guie; Jiang, Man; Huang, Shuang; Kumar, M. Vijay; Messing, Robert O.; Dong, Zheng

    2011-01-01

    Cisplatin is a widely used cancer therapy drug that unfortunately has major side effects in normal tissues, notably nephrotoxicity in kidneys. Despite intensive research, the mechanism of cisplatin-induced nephrotoxicity remains unclear, and renoprotective approaches during cisplatin-based chemotherapy are lacking. Here we have identified PKCδ as a critical regulator of cisplatin nephrotoxicity, which can be effectively targeted for renoprotection during chemotherapy. We showed that early during cisplatin nephrotoxicity, Src interacted with, phosphorylated, and activated PKCδ in mouse kidney lysates. After activation, PKCδ regulated MAPKs, but not p53, to induce renal cell apoptosis. Thus, inhibition of PKCδ pharmacologically or genetically attenuated kidney cell apoptosis and tissue damage, preserving renal function during cisplatin treatment. Conversely, inhibition of PKCδ enhanced cisplatin-induced cell death in multiple cancer cell lines and, remarkably, enhanced the chemotherapeutic effects of cisplatin in several xenograft and syngeneic mouse tumor models while protecting kidneys from nephrotoxicity. Together these results demonstrate a role of PKCδ in cisplatin nephrotoxicity and support targeting PKCδ as an effective strategy for renoprotection during cisplatin-based cancer therapy. PMID:21633170

  20. Induction of autophagy counteracts the anticancer effect of cisplatin in human esophageal cancer cells with acquired drug resistance.

    PubMed

    Yu, Le; Gu, Chunping; Zhong, Desheng; Shi, Lili; Kong, Yi; Zhou, Zhitao; Liu, Shuwen

    2014-12-01

    Cisplatin-based chemotherapy frequently resulted in acquired resistance. The underpinning mechanism of such resistance remains obscure especially in relation to autophagic response. This study thus investigated the role of autophagy in the anticancer activity of cisplatin in human esophageal cancer cells with acquired cisplatin resistance. In response to cisplatin treatment, EC109 cells exhibited substantial apoptosis and senescence whereas cisplatin-resistant EC109/CDDP cells exhibited resistance. In this respect, cisplatin increased ERK phosphorylation whose inhibition by MEK inhibitor significantly attenuated the cytotoxic and cytostatic effect of cisplatin. Notably, cisplatin preferentially induces autophagy in EC109/CDDP cells but not in EC109 cells. Moreover, the induction of autophagy was accompanied by the suppression of mTORC1 activity. Abolition of autophagy by pharmacological inhibitors or knockdown of ATG5/7 re-sensitized EC109/CDDP cells. Co-administration of an autophagy inhibitor chloroquine and cisplatin significantly suppressed tumor growth whereas cisplatin monotherapy failed to elicit anticancer activity in nude mice xenografted with EC109/CDDP cells. To conclude, our data implicate autophagic response as a key mechanism of acquired resistance to cisplatin, suggesting that autophagy is a novel target to improve therapy efficiency of cisplatin toward human esophageal cancers with acquired resistance.

  1. Antibody-drug conjugates: targeting melanoma with cisplatin encapsulated in protein-cage nanoparticles based on human ferritin.

    PubMed

    Falvo, Elisabetta; Tremante, Elisa; Fraioli, Rocco; Leonetti, Carlo; Zamparelli, Carlotta; Boffi, Alberto; Morea, Veronica; Ceci, Pierpaolo; Giacomini, Patrizio

    2013-12-21

    A novel antibody-drug conjugate (ADC) was synthesized incorporating ferritin-based nanoparticles. An average of three molecules of monoclonal antibody (mAb) Ep1 to the human melanoma-specific antigen CSPG4 were conjugated to a single ferritin cage encapsulating about 50 cisplatin molecules (HFt-Pt-Ep1). The HFt-Pt-Ep1 nanoparticle had an estimated molecular size of about 900 kD and 33 nm, and flow cytometry demonstrated specific binding to a CSPG4(+) melanoma cell line, but not to a CSPG4(-) breast carcinoma cell line. As compared to the cisplatin-containing ferritin nanoparticle alone (HFt-Pt), which inhibited thymidine incorporation more efficiently in breast carcinoma than melanoma cells, the mAb-derivatized HFt-Pt-Ep1 nanoparticle had a 25-fold preference for the latter. A similar preference for melanoma was observed upon systemic intravenous administration of HFt-Pt-Ep1 to nude mice xenotransplanted with pre-established, palpable melanoma and breast carcinoma tumors. Thus, we have been able to determine precise combinations and stoichiometric relationships between mAbs and nanoparticle protein cages, whereby the latter lose their tropism for ubiquitously distributed cellular receptors, and acquire instead remarkably lineage-selective binding. HFt-Pt-Ep1 is therefore an interesting model to improve the therapeutic index of antiblastic therapy in a tumor such as melanoma, which at its advanced stages is totally refractory to mono- and combination-chemotherapy.

  2. Chemotherapy

    MedlinePlus

    ... needs plenty of rest to recover from chemotherapy. Scale back on strenuous stuff, and make time to ... teeth very gently to avoid bleeding. Once you've finished chemo, it's still important to visit the ...

  3. A phase III, multicenter randomized controlled trial of neo-adjuvant chemotherapy paclitaxel plus cisplatin versus surgery alone for stage IIA–IIIB esophageal squamous cell carcinoma

    PubMed Central

    Zheng, Yan; Liu, Xianben; Zhang, Ruixiang; Wang, Zongfei; Sun, Haibo; Liu, Shilei

    2017-01-01

    Background The survival benefits of neoadjuvant chemotherapy (NAC) for esophagus squamous cell carcinoma (ESCC) remains controversial. The surgical procedure was not well defined in NAC strategy, in past trials. The different surgical procedure and different levels of lymphadenectomy may decrease the survival benefits from NAC. The new chemotherapy regimen with paclitaxel is promising. The purpose of this study is to confirm the superiority of paclitaxel, cisplatin and McKeown esophagectomy with total two-field lymphadenectomy compared with surgery alone for ESCC. Methods A two-arm phase III trial was launched in June 2015. A total of 528 patients will be recruited from eight Chinese institutions within 2.5 years. The overall survival (OS) is the primary endpoint, and the secondary endpoints include disease-free survival (DFS), R0 resection rate, complication rate, perioperation mortality, days of hospitalization, quality of life (QOL), NAC response rate, pathologic response rate, toxicities of NAC, prognostic factors, predictive factors, progression-free survival (PFS), and adverse events. Discussion The study will provide the final conclusion of NAC for ESCC in China. Trial registration NCT02442440 (https://register.clinicaltrials.gov/). PMID:28203424

  4. Histological complete response in a patient with advanced biliary tract cancer treated by gemcitabine/cisplatin/S-1 combination chemotherapy: A case report

    PubMed Central

    Matsubara, Tokuhiro; Nishida, Tsutomu; Tomimaru, Yoshito; Yamamoto, Masashi; Hayashi, Shiro; Nakajima, Sachiko; Fukui, Koji; Dono, Keizo; Adachi, Shiro; Ioka, Tatsuya; Kanai, Masashi; Inada, Masami

    2016-01-01

    A 68-year-old woman was referred to our hospital with increased levels of biliary enzymes. On imaging, the patient was diagnosed with unresectable intrahepatic biliary tract cancer (BTC) with invasion of the portal vein and para-aortic lymph node metastasis (cT3N1M1, cStage IVb) and underwent endoscopic biliary drainage for the biliary stricture prior to therapy. The patient was subsequently enrolled in a phase III randomized trial (UMIN000014371/NCT02182778) and randomly assigned to receive gemcitabine/cisplatin/S-1 (GCS) combination therapy intravenously at doses of 1,000 or 25 mg/m2 on day 1 and orally twice daily at a dose of 80 mg/m2 on days 1–7 every 2 weeks. After 12 cycles of scheduled therapy without uncontrollable adverse effects, the patient achieved a good partial response with chemotherapy. Computed tomography (CT) revealed a marked reduction of the primary and metastatic lesions. In addition,18F-fluorodeoxyglucose-positron emission tomography/CT revealed diminishing abnormal uptake and no macroscopic evidence of factors adversely affecting tumor resectability. Therefore, the patient underwent extended right hepatic lobectomy, lymph node dissection and left hepaticojejunostomy. Finally, histological examination of the resected tissues revealed no residual cancer cells, suggesting a pathologically complete response. We herein present the case of a patient with intrahepatic BTC who achieved a pathologically complete response following combination chemotherapy with GCS. PMID:28101354

  5. Weekly nanoparticle albumin-bound paclitaxel in combination with cisplatin versus weekly solvent-based paclitaxel plus cisplatin as first-line therapy in Chinese patients with advanced esophageal squamous cell carcinoma

    PubMed Central

    Wang, Hai-ying; Yao, Zhi-hua; Tang, Hong; Zhao, Yan; Zhang, Xiao-san; Yao, Shu-na; Yang, Shu-jun; Liu, Yan-yan

    2016-01-01

    Objective More effective regimens for advanced esophageal squamous cell carcinoma (ESCC) are urgently needed. Therefore, a retrospective study concerning the efficacy and safety of nanoparticle albumin-bound paclitaxel plus cisplatin (nab-TP) versus solvent-based paclitaxel plus cisplatin (sb-TP) as a first-line therapy was conducted in Chinese patients with advanced ESCC. Methods From June 2009 to June 2015, 32 patients were treated with nab-paclitaxel (125 mg/m2) on the first and eighth days (30 minutes infusion) and cisplatin (75 mg/m2) on the second day every 21 days (nab-TP arm). Also, 43 patients were treated with solvent-based paclitaxel (80 mg/m2) intravenously on the first and eighth days and the same dose of cisplatin (sb-TP arm). The two groups were compared in terms of objective response rate (ORR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety profile. OS and PFS were estimated using Kaplan–Meier methods to determine associations between chemotherapy regimens and survival outcomes. Results Nab-TP demonstrated a higher ORR (50% vs 30%; P=0.082) and disease control rate (81% vs 65%; P=0.124) than sb-TP. Median OS was similar for nab-TP and sb-TP (12.5 vs 10.7 months; P=0.269). However, nab-TP resulted in a longer median PFS (6.1 months [95% confidence interval: 5.3–6.9]) than sb-TP (5.0 months [95% confidence interval: 4.4–5.6]) (P=0.029). The most common adverse events included anemia, leukopenia, neutropenia, febrile neutropenia, and thrombocytopenia in both the groups and no statistically significant differences were observed between the groups. With statistically significant differences, significantly less grade ≥3 peripheral neuropathy, arthralgia, and myalgia occurred in the nab-TP arm (all P<0.05). Dose reduction, treatment delays, and second-line therapy were similar between the two regimens. There were no treatment-related deaths in either group. Conclusion Nab-paclitaxel plus cisplatin is found

  6. A phase II prospective study of the "Sandwich" protocol, L-asparaginase, cisplatin, dexamethasone and etoposide chemotherapy combined with concurrent radiation and cisplatin, in newly diagnosed, I/II stage, nasal type, extranodal natural killer/T-cell lymphoma.

    PubMed

    Jiang, Ming; Zhang, Li; Xie, Li; Zhang, Hong; Jiang, Yu; Liu, Wei-Ping; Zhang, Wen-Yan; Tian, Rong; Deng, Yao-Tiao; Zhao, Sha; Zou, Li-Qun

    2017-03-17

    Nasal-type, extranodal NK/T cell lymphoma (ENKTCL) is a special type of lymphomas with geographic and racial specificity. Up to now, the standard first-line treatment is still not unified. In our previous report, the "sandwich" protocol produced good results. Continuing to use the "sandwich" mode, a new chemotherapy composed of L-asparaginase, cisplatin, etoposide and dexamethasone (LVDP) plus concurrent chemoradiotherapy (CCRT) was conducted in more patients with newly diagnosed, I/II stage ENKTCL. The results showed that 66 patients were enrolled. Overall response rate was 86.4% including 83.3% complete response and 3.0% partial remission. With the median follow-up of 23.5 months, 3-year overall survival and 3-year progression-free survival were 70.1% and 67.4%, respectively. The survival rate in stage II and extra-cavity stage I was significantly less than that in limited stage I (p < 0.05). Therefore, we thought that the "sandwich" mode was worthy of being generalized and LVDP combined with CCRT was an effective protocol for I/II stage ENKTCL. But this regimen was not suitable for all stage I/II patients and warrants larger sample and layering investigation. This study was a registered clinical trial with number ChiCTR-TNC-12002353.

  7. TET1 promotes cisplatin-resistance via demethylating the vimentin promoter in ovarian cancer.

    PubMed

    Han, Xi; Zhou, Yuanyuan; You, Yuanyi; Lu, Jiaojiao; Wang, Lijie; Hou, Huilian; Li, Jing; Chen, Wei; Zhao, Le; Li, Xu

    2017-04-01

    The development of chemo-resistance impairs the outcome of the first line platinum-based chemotherapies for ovarian cancer. Deregulation of DNA methylation/demethylation provides a critical mechanism for the occurrence of chemo-resistance. The ten-eleven translocation (TET) family of dioxygenases including TET1/2/3 plays an important part in DNA demethylation, but their roles in cisplatin resistance have not been elucidated. Using cisplatin-sensitive and cisplatin-resistant ovarian cancer cell models, we found that TET1 was significantly upregulated in cisplatin-resistant CP70 cells compared with that in cisplatin-sensitive A2780 cells. Ectopic expression of TET1 in A2780 cells promoted cisplatin resistance and decreased cytotoxicity induced by cisplatin, while inhibition of TET1 by siRNA transfection in CP70 cells attenuated cisplatin resistance and enhanced cytotoxicity of cisplatin. Increased TET1 induced re-expression of vimentin through active DNA demethylation, and cause partial epithelial-to-mesenchymal (EMT) in A2780 cells. Contrarily, knocking down of TET1 in CP70 cells reduced vimentin expression and reversed EMT process. Immunohistochemical analysis of TET1 in human ovarian cancer tissues revealed that TET1 existed in nucleus and cytoplasm in ovarian cancer tissues. And the expression of nuclear TET1 was positively correlated with residual tumor and chemotherapeutic response. Thus, TET1 expression causes resistance to cisplatin and one of the targets of TET1 action is vimentin in ovarian cancer.

  8. A comparative study of cisplatin-based definitive chemo-radiation in non-metastatic squamous cell carcinoma of the esophagus

    PubMed Central

    Mofid, Bahram; Razzaghdoust, Abolfazl; Kashi, Amir Shahram Yousefi; Mirzaei, Hamid Reza

    2016-01-01

    Introduction Esophageal cancer is the seventh most frequent malignancy in Iranian men and the fourth most common cancer in Iranian women. It is also among the 10 most frequent cancers in the world. Definitive chemo-radiation using cisplatin with 5-fluorouracil (5-FU) is known as the standard of care among various chemotherapy regimens used with esophageal cancer patients who are not eligible for surgery. Cisplatin with paclitaxel and cisplatin with irinotecan also have been used often during the past five years. The aim of this research was to compare overall survival (OS) and hematological toxicity rates between these regimens. Methods This single-institutional study included 55 patients who were treated with definitive chemo-radiation in the radiation-oncology ward at Shohada-e-Tajrish Hospital in Tehran, Iran, between 2006 and 2013. They received one of four regimens, i.e., cisplatin, cisplatin with 5-FU (old chemotherapy regimens), cisplatin with paclitaxel, or cisplatin with irinotecan (new chemotherapy regimens) as part of their definitive chemo-radiation with curative intent. The Kaplan-Meier estimator was used to estimate the overall survival times, which were compared by using the Breslow test. Results The follow-up period was between 26–109 months, with a median of 72 months. OS was not different between the old and new chemotherapy regimen groups (p = 0.18). Hematological toxicity (leucopenia) in the old chemotherapy regimen groups (10%) was significantly lower than in the new chemotherapy regimen groups (43%, p = 0.012). But OS in cisplatin or cisplatin with 5-FU scheme was statistically better than with the cisplatin with paclitaxel scheme (p = 0.026, p = 0.028, respectively). Conclusion This study showed that OS are similar in both the old and new chemotherapy treatment regimens in esophageal cancer patients who were treated with definitive chemo-radiation. The new chemotherapy treatment regimens should be used with caution as an alternative

  9. Surgical outcome after docetaxel-based neoadjuvant chemotherapy in locally-advanced gastric cancer

    PubMed Central

    Biffi, Roberto; Fazio, Nicola; Luca, Fabrizio; Chiappa, Antonio; Andreoni, Bruno; Zampino, Maria Giulia; Roth, Arnaud; Schuller, Jan Christian; Fiori, Giancarla; Orsi, Franco; Bonomo, Guido; Crosta, Cristiano; Huber, Olivier

    2010-01-01

    AIM: To investigate feasibility, morbidity and surgical mortality of a docetaxel-based chemotherapy regimen randomly administered before or after gastrectomy in patients suffering from locally-advanced resectable gastric cancer. METHODS: Patients suffering from locally-advanced (T3-4 any N M0 or any T N1-3 M0) gastric carcinoma, staged with endoscopic ultrasound, bone scan, computed tomography, and laparoscopy, were assigned to receive four 21 d/cycles of TCF (docetaxel 75 mg/m2 day 1, cisplatin 75 mg/m2 day 1, and fluorouracil 300 mg/m2 per day for days 1-14), either before (Arm A) or after (Arm B) gastrectomy. Operative morbidity, overall mortality, and severe adverse events were compared by intention-to-treat analysis. RESULTS: From November 1999 to November 2005, 70 patients were treated. After preoperative TCF (Arm A), thirty-two (94%) resections were performed, 85% of which were R0. Pathological response was complete in 4 patients (11.7%), and partial in 18 (55%). No surgical mortality and 28.5% morbidity rate were observed, similar to those of immediate surgery arm (P = 0.86). Serious chemotherapy adverse events tended to be more frequent in arm B (23% vs 11%, P = 0.07), with a single death per arm. CONCLUSION: Surgery following docetaxel-based chemotherapy was safe and with similar morbidity to immediate surgery in patients with locally-advanced resectable gastric carcinoma. PMID:20143466

  10. Mitomycin-C- or Cisplatin-Based Chemoradiotherapy for Anal Canal Carcinoma: Long-Term Results

    SciTech Connect

    Olivatto, Luis O.; Cabral, Vania; Rosa, Arthur; Bezerra, Marcos; Santarem, Erick; Fassizoli, Ana; Castro, Leonaldson; Simoes, Jose Humberto; Small, Isabele A.; Ferreira, Carlos Gil

    2011-02-01

    Purpose: To evaluate the long-term efficacy of concurrent radiotherapy with mitomycin-C (MMC)-based or cisplatin (CP)-based combinations in a cohort of patients with locally advanced anal canal carcinoma. Methods and Materials: Between 1988 and 2000, 179 patients with locally advanced anal canal carcinoma were treated at the Instituto Nacional de Cancer with two cycles of chemotherapy during Weeks 1 and 5 of radiotherapy. 5-Fluorouracil (750 mg/m{sup 2} 120-hour infusion or 1,000 mg/m{sup 2} 96-hour infusion) plus CP (100 mg/m{sup 2}) on the first day of each cycle or MMC (10-15 mg/m{sup 2}) on the first day of Cycle 1 was administered concurrent with radiotherapy (total dose, 55-59.4 Gy). Of the 179 patients, 60% were included from a randomized trial initiated at the Instituto Nacional de Cancer in 1991 that compared concurrent chemoradiotherapy with MMC vs. CP. Results: The median follow-up for the whole chemoradiotherapy group was 83 months. The median patient age was 58 years, 57% had Stage T3-T4 tumors, and 35% had N-positive disease. The 5-year cumulative colostomy rate was not significantly different between the CP group (22%) and MMC group (29%; p = .28). The actuarial 10-year overall survival and disease-free survival rate for the CP group was 54% and 49% and for the MMC group was 52% and 53%, respectively (p = .32 and p = .92, respectively). On multivariate analysis, male gender (p = .042) and advanced Stage T3-T4 disease (p <.0001) were statistically significant for worse disease-free survival. Stage T3-T4 (p = .039) and N+ (p = .039) disease remained independently significant for overall survival. Conclusion: Long-term follow-up has confirmed the good results of chemoradiotherapy with CP plus 5-fluorouracil, which seem to provide results equivalent to those with MMC plus 5-fluorouracil.

  11. Chemotherapy

    MedlinePlus

    ... cell death (apoptosis). Types There are two main types of chemotherapy drugs: Cytostatic: These drugs prevent cells from reproducing. They include: Anti-angiogenesis agents/Angiogenesis inhibitors—These drugs prevent the development of blood vessels around the tumor that provide it with ...

  12. Efficacy and safety of single-dose fosaprepitant in the prevention of chemotherapy-induced nausea and vomiting in patients receiving high-dose cisplatin: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial

    PubMed Central

    Saito, H.; Yoshizawa, H.; Yoshimori, K.; Katakami, N.; Katsumata, N.; Kawahara, M.; Eguchi, K.

    2013-01-01

    Background We evaluated the efficacy and safety of single-dose fosaprepitant in combination with intravenous granisetron and dexamethasone. Patients and methods Patients receiving chemotherapy including cisplatin (≥70 mg/m2) were eligible. A total of 347 patients (21% had received cisplatin with vomiting) were enrolled in this trial to receive the fosaprepitant regimen (fosaprepitant 150 mg, intravenous, on day 1 in combination with granisetron, 40 μg/kg, intravenous, on day 1 and dexamethasone, intravenous, on days 1–3) or the control regimen (placebo plus intravenous granisetron and dexamethasone). The primary end point was the percentage of patients who had a complete response (no emesis and no rescue therapy) over the entire treatment course (0–120 h). Results The percentage of patients with a complete response was significantly higher in the fosaprepitant group than in the control group (64% versus 47%, P = 0.0015). The fosaprepitant regimen was more effective than the control regimen in both the acute (0–24 h postchemotherapy) phase (94% versus 81%, P = 0.0006) and the delayed (24–120 h postchemotherapy) phase (65% versus 49%, P = 0.0025). Conclusions Single-dose fosaprepitant used in combination with granisetron and dexamethasone was well-tolerated and effective in preventing chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic cancer chemotherapy, including high-dose cisplatin. PMID:23117073

  13. 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

  14. Practical use of perioperative chemotherapy for muscle-invasive bladder cancer: summary of session at the Society of Urologic Oncology annual meeting.

    PubMed

    Apolo, Andrea B; Grossman, Herbert Barton; Bajorin, Dean; Steinberg, Gary; Kamat, Ashish M

    2012-01-01

    At the 11th annual meeting of the Society of Urologic Oncology, an expert panel was convened to discuss the practical use of perioperative chemotherapy for muscle-invasive bladder cancer. The discussion was structured as a case-based debate among the panelists. The topics included: neoadjuvant chemotherapy with a focus on T2 disease, pros and cons, survival data, tolerability of cisplatin-based therapy, can we avoid radical cystectomy in complete responders, limitations and alternatives to cisplatin-based therapy, management of 'suboptimal' chemotherapy, residual disease after neoadjuvant chemotherapy, adjuvant chemotherapy, and key aspects of radical cystectomy and lymph-node dissection in multimodal therapy. The presentations were derived from published literature. The panelists agreed that patients with muscle-invasive bladder cancer should be managed with a multidisciplinary team, including urologist and medical oncologist. Cisplatin-based neoadjuvant chemotherapy has demonstrated improved survival and should be incorporated into the management of all eligible patients with muscle-invasive bladder cancer. However, in some centers, neoadjuvant chemotherapy is reserved for patients with >T2 disease or high-risk features. There are no data for the administration of non-cisplatin-based neoadjuvant chemotherapy, such as carboplatin-combinations. Cisplatin-ineligible patients should proceed directly to surgical extirpation with adjuvant cisplatin-based chemotherapy considered based on pathologic findings. However, the data for adjuvant chemotherapy is less compelling. As our refinement of the selection process continues, we may be able to better identify subsets of patients who may be spared chemotherapy, but much work remains to be done in this arena. The current standard for muscle-invasive bladder cancer patients is cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy and pelvic lymph-node dissection.

  15. HeLa cell tumor response to 60Co, Cs-137, Cf-252 radiations and cisplatin chemotherapy in nude mice.

    PubMed

    Maruyama, Y; Feola, J M; Beach, J L

    1984-07-15

    HeLa cells were implanted into athymic nude mice from tissue culture and solid tumors established (HeLa cell tumor or HCT). Large cell numbers of 1 X 10(7) were required to obtain consistent and progressive growth, and tumor growth followed a Gompertzian mode. Irradiation studies were carried out using acute Cobalt-60 (60Co), low-dose-rate (LDR) Cs-137 and LDR Cf-252. Cf-252, a neutron-emitting radioisotope, produced an immediate tumor shrinkage and regression response after a dose of 279 cGy. Acute 60Co or LDR Cs-137 irradiation with 1000 cGy had little effect on the HCT. After a dose of 2000 cGy of 60Co radiation tumor shrinkage followed a latent period of approximately 5 days. Cisplatin had no effect on the HCT in nude mice in stationary or late exponential growth.

  16. HeLa cell tumor response to 60Co, Cs-137, Cf-252 radiations and cisplatin chemotherapy in nude mice

    SciTech Connect

    Maruyama, Y.; Feola, J.M.; Beach, J.L.

    1984-07-15

    HeLa cells were implanted into athymic nude mice from tissue culture and solid tumors established (HeLa cell tumor or HCT). Large cell numbers of 1 X 10/sup 7/ were required to obtain consistent and progressive growth, and tumor growth followed a Gompertzian mode. Irradiation studies were carried out using acute Cobalt-60 (60Co), low-dose-rate (LDR) Cs-137 and LDR Cf-252. Cf-252, a neutron-emitting radioisotope, produced an immediate tumor shrinkage and regression response after a dose of 279 cGy. Acute 60Co or LDR Cs-137 irradiation with 1000 cGy had little effect on the HCT. After a dose of 2000 cGy of 60Co radiation tumor shrinkage followed a latent period of approximately 5 days. Cisplatin had no effect on the HCT in nude mice in stationary or late exponential growth.

  17. Phase II study of second-line therapy with DTIC, BCNU, cisplatin and tamoxifen (Dartmouth regimen) chemotherapy in patients with malignant melanoma previously treated with dacarbazine.

    PubMed

    Propper, D J; Braybrooke, J P; Levitt, N C; O'Byrne, K; Christodoulos, K; Han, C; Talbot, D C; Ganesan, T S; Harris, A L

    2000-06-01

    This study assessed response rates to combination dacarbazine (DTIC), BCNU (carmustine), cisplatin and tamoxifen (DBPT) chemotherapy in patients with progressive metastatic melanoma previously treated with DTIC, as an evaluation of DBPT as a second-line regimen, and as an indirect comparison of DBPT with DTIC. Thirty-five consecutive patients received DBPT. The patients were divided into two groups. Group 1 comprised 17 patients with progressive disease (PD) on DTIC + tamoxifen therapy who were switched directly to DBPT. Group 2 comprised 18 patients not immediately switched to DBPT and included patients who had either a partial response (PR; one patient) or developed stable disease (SD; four patients) with DTIC, or received adjuvant DTIC (nine patients). All except four patients had received tamoxifen at the time of initial DTIC treatment. Median times since stopping DTIC were 22 days (range 20-41) and 285 days (range 50-1,240) in Groups 1 and 2 respectively. In Group 1, one patient developed SD for 5 months and the remainder had PD. In Group 2, there were two PRs, four patients with SD (4, 5, 6, and 6 months), and 11 with PD. These results indicate that the DBPT regimen is not of value in melanoma primarily refractory to DTIC. There were responses in patients not directly switched from DTIC to DBPT, suggesting combination therapy may be of value in a small subgroup of melanoma patients.

  18. [Combination of etoposide, cisplatin and ifosfamide (VPH) in the salvage chemotherapy of relapsing or refractory aggressive malignant lymphoma. Study of 51 patients].

    PubMed

    Eghbali, H; Catry-Thomas, I; Soubeyran, P; Bonnel, C; Hoerni, B

    1994-09-01

    Fifty-one patients with non-Hodgkin's lymphoma refractory or relapsing after CHOP-like regimen, underwent a salvage chemotherapy by VPH: etoposide 100 mg/m2/d, D1 to D3, cisplatin 20 mg/m2/d, D1 to D5, ifosfamide 1 g/m2/d D1 to D5, mesna 1.2 g/m2/d D1 to D5, every 4 weeks. Among 46 evaluable patients for efficacy, 21 (45.6%) achieved complete or partial response according to WHO criteria and 25 (54.3%) failed, while five cases (9.8% of all patients) were not evaluable (two initial complete remission before VPH, two early toxic deaths and one confusional syndrome). Thirty-five patients (68.6%) died of lymphoma, three (5.8%) of acute toxicity and 13 (25.5%) are alive: five in complete remission. The toxicity is mainly myelo-suppression, digestive and renal but could be managed as usually. Although the follow-up is short, this regimen appears effective in these circumstances after CHOP failure but it should be used early, before overt chemoresistance. It does not hinder a bone marrow transplantation programme.

  19. The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB2 receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy

    PubMed Central

    2012-01-01

    Background Chemotherapeutic agents produce dose-limiting peripheral neuropathy through mechanisms that remain poorly understood. We previously showed that AM1710, a cannabilactone CB2 agonist, produces antinociception without producing central nervous system (CNS)-associated side effects. The present study was conducted to examine the antinociceptive effect of AM1710 in rodent models of neuropathic pain evoked by diverse chemotherapeutic agents (cisplatin and paclitaxel). A secondary objective was to investigate the potential contribution of alpha-chemokine receptor (CXCR4) signaling to both chemotherapy-induced neuropathy and CB2 agonist efficacy. Results AM1710 (0.1, 1 or 5 mg/kg i.p.) suppressed the maintenance of mechanical and cold allodynia in the cisplatin and paclitaxel models. Anti-allodynic effects of AM1710 were blocked by the CB2 antagonist AM630 (3 mg/kg i.p.), but not the CB1 antagonist AM251 (3 mg/kg i.p.), consistent with a CB2-mediated effect. By contrast, blockade of CXCR4 signaling with its receptor antagonist AMD3100 (10 mg/kg i.p.) failed to attenuate mechanical or cold hypersensitivity induced by either cisplatin or paclitaxel. Moreover, blockade of CXCR4 signaling failed to alter the anti-allodynic effects of AM1710 in the paclitaxel model, further suggesting distinct mechanisms of action. Conclusions Our results indicate that activation of cannabinoid CB2 receptors by AM1710 suppresses both mechanical and cold allodynia in two distinct models of chemotherapy-induced neuropathic pain. By contrast, CXCR4 signaling does not contribute to the maintenance of chemotherapy-induced established neuropathy or efficacy of AM1710. Our studies suggest that CB2 receptors represent a promising therapeutic target for the treatment of toxic neuropathies produced by cisplatin and paclitaxel chemotherapeutic agents. PMID:22998838

  20. Correlation of Serum Cystatin C with Glomerular Filtration Rate in Patients Receiving Platinum-Based Chemotherapy.

    PubMed

    Cavalcanti, Ernesta; Barchiesi, Vittoria; Cerasuolo, Dionigio; Di Paola, Flaviano; Cantile, Monica; Cecere, Sabrina Chiara; Pignata, Sandro; Morabito, Alessandro; Costanzo, Raffaele; Di Maio, Massimo; Perrone, Francesco

    2016-01-01

    Objectives. Serum cystatin C seems to be an accurate marker of glomerular filtration rate (GFR) compared to serum creatinine. The aim of this work was to explore the possibility of using serum cystatin C instead of serum creatinine to early predict renal failure in cancer patients who received platinum based chemotherapy. Design and Methods. Serum creatinine, serum cystatin C concentrations, and GFR were determined simultaneously in 52 cancer patients received carboplatin-based or cisplatin-based chemotherapy. Serum creatinine was assayed on Cobas C6000-Roche, serum cystatin C assay was performed on AIA 360-Tosoh, and GFR was determined in all patients, before the first cycle of chemotherapy and before the subsequent administrations. Results. In the overall series, for the prediction of a fall of GFR < 80 mL/min/1.73 m(2), the AUC of the ROC curve for cystatin C was 0,667 and the best threshold was 1.135 mg/L (sensitivity 90.5%, specificity 61.1%). For a GFR fall < 60 mL/min/1.73 m(2), the AUC of ROC curve for cystatin C was 74.3% and the best threshold was 1.415 mg/L (sensitivity 66.7%, specificity 73.2%). Conclusions. Baseline cystatin C values were not able to predict renal failure during subsequent treatment. In conclusion, serum cystatin C is not a reliable early marker to efficiently predict renal failure in patients receiving chemotherapy.

  1. Correlation of Serum Cystatin C with Glomerular Filtration Rate in Patients Receiving Platinum-Based Chemotherapy

    PubMed Central

    Barchiesi, Vittoria; Cerasuolo, Dionigio; Di Paola, Flaviano; Cantile, Monica; Cecere, Sabrina Chiara; Pignata, Sandro; Morabito, Alessandro; Costanzo, Raffaele; Di Maio, Massimo; Perrone, Francesco

    2016-01-01

    Objectives. Serum cystatin C seems to be an accurate marker of glomerular filtration rate (GFR) compared to serum creatinine. The aim of this work was to explore the possibility of using serum cystatin C instead of serum creatinine to early predict renal failure in cancer patients who received platinum based chemotherapy. Design and Methods. Serum creatinine, serum cystatin C concentrations, and GFR were determined simultaneously in 52 cancer patients received carboplatin-based or cisplatin-based chemotherapy. Serum creatinine was assayed on Cobas C6000-Roche, serum cystatin C assay was performed on AIA 360-Tosoh, and GFR was determined in all patients, before the first cycle of chemotherapy and before the subsequent administrations. Results. In the overall series, for the prediction of a fall of GFR < 80 mL/min/1.73 m2, the AUC of the ROC curve for cystatin C was 0,667 and the best threshold was 1.135 mg/L (sensitivity 90.5%, specificity 61.1%). For a GFR fall < 60 mL/min/1.73 m2, the AUC of ROC curve for cystatin C was 74.3% and the best threshold was 1.415 mg/L (sensitivity 66.7%, specificity 73.2%). Conclusions. Baseline cystatin C values were not able to predict renal failure during subsequent treatment. In conclusion, serum cystatin C is not a reliable early marker to efficiently predict renal failure in patients receiving chemotherapy. PMID:28078200

  2. Alterations in endocannabinoid tone following chemotherapy-induced peripheral neuropathy: Effects of endocannabinoid deactivation inhibitors targeting fatty-acid amide hydrolase and monoacylglycerol lipase in comparison to reference analgesics following cisplatin treatment

    PubMed Central

    Guindon, Josée; Lai, Yvonne; Takacs, Sara M.; Bradshaw, Heather B.; Hohmann, Andrea G.

    2012-01-01

    SUMMARY Cisplatin, a platinum-derived chemotherapeutic agent, produces mechanical and cold allodynia reminiscent of chemotherapy-induced neuropathy in humans. The endocannabinoid system represents a novel target for analgesic drug development. The endocannabinoid consists of endocannabinoids (e.g. anandamide (AEA) and 2-arachidonoylglycerol (2-AG)), cannabinoid receptors (e.g. CB1 and CB2) and the enzymes controlling endocannabinoid synthesis and degradation. AEA is hydrolyzed by fatty-acid amide hydrolase (FAAH) whereas 2-AG is hydrolyzed primarily by monoacylglycerol lipase (MGL). We compared effects of brain permeant (URB597) and impermeant (URB937) inhibitors of FAAH with an irreversible inhibitor of MGL (JZL184) on cisplatin-evoked behavioral hypersensitivities. Endocannabinoid modulators were compared with agents used clinically to treat neuropathy (i.e. the opioid analgesic morphine, the anticonvulsant gabapentin and the tricyclic antidepressant amitriptyline). Cisplatin produced robust mechanical and cold allodynia but did not alter responsiveness to heat. After neuropathy was fully established, groups received acute intraperitoneal (i.p.) injections of vehicle, amitriptyline (30 mg/kg), gabapentin (100 mg/kg), morphine (6 mg/kg), URB597 (0.1 or 1 mg/kg), URB937 (0.1 or 1 mg/kg) or JZL184 (1, 3 or 8 mg/kg). Pharmacological specificity was assessed by coadministering each endocannabinoid modulator with either a CB1 (AM251 3 mg/kg), CB2 (AM630 3 mg/kg), TRPV1 (AMG9810 3 mg/kg) or TRPA1 (HC030031 8 mg/kg) antagonist. Effects of cisplatin on endocannabinoid levels and transcription of receptors (CB1, CB2, TRPV1, TRPA1) and enzymes (FAAH, MGL) linked to the endocannabinoid system were also assessed. URB597, URB937, JZL184 and morphine reversed cisplatin-evoked mechanical and cold allodynia to pre-cisplatin levels. By contrast, gabapentin only partially reversed the neuropathy while amitriptyline, administered acutely, was ineffective. CB1 or CB2 antagonist

  3. Docetaxel, cisplatin and 5-fluorouracil adjuvant chemotherapy following three-field lymph node dissection for stage II/III N1, 2 esophageal cancer.

    PubMed

    Hashiguchi, Tadasuke; Nasu, Motomi; Hashimoto, Takashi; Kuniyasu, Tetsuji; Inoue, Hirohumi; Sakai, Noritaka; Ouchi, Kazutomo; Amano, Takayuki; Isayama, Fuyumi; Tomita, Natsumi; Iwanuma, Yoshimi; Tsurumaru, Masahiko; Kajiyama, Yoshiaki

    2014-09-01

    To determine the efficacy of postoperative adjuvant chemotherapy with docetaxel + cisplatin + 5-fluorouracil (DCF) in lymph node metastasis-positive esophageal cancer, we retrospectively analyzed 139 patients with stage II/III (non-T4) esophageal cancer with lymph node metastasis (1-6 nodes), who did not receive preoperative treatment and underwent three-field lymph node dissection in the Juntendo University Hospital between December, 2004 and December, 2009. The tumors were histologically diagnossed as squamous cell carcinoma. The patients were divided into two groups, a surgery alone group (S group, 88 patients) and a group that received postoperative DCF therapy (DCF group, 51 patients). The disease-free and overall survival were compared between the groups and a multivariate analysis of prognostic factors was performed. The same analysis was performed for cases classified as N1 and N2, according to the TNM classification. There were no significant differences between the S and DCF groups regarding clinicopathological factors other than intramural metastasis and main tumor location. The presence of intramural metastasis, blood vessel invasion and the number of lymph nodes were identified as prognostic factors. The 5-year disease-free and overall survival were 55.8 and 57.3%, respectively, in the S group and 52.8 and 63.0%, respectively, in the DCF group. These differences were not considered to be statistically significant (P=0.789 and 0.479 for disease-free and overall survival, respectively). Although there were no significant differences in disease-free and overall survival between the S and DCF groups in N1 cases, both disease-free and overall survival were found to be better in the DCF group (54.2 and 61.4%, respectively) compared to the S group (29.6 and 28.8%, respectively) in N2 cases (P=0.029 and 0.020 for disease-free and overall survival, respectively). Therefore, postoperative adjuvant chemotherapy with DCF was shown to improve disease-free and

  4. Antibody-drug conjugates: targeting melanoma with cisplatin encapsulated in protein-cage nanoparticles based on human ferritin

    NASA Astrophysics Data System (ADS)

    Falvo, Elisabetta; Tremante, Elisa; Fraioli, Rocco; Leonetti, Carlo; Zamparelli, Carlotta; Boffi, Alberto; Morea, Veronica; Ceci, Pierpaolo; Giacomini, Patrizio

    2013-11-01

    A novel antibody-drug conjugate (ADC) was synthesized incorporating ferritin-based nanoparticles. An average of three molecules of monoclonal antibody (mAb) Ep1 to the human melanoma-specific antigen CSPG4 were conjugated to a single ferritin cage encapsulating about 50 cisplatin molecules (HFt-Pt-Ep1). The HFt-Pt-Ep1 nanoparticle had an estimated molecular size of about 900 kD and 33 nm, and flow cytometry demonstrated specific binding to a CSPG4+ melanoma cell line, but not to a CSPG4- breast carcinoma cell line. As compared to the cisplatin-containing ferritin nanoparticle alone (HFt-Pt), which inhibited thymidine incorporation more efficiently in breast carcinoma than melanoma cells, the mAb-derivatized HFt-Pt-Ep1 nanoparticle had a 25-fold preference for the latter. A similar preference for melanoma was observed upon systemic intravenous administration of HFt-Pt-Ep1 to nude mice xenotransplanted with pre-established, palpable melanoma and breast carcinoma tumors. Thus, we have been able to determine precise combinations and stoichiometric relationships between mAbs and nanoparticle protein cages, whereby the latter lose their tropism for ubiquitously distributed cellular receptors, and acquire instead remarkably lineage-selective binding. HFt-Pt-Ep1 is therefore an interesting model to improve the therapeutic index of antiblastic therapy in a tumor such as melanoma, which at its advanced stages is totally refractory to mono- and combination-chemotherapy.A novel antibody-drug conjugate (ADC) was synthesized incorporating ferritin-based nanoparticles. An average of three molecules of monoclonal antibody (mAb) Ep1 to the human melanoma-specific antigen CSPG4 were conjugated to a single ferritin cage encapsulating about 50 cisplatin molecules (HFt-Pt-Ep1). The HFt-Pt-Ep1 nanoparticle had an estimated molecular size of about 900 kD and 33 nm, and flow cytometry demonstrated specific binding to a CSPG4+ melanoma cell line, but not to a CSPG4- breast carcinoma cell

  5. A density functional reactivity theory (DFRT) based approach to understand the interaction of cisplatin analogues with protecting agents

    NASA Astrophysics Data System (ADS)

    Sarmah, Amrit; Roy, Ram Kinkar

    2014-12-01

    In the present study some new insights are put into one of the major concern of cisplatin therapy and that is on the reduction of various cytotoxic and nephrotoxic side-effects of cisplatin analogues in cancer treatment. A better understanding of the interaction between different cisplatin analogues with various protecting agents can be achieved from the descriptors generated by density functional reactivity theory based comprehensive decomposition analysis of stabilization energy (Bagaria et al. in Phys Chem Chem Phys 11:8306-8315, 2009) scheme. Taking into account of three types of interactions i.e., of (1) Cisplatin analogues with DNA bases and base pairs (2) Cisplatin analogues with protecting agents and (3) Protecting agents with DNA bases, it is possible to develop a strategy (albeit qualitative) that suggests the best possible combinations of these drugs with protecting agents which can cause reduction in the toxic side-effects of cisplatin therapy. The sample set comprises of 96 pairs of cisplatin analogues and rescue agents and the generated data confirms the predictive power of the adopted strategy.

  6. A phase II trial of TIP (paclitaxel, ifosfamide and cisplatin) given as second-line (post-BEP) salvage chemotherapy for patients with metastatic germ cell cancer: a medical research council trial.

    PubMed

    Mead, G M; Cullen, M H; Huddart, R; Harper, P; Rustin, G J S; Cook, P A; Stenning, S P; Mason, M

    2005-07-25

    This phase II trial describes the use of TIP chemotherapy (paclitaxel, ifosfamide and cisplatin) as salvage for patients with metastatic germ cell cancer (GCC) who have failed initial BEP (bleomycin, etoposide and cisplatin) chemotherapy. Patients with first relapse following BEP for metastatic GCC, confirmed by biopsy or sequentially rising markers, received four courses of TIP (paclitaxel 175 mg m(-2) day 1, followed on days 1-5 by ifosfamide 1 g m(-2) intravenously (i.v.) and cisplatin 20 mg2 i.v.) at 3-weekly intervals. The primary outcome measure was response to TIP. In all, 51 patients were registered, of whom 43 were eligible for response assessment. Eight achieved complete remission (CR) and 18 a partial remission with negative markers (PR(-ve)); favourable response rate (FRR = CR + PR(-ve)) 60%, 95% CI (44-75%); survival at 1 year was 70% (56-84%) and failure-free survival 36% (22-50%). In the group of 26 patients meeting the 'good-risk' criteria described by the Memorial Hospital, the FRR was 73% (52-88%) compared with 41% (18-67%) for the 17 'poor-risk' patients. These results are inferior to those previously reported for TIP in a single-centre study when it was given more intensively, at higher dose and with growth factor support. Nonetheless, TIP as described here can cure a substantial proportion of patients.

  7. Cisplatin Induced Renal Insufficiency Measured by Glomerular Filtration Rate with 99mTc-DTPA and by using Serum Creatinine based Formulae: A Prospective Study

    PubMed Central

    Deswal, Satyawati; Prakash, Chandra; Singh, Dhananjay Kumar

    2016-01-01

    Introduction Cisplatin also known as Cis-Diammine-Dichloroplatinum (CDDP) is a chemotherapeutic alkylating nephrotoxic agent. Thus, it is necessary to know if renal function is normal before starting chemotherapy. Glomerular Filtration Rate (GFR) can be assessed directly by using a radiopharmaceutical (dGFR). Estimated GFR (eGFR) method use, Serum Creatinine (SCR) levels in mathematical formulae such as Cockroft-Gault (CG) and abbreviated. Modified Diet in Renal Disease (aMDRD). The serum creatinine level is a function of GFR but is relatively insensitive for detecting early renal insufficiency. Aim We aimed to correlate the incidence of Renal Insufficiency (RI) before and one month after completion of chemotherapy treatment by various methods. Materials and Methods In this prospective study, we examined 64 patients with locally advanced head neck and uterine cervix cancers, before and one month after chemotherapy treatment with CDDP. Single agent CDDP was used with dose range between 35mg/m2 as concurrent weekly chemotherapy. Results Baseline RI was seen in 9.3% of patients by SCR levels, in 21.8% by the dGFR method, in 43.75% by the GFR-CG method and in 25% by the GFR-aMDRD formula. We considered GFR of <60 ml/min and SCR >1.5mg% as RI. After completion of treatment, the median RI was seen in 12.5% by SCR levels, 34.38% by dGFR method, 53.13% by GFR-CG method and 40.63% by GFR-aMDRD formula. None of the methods of GFR estimation showed statistically significant increase in RI one month after CDDP infusion. Only a weak correlation was seen between dGFR and eGFR based on SCR value (p=0.006). Conclusion Baseline RI was detected in 12% more cases when measured by dGFR as compared with SCR level. However, mathematical formulae overestimated baseline RI as compared to dGFR. One month after completion of treatment with CDDP chemotherapy, RI increased in 10%-15% cases as detected by all the four evaluated methods. There is weak correlation between SCR and dGFR thus

  8. Thalidomide ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in an experimental model.

    PubMed

    Amirshahrokhi, Keyvan; Khalili, Ali-Reza

    2015-04-01

    Cisplatin is a platinum-based chemotherapy drug. However, its chemotherapeutic use is restricted by serious side effects, especially nephrotoxicity. Inflammatory mechanisms have a significant role in the pathogenesis of cisplatin-induced nephrotoxicity. Thalidomide is an immunomodulatory and anti-inflammatory agent and is used for the treatment of various inflammatory diseases. The purpose of this study was to investigate the potential nephroprotective effect of thalidomide in a mouse model of cisplatin-induced nephrotoxicity. Nephrotoxicity was induced in mice by a single injection of cisplatin (15 mg/kg, i.p.) and treated with thalidomide (50 and 100 mg/kg/day, orally) for 4 days, beginning 24 h prior to the cisplatin injection. Renal toxicity induced by cisplatin was demonstrated by increasing plasma levels of creatinine and blood urea nitrogen (BUN). Cisplatin increased the renal production of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and transforming growth factor (TGF)-β1. In addition, kidney levels of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) were increased by cisplatin. Biochemical results showed that thalidomide reduced cisplatin-induced increase in plasma creatinine and BUN. Thalidomide treatment also significantly reduced tissue levels of the proinflammatory cytokines, MDA, MPO, and NO and increased anti-inflammatory cytokine IL-10. Furthermore, histological examination indicated that thalidomide ameliorated renal damage caused by cisplatin. These data suggest that thalidomide attenuates cisplatin-induced nephrotoxicity possibly by inhibition of inflammatory reactions. Taken together, our findings indicate that thalidomide might be a valuable candidate for the prevention of nephrotoxicity in patients receiving cisplatin.

  9. Renal Medulla is More Sensitive to Cisplatin than Cortex Revealed by Untargeted Mass Spectrometry-Based Metabolomics in Rats

    PubMed Central

    Zhang, Pei; Chen, Jia-Qing; Huang, Wan-Qiu; Li, Wei; Huang, Yin; Zhang, Zun-Jian; Xu, Feng-Guo

    2017-01-01

    Nephrotoxicity has long been the most severe and life-threatening side-effect of cisplatin, whose anticancer effect is therefore restricted. Previous pathological studies have shown that both renal cortex and medulla could be injured by cisplatin. Our TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling) assay results further uncovered that medulla subjected more severe injury than cortex. In order to depict the underlying metabolic mechanism of spatial difference in response to cisplatin, in the present study, mass spectrometry-based untargeted metabolomics approach was applied to profile renal cortex and medulla metabolites of rat after receiving a single dose of cisplatin (2.5, 5 or 10 mg/kg). Eventually, 53 and 55 differential metabolites in cortex and medulla were screened out, respectively. Random forest, orthogonal partial least squares-discriminant analysis and metabolic cumulative fold change analysis revealed that metabolic changes in medulla were more obviously dose-dependent than those in cortex, which confirmed the conclusion that medulla was more sensitive to cisplatin exposure. Furthermore, 29 intermediates were recognized as the most contributive metabolites for the sensitivity difference. Metabolic pathways interrupted by cisplatin mainly included amino acid, energy, lipid, pyrimidine, purine, and creatine metabolism. Our findings provide new insight into the mechanism study of cisplatin-induced nephrotoxicity. PMID:28300186

  10. Complex cisplatin-double strand break (DSB) lesions directly impair cellular non-homologous end-joining (NHEJ) independent of downstream damage response (DDR) pathways.

    PubMed

    Sears, Catherine R; Turchi, John J

    2012-07-13

    The treatment for advanced stage non-small cell lung cancer (NSCLC) often includes platinum-based chemotherapy and IR. Cisplatin and IR combination therapy display schedule and dose-dependent synergy, the mechanism of which is not completely understood. In a series of in vitro and cell culture assays in a NSCLC model, we investigated both the downstream and direct treatment and damage effects of cisplatin on NHEJ catalyzed repair of a DNA DSB. The results demonstrate that extracts prepared from cisplatin-treated cells are fully capable of NHEJ catalyzed repair of a DSB using a non-cisplatin-damaged DNA substrate in vitro. Similarly, using two different host cell reactivation assays, treatment of cells prior to transfection of a linear, undamaged reporter plasmid revealed no reduction in NHEJ compared with untreated cells. In contrast, transfection of a linear GFP-reporter plasmid containing site-specific, cisplatin lesions 6-bp from the termini revealed a significant impairment in DSB repair of the cisplatin-damaged DNA substrates in the absence of cellular treatment with cisplatin. Together, these data demonstrate that impaired NHEJ in combined cisplatin-IR treated cells is likely the result of a direct effect of cisplatin-DNA lesions near a DSB and that the indirect cellular effects of cisplatin treatment are not significant contributors to the synergistic cytotoxicity observed with combination cisplatin-IR treatment.

  11. Reversal of multidrug resistance in human lung cancer cells by delivery of 3-octadecylcarbamoylacrylic acid–cisplatin-based liposomes

    PubMed Central

    Song, Juan; Ren, Weifang; Xu, Tingting; Zhang, Yi; Guo, Hongyu; Zhu, Shanshan; Yang, Li

    2017-01-01

    Liposome-based drug delivery system would be an innovative and promising candidate to circumvent multidrug resistance (MDR) of cisplatin (CDDP). However, the reversal efficacy of liposomal CDDP was severely impaired by weak cellular uptake and insufficient intracellular drug release. In this study, 3-octadecylcarbamoylacrylic acid–CDDP nanocomplex (OMI–CDDP–N)-based liposomes (OCP-L) with high cellular uptake and sufficient intracellular drug release were designed to circumvent MDR of lung cancer. OMI–CDDP–N was synthesized through a pH-sensitive monocarboxylato and an O→Pt coordinate bond, which is more efficient than CDDP. Also, OCP-L incorporated with OMI–CDDP–N could induce effective cellular uptake, enhanced nuclear distribution, and optimal cellular uptake kinetics. In particular, OCP-L presented superior effects on enhancing cell apoptosis and in vitro cytotoxicity in CDDP-resistant human lung cancer (A549/CDDP) cells. The mechanisms of MDR reversal in A549/CDDP cells by OCP-L could attribute to organic cation transporter 2 restoration, ATPase copper-transporting beta polypeptide suppression, hypoxia-inducible factor 1 α-subunit depletion, and phosphatidylinositol 3-kinase/Akt pathway inhibition. These results demonstrated that OCP-L may provide an effective delivery of CDDP to resistant cells to circumvent MDR and enhance the therapeutic index of the chemotherapy. PMID:28255230

  12. Cisplatin Injection

    MedlinePlus

    Cisplatin is used combination with other medications to treat cancer of the testicles that has not improved ... after treatment with other medications or radiation therapy. Cisplatin is used alone or in combination with other ...

  13. What Is the Most Effective Drug Delivery System for Cisplatin during the Treatment of Hepatic Tumors with Single-Session Transcatheter Chemotherapy? A Pilot Study

    PubMed Central

    Ikeda, Kenji; Fukushima, Taito; Seko, Yuya; Hara, Tasuku; Sezaki, Hitomi; Hosaka, Tetsuya; Akuta, Norio; Kobayashi, Masahiro; Saitoh, Satoshi; Suzuki, Fumitaka; Suzuki, Yoshiyuki; Arase, Yasuji; Kumada, Hiromitsu

    2013-01-01

    Background/Aims The aim of this study was to determine the pharmacodynamics of cisplatin following three different treatment procedures for intrahepatic arterial infusion therapy for hepatocellular carcinoma (HCC). Methods We divided 13 HCC patients into the following three groups: group A, lone injection of cisplatin (n=3); group B, combined injection of cisplatin and lipiodol, with embolization using small gelatin cubes (GCs) (n=5); and group C, injection of suspended lipiodol with cisplatin powder, with embolization using small GCs (n=5). In each group, the free cisplatin concentration in the hepatic vein was measured at 0, 5, 10, and 30 minutes. Results The mean free cisplatin concentrations were as follows. For group A, the mean was 48.58 µg/mL at 0 minute, 7.31 µg/mL at 5 minutes, 5.70 µg/mL at 10 minutes, and 7.15 µg/mL at 30 minutes. For the same time points, for group B, the concentrations were 8.66, 4.23, 3.22, and 1.65 µg/mL, respectively, and for group C, the concentrations were 4.81, 2.61, 2.52, and 1.75 µg/mL, respectively. The mean area under the curve (AUC)0-infinity for the free cisplatin concentration was 7.80 in group A, 2.48 in group B, and 2.27 in group C. The AUC0-infinity for the free cisplatin concentration gradually decreased, from group A to group C. Conclusions These results indicate that the combination of lipiodol and small GCs may be useful for delaying cisplatin drainage from the liver. PMID:24073316

  14. A 2-DE-based proteomic study on the toxicological effects of cisplatin in L02 cells.

    PubMed

    Liu, Shu; Wang, Wei; Zhou, Xueyi; Ding, Zongli; Gu, Runhuan

    2015-01-01

    Cisplatin is a chemotherapeutic agent for the treatment of various cancers. In this study, cisplatin-induced effects were characterized in vitro model of human liver cells (L02) using 2-DE-based proteomics. Results indicated that different cisplatin treatments primarily induced disturbances in protein synthesis and oxidative stress via differential mechanisms. Since the experimental concentrations of cisplatin described a hormesis effect in cell proliferation of L02 cells, it was expected to reveal the hormesis effects using proteomic markers. However, only confilin-1 was commonly up-regulated in three concentrations of cisplatin treatments showing a hormesis effects with a U-shape regulation. These results were highly consistent with many other toxico-proteomic studies, indicating that the toxico-proteomic responses based on dose-dependent protein responses were incongruent with the theoretically linear or hormetic concentration-effect relationship. Our findings suggested that a macroscopic hormesis phenomenon on the cell proliferation could not be reflected by proteomic responses induced by cisplatin treatments.

  15. Paclitaxel and platinum-based chemotherapy results in transient dyslipidemia in cancer patients

    PubMed Central

    Wang, Guoping; Su, Chao; Yin, Tao

    2017-01-01

    Paclitaxel and cisplatin (TP) are common chemotherapeutic agents extensively used for treating lung and esophageal cancers. The present study reported three patients with transient hypertriglyceridemia (HTG) following TP chemotherapy. Serum triglyceride (TG) levels returned to baseline at chemotherapy intermission. No patient had any history of HTG or any evidence of pancreatitis or other complications of HTG. No regular elevation of any other serum lipids, including cholesterol, high-density lipoprotein and low-density lipoprotein, was observed. However, treatment of mice with TP decreased TG and slightly increased cholesterol. The findings of the present study suggested that TP chemotherapy results in transient dyslipidemia, and physicians must monitor TG levels during chemotherapy to avoid TG-associated complications. PMID:28357107

  16. 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.

  17. RTOG 0417: Efficacy of Bevacizumab in Combination With Definitive Radiation Therapy and Cisplatin Chemotherapy in Untreated Patients With Locally Advanced Cervical Carcinoma

    SciTech Connect

    Schefter, Tracey; Winter, Kathryn; Kwon, Janice S.; Stuhr, Kelly; Balaraj, Khalid; Yaremko, Brian Patrick; Small, William; Sause, William; Gaffney, David

    2014-01-01

    Purpose: Radiation Therapy Oncology Group 0417 was a phase II study that explored the safety and efficacy of the addition of bevacizumab to chemoradiation therapy. The safety results have been previously reported. Herein we report the secondary efficacy endpoints of overall survival (OS), locoregional failure (LRF), para-aortic nodal failure (PAF), distant failure (DF), and disease-free survival (DFS). Methods and Materials: Eligible patients with bulky Stage IB-IIIB disease were treated with once-weekly cisplatin (40 mg/m{sup 2}) chemotherapy and standard pelvic radiation therapy and brachytherapy. Bevacizumab was administered at 10 mg/kg intravenously every 2 weeks for 3 cycles during chemoradiation. For OS, failure was defined as death of any cause and was measured from study entry to date of death. LRF was defined as any failure in the pelvis. PAF was defined as any para-aortic nodal failure. DF was analyzed both including and excluding PAF. DFS was measured from study entry to date of first LRF. DF was measured with or without PAF or death. OS and DFS were estimated by the Kaplan-Meier method, and LRF and DF rates were estimated by the cumulative incidence method. Results: 49 eligible patients from 28 institutions were enrolled between 2006 and 2009. The median follow-up time was 3.8 years (range, 0.8-6.0 years). The surviving patients had a median follow-up time of 3.9 years (range, 2.1-6.0 years). Most patients had tumors of International Federation of Gynecology and Obstetrics Stage IIB (63%), and 80% were squamous. The 3-year OS, DFS, and LRF were 81.3% (95% confidence interval [CI], 67.2%-89.8%), 68.7% (95% CI, 53.5%-79.8%), and 23.2% (95% CI, 11%-35.4%), respectively. The PAF, DF without PAF, and DF with PAF at 3 years were 8.4% (95% CI, 0.4%-16.3%), 14.7% (95% CI, 4.5%-24.9%), and 23.1% (95% CI 11.0%-35.2%), respectively. Conclusion: In this study, bevacizumab in combination with standard pelvic chemoradiation therapy for locally advanced cervical

  18. Feasibility of concurrent chemoradiotherapy with high-dose cisplatin after induction TPF chemotherapy in head and neck cancer: a critical review of the literature and the experience of the European Institute of Oncology.

    PubMed

    Alterio, D; Cossu Rocca, M; Russell-Edu, W; Dicuonzo, S; Fanetti, G; Marvaso, G; Preda, L; Zorzi, S; Verri, E; Nole', F; Jereczek-Fossa, B A

    2017-05-01

    Many concerns are related to the idea that the acute toxicity of induction chemotherapy (IC) performed with TPF (docetaxel, cisplatin, 5-fluorouracil) could reduce the ability to deliver the subsequent standard concurrent chemoradiotherapy (CRT) in head and neck cancer patients. We performed a critical review of the literature on the toxicity profile of the standard CRT administered after the IC with TPF. A total of 13 papers (including 950 patients) were selected. Results showed that most patients were treated with an adequate radiation total dose although a significant proportion of them (from 15 to 30%) completed the planned treatment with a delay of more than 5 days. A minority of patients were able to be treated with three cycles of concurrent cisplatin, but only few papers reported how many of patients reached the cumulative total dose of almost 200 mg/m(2) cisplatin. The rate of deaths due to treatment-related toxicity varied from 0 to 9% (median and mean 2%). Two prospective trials stopped patient enrollment due to acute treatment-related toxicity and because a low number of patients were able to undergo the planned full schedule of cisplatin during the CRT, respectively. Retrospective analysis of 45 patients treated at our institute showed that this schedule was feasible with manageable side effects. In conclusion, the literature data did not provide homogeneous information on the feasibility of the standard CRT after induction TPF. A more uniform data collection of treatment-related toxicity will be helpful in better selecting the patients who might adequately tolerate this multimodality strategy.

  19. Urinary neutrophil gelatinase-associated lipocalin levels predict cisplatin-induced acute kidney injury better than albuminuria or urinary cystatin C levels.

    PubMed

    Lin, Hugo You-Hsien; Lee, Su-Chu; Lin, Sheng-Fung; Hsiao, Hui-Hua; Liu, Yi-Chang; Yang, Wen-Chi; Hwang, Daw-Yang; Hung, Chi-Chih; Chen, Hung-Chun; Guh, Jinn-Yuh

    2013-06-01

    Cisplatin-induced acute kidney injury (AKI) is a major concern among clinicians in prescribing cisplatin-based chemotherapy. This study evaluated and compared the ability of urinary biomarkers, including urinary neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, and the urinary albumin to creatinine ratio (ACR) to predict cisplatin-induced AKI. Thirty-three cancer patients receiving cisplatin-based chemotherapy were prospectively studied, including 10 (30%) who developed AKI (the study group). Changes of urinary biomarkers were compared at 4 hours, 8 hours, and 12 hours, and 1 day, 2 days, 3 days, and 4 days after cisplatin intravenous infusions (75mg/m(2)) versus the baseline. There was a significant increase in urinary NGAL levels from 12 hours to 4 days (p<0.05) compared to baseline after cisplatin infusion in the AKI group. The magnitude of these changes over time differed significantly by group (p<0.001). The area under the receiver operating curve describing the relationship between urinary NGAL levels and AKI within 12 hours was 0.865 (95% confidence interval=0.691-1.000). Urinary NGAL levels independently predicted AKI 12 hours after cisplatin (p=0.045) after adjustments for age, gender, body mass index, baseline serum creatinine, and urinary total protein. Urinary NGAL levels may be an early biomarker of AKI in patients receiving cisplatin-based treatment.

  20. Paclitaxel plus cisplatin vs. 5-fluorouracil plus cisplatin as first-line treatment for patients with advanced squamous cell esophageal cancer.

    PubMed

    Liu, Ying; Ren, Zhonghai; Yuan, Long; Xu, Shuning; Yao, Zhihua; Qiao, Lei; Li, Ke

    2016-01-01

    Paclitaxel plus cisplatin and 5-fluorouracil plus cisplatin treatments are effective strategies for patients with advanced esophageal squamous cell carcinoma. This study was to evaluate the safety and efficacy of paclitaxel plus cisplatin and 5-fluorouracil plus cisplatin as first-line chemotherapy for patients with advanced esophageal squamous cell carcinoma. A total of 398 patients with advanced esophageal squamous cell carcinoma who received chemotherapy were included and divided into 2 groups: paclitaxel plus cisplatin group and 5-fluorouracil plus cisplatin group. 195 patients received paclitaxel plus cisplatin and 203 patients received 5-fluorouracil plus cisplatin. The objective response rates were 42.5% and 38.4% for paclitaxel plus cisplatin group and 5-fluorouracil plus cisplatin group, respectively (P=0.948). The median progression-free survival was 7.85 months (95% CI, 6.77-8.94 months) for the paclitaxel plus cisplatin group and 6.53 months (95% CI, 5.63-7.43 months) for the 5-fluorouracil plus cisplatin group with significant difference (P=0.02). The median overall survival was 13.46 months (95% CI, 12.01-14.91 months) for the paclitaxel plus cisplatin group and 12.67 months (95% CI, 11.87-13.47 months) for the 5-fluorouracil plus cisplatin group (P=0.204). The first-line chemotherapy of paclitaxel plus cisplatin had better median progression-free survival than 5-fluorouracil plus cisplatin in patients with advanced esophageal squamous cell carcinoma with tolerable toxicities.

  1. The effects of miR-1207-5p expression in peripheral blood on cisplatin-based chemosensitivity of primary gallbladder carcinoma

    PubMed Central

    Shen, Er-Dong; Liu, Bo; Yu, Xin-Shuang; Xiang, Zhen-Fei; Huang, Hui-Yun

    2016-01-01

    Objective The aim of this study was to investigate the association between miR-1207-5p expression in peripheral blood and the chemosensitivity of primary gallbladder carcinoma (PGBC). Methods A total of 85 patients with PGBC undergoing preoperative chemotherapy were divided into effective (n=18) and ineffective (n=67) groups. Another 70 healthy individuals were selected as the control group. An miR-1207-5p mimic (mimic group), an inhibitor (inhibitor group), and a negative control (NC group) sequence were transfected into human gallbladder carcinoma GBC-SD cells. Real-time quantitative polymerase chain reaction was used to determine miR-1207-5p expression. After 48 hours of cisplatin treatment, CCK-8 method was used to detect cell proliferation and flow cytometry were performed to examine cell apoptosis. Results miR-1207-5p expression in peripheral blood was significantly associated with tumor node metastasis staging of PGBC (P<0.05). Before chemotherapy, miR-1207-5p expression in patients was higher than in healthy individuals (P<0.05). After chemotherapy, the effective group had lower miR-1207-5p expression than the ineffective group (P<0.05). The rates of positive expression of Ki67 protein in the effective group were significantly lower than those in the ineffective group (P<0.05). Receiver operating characteristic curves showed that the area under curve, sensitivity, and specificity of miR-1207-5p used to diagnose PGBC were 0.898, 77.6%, and 97.1% at a cutoff of 1.470, respectively. After 48 hours of cisplatin treatment, compared with the NC group and nontransfected (non-T) group, the mimic group had decreased rates of cell inhibition and apoptosis, but the inhibitor group had increased rates (all P<0.05). The expression levels of caspase3 protein were increased in the mimic group and decreased in the inhibitor group. Cell survival rates in the mimic group at different time points after cisplatin treatment were significantly higher than the corresponding rates

  2. Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell

    SciTech Connect

    Xu, Ning; Zhang, Jianjun; Shen, Conghuan; Luo, Yi; Xia, Lei; Xue, Feng; Xia, Qiang

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer miR-199a-5p levels were significantly decreased after cisplatin treatment. Black-Right-Pointing-Pointer Cisplatin treatment induced autophagy activation. Black-Right-Pointing-Pointer Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell. -- Abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Systemic chemotherapy plays an important role in the treatment of patients with advanced liver cancer. However, chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic, and the underlying mechanism of such resistance is not fully understood. In the study, we found that miR-199a-5p levels were significantly reduced in HCC patients treated with cisplatin-based chemotherapy. Cisplatin treatment also resulted in decreased miR-199a-5p levels in human HCC cell lines. Forced expression of miR-199a-5p promoted cisplatin-induced inhibition of cell proliferation. Cisplatin treatment activated autophagy in Huh7 and HepG2 cells, which increased cell proliferation. We further demonstrated that downregulated miR-199a-5p enhanced autophagy activation by targeting autophagy-associated gene 7 (ATG7). More important, autophagy inhibition abrogated miR-199a-5p downregulation-induced cell proliferation. These data demonstrated that miR-199a-5p/autophagy signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC.

  3. Empirical force field for cisplatin based on quantum dynamics data: case study of new parameterization scheme for coordination compounds.

    PubMed

    Yesylevskyy, S; Cardey, Bruno; Kraszewski, S; Foley, Sarah; Enescu, Mironel; da Silva, Antônio M; Dos Santos, Hélio F; Ramseyer, Christophe

    2015-10-01

    Parameterization of molecular complexes containing a metallic compound, such as cisplatin, is challenging due to the unconventional coordination nature of the bonds which involve platinum atoms. In this work, we develop a new methodology of parameterization for such compounds based on quantum dynamics (QD) calculations. We show that the coordination bonds and angles are more flexible than in normal covalent compounds. The influence of explicit solvent is also shown to be crucial to determine the flexibility of cisplatin in quantum dynamics simulations. Two empirical topologies of cisplatin were produced by fitting its atomic fluctuations against QD in vacuum and QD with explicit first solvation shell of water molecules respectively. A third topology built in a standard way from the static optimized structure was used for comparison. The later one leads to an excessively rigid molecule and exhibits much smaller fluctuations of the bonds and angles than QD reveals. It is shown that accounting for the high flexibility of cisplatin molecule is needed for adequate description of its first hydration shell. MD simulations with flexible QD-based topology also reveal a significant decrease of the barrier of passive diffusion of cisplatin accross the model lipid bilayer. These results confirm that flexibility of organometallic compounds is an important feature to be considered in classical molecular dynamics topologies. Proposed methodology based on QD simulations provides a systematic way of building such topologies.

  4. Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy

    PubMed Central

    Chen, Helen HW; Chen, Wen-Chung; Liang, Zhang-Dong; Tsai, Wen-Bin; Long, Yan; Aiba, Isamu; Fu, Siqing; Broaddus, Russell; Liu, Jinsong; Feun, Lynn G; Savaraj, Niramol; Kuo, Macus Tien

    2016-01-01

    Introduction Platinum (Pt)-based antitumor agents remain important chemotherapeutic agents for treating many human malignancies. Elevated expression of the human high-affinity copper transporter 1 (hCtr1), resulting in enhanced Pt drug transport into cells, has been shown to be associated with improved treatment efficacy. Thus, targeting hCtr1 upregulation is an attractive strategy for improving the treatment efficacy of Pt-based cancer chemotherapy. Area covered Regulation of hCtr1 expression by cellular copper homeostasis is discussed. Association of elevated hCtr1 expression with intrinsic sensitivity of ovarian cancer to Pt drugs is presented. Mechanism of copper-lowering agents in enhancing hCtr1-mediated cis-diamminedichloroplatinum (II) (cisplatin, cDDP) transport is reviewed. Applications of copper chelation strategy in overcoming cDDP resistance through enhanced hCtr1 expression are evaluated. Expert opinion While both transcriptional and posttranslational mechanisms of hCtr1 regulation by cellular copper bioavailability have been proposed, detailed molecular insights into hCtr1 regulation by copper homeostasis remain needed. Recent clinical study using a copper-lowering agent in enhancing hCtr1-mediated drug transport has achieved incremental improvement in overcoming Pt drug resistance. Further improvements in identifying predictive measures in the subpopulation of patients that can benefit from the treatment are needed. PMID:26004625

  5. Selective activation of SHP2 activity by cisplatin revealed by a novel chemical probe-based assay

    SciTech Connect

    Kuo, Chun-Chen; Chu, Chi-Yuan; Lin, Jing-Jer; Lo, Lee-Chiang

    2010-01-01

    Src homology-2 (SH2) domain-containing phosphatase 2 (SHP2) is known to participate in several different signaling pathways to mediate cell growth, survival, migration, and differentiation. However, due to the lack of proper analytical tools, it is unclear whether the phosphatase activity of SHP2 is activated in most studies. We have previously developed an activity-based probe LCL2 that formed covalent linkage with catalytically active protein tyrosine phosphatases (PTPs). Here, by combining LCL2 with a SHP2 specific antibody, we established an assay system that enables the direct monitoring of SHP2 activity upon cisplatin treatment of cancer cells. The protocol is advantageous over conventional colorimetric or in-gel PTP assays as it is specific and does not require the use of radioisotope reagents. Using this assay, we found SHP2 activity was selectively activated by cisplatin. Moreover, the activation of SHP2 appeared to be specific for cisplatin as other DNA damage agents failed to activate the activity. Although the role of SHP2 activation by cisplatin treatments is still unclear to us, our results provide the first direct evidence for the activation of SHP2 during cisplatin treatments. More importantly, the concept of using activity-based probe in conjunction with target-specific antibodies could be extended to other enzyme classes.

  6. Enhancement of cisplatin efficacy by thalidomide in a 9L rat gliosarcoma model.

    PubMed

    Murphy, Susan; Davey, Ross A; Gu, Xiao-Qing; Haywood, Miriam C; McCann, Lauren A; Mather, Laurence E; Boyle, Frances M

    2007-11-01

    With the aim of improving the treatment of glioblastoma multiforme, we investigated the potential of thalidomide to enhance the effectiveness of cisplatin chemotherapy in a rat glioma model. Female F344 rats were implanted with 9L gliosarcoma tumors either intracranially or subcutaneously and treated with 1 mg/kg cisplatin injected i.p. or with 1% thalidomide in the food or with these treatments combined. Cisplatin in combination with thalidomide significantly reduced both the subcutaneous tumor volume at 30 days to 22 +/- 5% (mean +/- SEM, P < 0.001) and the intracranial tumor volume at 18 days to 44 +/- 15% (P < 0.05) of that with cisplatin alone. Thalidomide selectively increased the cisplatin concentration 10-fold in intracranial tumors (P < 0.05) and 2-fold in the subcutaneous tumors (P < 0.05) without increasing its concentration in major organs including brain and kidney. Cisplatin combined with thalidomide caused a significant decrease in vascular endothelial growth factor (VEGF) levels by 73% in intracranial tumors (P < 0.05) and by 50% in subcutaneous tumors (P < 0.05) and caused the level of active hepatic growth factor (a-HGF) to double in both the subcutaneous and intracranial tumors (P < 0.05), suggesting this treatment altered the vasculature in these tumors. We conclude the increased efficacy of cisplatin in the presence of thalidomide was due to the selective increase in cisplatin concentration within the tumors and speculate that this is the result of thalidomide or the cisplatin/thalidomide combination, selectively altering the tumor vasculature. Based on the selective effects of thalidomide on tumor cisplatin concentrations and the resulting increase in efficacy, thalidomide may also increase the efficacy of other drugs that are presently considered ineffective against glioma.

  7. Similar cisplatin sensitivity of HPV-positive and -negative HNSCC cell lines

    PubMed Central

    Kriegs, Malte; Gatzemeier, Fruzsina; Krüger, Katharina; Möckelmann, Nikolaus; Fritz, Gerhard; Petersen, Cordula; Knecht, Rainald; Rothkamm, Kai; Rieckmann, Thorsten

    2016-01-01

    Patients with HPV-positive head and neck squamous cell carcinoma (HNSCC) show better survival rates than those with HPV-negative HNSCC. While an enhanced radiosensitivity of HPV-positive tumors is clearly evident from single modality treatment, cisplatin is never administered as monotherapy and therefore its contribution to the enhanced cure rates of HPV-positive HNSCC is not known. Both cisplatin and radiotherapy can cause severe irreversible side effects and therefore various clinical studies are currently testing deintensified regimes for patients with HPV-positive HNSCC. One strategy is to omit cisplatin-based chemotherapy or replace it by less toxic treatments but the risk assessment of these approaches remains difficult. In this study we have compared the cytotoxic effects of cisplatin in a panel of HPV-positive and -negative HNSCC cell lines alone and when combined with radiation. While cisplatin-treated HPV-positive strains showed a slightly stronger inhibition of proliferation, there was no difference regarding colony formation. Cellular responses to the drug, namely cell cycle distribution, apoptosis and γH2AX-induction did not differ between the two entities but assessment of cisplatin-DNA-adducts suggests differences regarding the mechanisms that determine cisplatin sensitivity. Combining cisplatin with radiation, we generally observed an additive but only in a minority of strains from both entities a clear synergistic effect on colony formation. In summary, HPV-positive and -negative HNSCC cells were equally sensitive to cisplatin. Therefore replacing cisplatin may be feasible but the substituting agent should be of similar efficacy in order not to jeopardize the high cure rates for HPV-positive HNSCC. PMID:27127883

  8. 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.

  9. Chemotherapy for bladder cancer: treatment guidelines for neoadjuvant chemotherapy, bladder preservation, adjuvant chemotherapy, and metastatic cancer.

    PubMed

    Sternberg, Cora N; Donat, S Machele; Bellmunt, Joaquim; Millikan, Randall E; Stadler, Walter; De Mulder, Pieter; Sherif, Amir; von der Maase, Hans; Tsukamoto, Taiji; Soloway, Mark S

    2007-01-01

    To determine the optimal use of chemotherapy in the neoadjuvant, adjuvant, and metastatic setting in patients with advanced urothelial cell carcinoma, a consensus conference was convened by the World Health Organization (WHO) and the Société Internationale d'Urologie (SIU) to critically review the published literature on chemotherapy for patients with locally advanced bladder cancer. This article reports the development of international guidelines for the treatment of patients with locally advanced bladder cancer with neoadjuvant and adjuvant chemotherapy. Bladder preservation is also discussed, as is chemotherapy for patients with metastatic urothelial cancer. The conference panel consisted of 10 medical oncologists and urologists from 3 continents who are experts in this field and who reviewed the English-language literature through October 2004. Relevant English-language literature was identified with the use of Medline; additional cited works not detected on the initial search regarding neoadjuvant chemotherapy, bladder preservation, adjuvant chemotherapy, and chemotherapy for patients with metastatic urothelial cancer were reviewed. Evidence-based recommendations for diagnosis and management of the disease were made with reference to a 4-point scale. Results of the authors' deliberations are presented as a consensus document. Meta-analysis of randomized trials on cisplatin-containing combination neoadjuvant chemotherapy revealed a 5% difference in favor of neoadjuvant chemotherapy. No randomized trials have yet compared survival with transurethral resection of bladder tumor alone versus cystectomy for the management of patients with muscle-invasive disease. Collaborative international adjuvant chemotherapy trials are needed to assist researchers in assessing the true value of adjuvant chemotherapy. Systemic cisplatin-based combination chemotherapy is the only current modality that has been shown in phase 3 trials to improve survival in responsive patients

  10. Multicenter Phase II Study Evaluating Two Cycles of Docetaxel, Cisplatin and Cetuximab as Induction Regimen Prior to Surgery in Chemotherapy-Naive Patients with NSCLC Stage IB-IIIA (INN06-Study)

    PubMed Central

    Hilbe, Wolfgang; Pall, Georg; Kocher, Florian; Pircher, Andreas; Zabernigg, August; Schmid, Thomas; Schumacher, Michael; Jamnig, Herbert; Fiegl, Michael; Gächter, Anne; Freund, Martin; Kendler, Dorota; Manzl, Claudia; Zelger, Bettina; Popper, Helmut; Wöll, Ewald

    2015-01-01

    Background Different strategies for neoadjuvant chemotherapy in patients with early stage NSCLC have already been evaluated. The aim of this study was to evaluate the tolerability and efficacy of a chemoimmunotherapy when limited to two cycles. Methods Between 01/2007 and 03/2010 41 patients with primarily resectable NSCLC stage IB to IIIA were included. Treatment consisted of two cycles cisplatin (40 mg/m2 d1+2) and docetaxel (75 mg/m2 d1) q3 weeks, accompanied by the administration of cetuximab (400 mg/m2 d1, then 250 mg weekly). The primary endpoint was radiological response according to RECIST. Results 40 patients were evaluable for toxicity, 39 for response. The main grade 3/4 toxicities were: neutropenia 25%, leucopenia 11%, febrile neutropenia 6%, nausea 8% and rash 8%. 20 patients achieved a partial response, 17 a stable disease, 2 were not evaluable. 37 patients (95%) underwent surgery and in three of them a complete pathological response was achieved. At a median follow-up of 44.2 months, 41% of the patients had died, median progression-free survival was 22.5 months. Conclusions Two cycles of cisplatin/ docetaxel/ cetuximab showed promising efficacy in the neoadjuvant treatment of early-stage NSCLC and rapid operation was possible in 95% of patients. Toxicities were manageable and as expected. Trial Registration EU Clinical Trials Register; Eudract-Nr: 2006-004639-31 PMID:26020783

  11. Phase I trial of split-dose induction docetaxel, cisplatin, and 5-fluorouracil (TPF) chemotherapy followed by curative surgery combined with postoperative radiotherapy in patients with locally advanced oral and oropharyngeal squamous cell cancer (TISOC-1)

    PubMed Central

    2012-01-01

    Background Induction chemotherapy (ICT) with docetaxel, cisplatin and fluorouracil (TPF) followed by radiotherapy is an effective treatment option for unresectable locally advanced head and neck cancer. This phase I study was designed to investigate the safety and tolerability of a split-dose TPF ICT regimen prior to surgery for locally advanced resectable oral and oropharyngeal cancer. Methods Patients received TPF split on two dosages on day 1 and 8 per cycle for one or three 3-week cycles prior to surgery and postoperative radiotherapy or radiochemotherapy. Docetaxel was escalated in two dose levels, 40 mg/m2 (DL 0) and 30 mg/m2 (DL −1), plus 40 mg/m2 cisplatin and 2000 mg/m2 fluorouracil per week using a 3 +3 dose escalation algorithm. Results Eighteen patients were enrolled and were eligible for toxicity and response. A maximum tolerated dose of 30 mg/m2 docetaxel per week was reached. The most common grade 3+ adverse event was neutropenia during ICT in 10 patients. Surgery reached R0 resection in all cases. Nine patients (50%) showed complete pathologic regression. Conclusions A split-dose regime of TPF prior to surgery is feasible, tolerated and merits additional investigation in a phase II study with a dose of 30 mg/m docetaxel per week. Trial registration number NCT01108042 (ClinicalTrials.gov Identifier) PMID:23083061

  12. Urachal Carcinoma with Choroidal, Lung, Lymph Node, Adrenal, Mammary, and Bone Metastases and Peritoneal Carcinomatosis Showing Partial Response after Chemotherapy Treatment with a Modified Docetaxel, Cisplatin and 5-Fluorouracil Regimen

    PubMed Central

    Dekeister, Kathleen; Viguier, Jean Louis; Martin, Xavier; Nguyen, Anh Minh; Boyle, Helen; Flechon, Aude

    2016-01-01

    Urachal carcinoma (UC) is a rare tumor mainly affecting middle-aged males. Metastases occur most frequently in lymph nodes and the lungs. There are no standard adjuvant and metastatic treatments. We report the case of a 36-year-old female with UC treated with partial cystectomy who relapsed 3 years after surgery with left choroidal, lung, mediastinal lymph node, right adrenal, mammary, and bone metastases as well as peritoneal carcinomatosis. She obtained a partial response after 10 cycles of chemotherapy with a modified docetaxel, cisplatin and 5-fluorouracil (mTPF) regimen. This is the first report on the use of the mTPF regimen in UC and on the existence of choroidal, adrenal, and mammary metastases. PMID:27194981

  13. CKD-EPI and cockcroft-gault equations identify similar candidates for neoadjuvant chemotherapy in muscle-invasive bladder cancer.

    PubMed

    Pal, Sumanta K; Ruel, Nora; Villegas, Sergio; Chang, Mark; DeWalt, Kara; Wilson, Timothy G; Vogelzang, Nicholas J; Yuh, Bertram E

    2014-01-01

    Clinical guidelines suggest neoadjuvant cisplatin-based chemotherapy prior to cystectomy in the setting of muscle-invasive bladder cancer (MIBC). A creatinine clearance (CrCl) >60 mL/min is frequently used to characterize cisplatin-eligible patients, and use of the CKD-EPI equation to estimate CrCl has been advocated. From a prospectively maintained institutional database, patients with MIBC who received cystectomy were identified and clinicopathologic information was ascertained. CrCl prior to surgery was computed using three equations: (1) Cockcroft-Gault (CG), (2) CKD-EPI, and (3) MDRD. The primary objective was to determine if the CG and CKD-EPI equations identified a different proportion of patients who were cisplatin-eligible, based on an estimated CrCl of >60 mL/min. Cisplatin-eligibility was also assessed in subsets based on age, CCI score and race. Actuarial rates of neoadjuvant cisplatin-based chemotherapy use were also reported. Of 126 patients, 70% and 71% of patients were found to be cisplatin-eligible by the CKD-EPI and CG equations, respectively (P = 0.9). The MDRD did not result in significantly different characterization of cisplatin-eligibility as compared to the CKD-EPI and CG equations. In the subset of patients age >80, the CKD-EPI equation identified a much smaller proportion of cisplatin-eligible patients (25%) as compared to the CG equation (50%) or the MDRD equation (63%). Only 34 patients (27%) received neoadjuvant cisplatin-based chemotherapy. Of the 92 patients who did not receive neoadjuvant chemotherapy, 64% had a CrCl >60 mL/min by CG. In contrast to previous reports, the CKD-EPI equation does not appear to characterize a broader span of patients as cisplatin-eligible. Older patients (age >80) may less frequently be characterized as cisplatin-eligible by CKD-EPI. The discordance between actual rates of neoadjuvant chemotherapy use and rates of cisplatin eligibility suggest that other factors (e.g., patient and physician preference

  14. Neoadjuvant chemotherapy for invasive bladder cancer.

    PubMed

    Sonpavde, Guru; Sternberg, Cora N

    2012-04-01

    Neoadjuvant cisplatin-based combination chemotherapy is an established standard for resectable muscle-invasive bladder cancer, a disease with a pattern of predominantly distant and early recurrences. Pathologic complete remission appears to be an intermediate surrogate for survival when employing combination chemotherapy. Moreover, baseline host and tumor tissue studies may enable the discovery of biomarkers predictive of activity. The neoadjuvant setting also provides a window of opportunity to evaluate novel biologic agents or rational combinations of biologic agents to obtain a signal of biologic activity. The residual tumor after neoadjuvant therapy may be exploited to study the mechanism of action and resistance. Cisplatin-ineligible patients warrant the evaluation of tolerable neoadjuvant regimens. Given that bladder cancer is characterized by initial localized presentation in the vast majority of cases, the paradigm of neoadjuvant therapy may expedite the development of novel systemic agents.

  15. Structure Determination of Cisplatin-Amino Acid Analogues by Infrared Multiple Photon Dissociation Action Spectroscopy

    NASA Astrophysics Data System (ADS)

    He, Chenchen; Bao, Xun; Zhu, Yanlong; Strobehn, Stephen; Kimutai, Bett; Nei, Y.-W.; Chow, C. S.; Rodgers, M. T.; Gao, Juehan; Oomens, J.

    2015-06-01

    To gain a better understanding of the binding mechanism and assist in the optimization of relevant drug and chemical probe design, both experimental and theoretical studies were performed on a series of amino acid-linked cisplatin derivatives, including glycine-, lysine-, and ornithine-linked cisplatin, Gplatin, Kplatin, and Oplatin, respectively. Cisplatin, the first FDA-approved platinum-based anticancer drug, has been widely used in cancer chemotherapy. Its pharmacological mechanism has been identified as its ability to coordinate to genomic DNA, and guanine is its major target. In previous reports, cisplatin was successfully utilized as a chemical probe to detect solvent accessible sites in ribosomal RNA (rRNA). Among the amino-acid-linked cisplatin derivatives, Oplatin exhibits preference for adenine over guanine. The mechanism behind its different selectivity compared to cisplatin may relate to its potential of forming a hydrogen bond between the carboxylate group in Pt (II) complex and the 6-amino moiety of adenosine stabilizes A-Oplatin products. Tandem mass spectrometry analysis also indicates that different coordination sites of Oplatin on adenosine affect glycosidic bond stability. Infrared multiple photon dissociation (IRMPD) action spectroscopy experiments were performed on all three amino acid-linked cisplatin to characterize their structures. An extensive theoretical study has been performed on Gplatin to guide the selection of the most effective theory and basis set based on its geometric information. The results for Gplatin provide the foundation for characterization of the more complex amino acid-linked cisplatin derivatives, Oplatin and Kplatin. Structural and energetic information elucidated for these compounds, particularly Oplatin reveal the reason for its alternative selectivity compared to cisplatin.

  16. Correlation of long non-coding RNA H19 expression with cisplatin-resistance and clinical outcome in lung adenocarcinoma.

    PubMed

    Wang, Qi; Cheng, Ningning; Li, Xuefei; Pan, Hui; Li, Chunyu; Ren, Shengxiang; Su, Chunxia; Cai, Weijing; Zhao, Chao; Zhang, Limin; Zhou, Caicun

    2017-01-10

    The acquired drug resistance would influence the efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer. The present study aimed to investigate the correlation of long non-coding RNA (lncRNA) H19 with cisplatin-resistance and clinical outcome in lung adenocarcinoma. In our study, the expression of H19 in cisplatin-resistant A549/DDP cells was unregulated. Knockdown of H19 restored the response of A549/DDP cells to cisplatin. H19-mediated chemosensitivity enhancement was associated with metastasis, induction of G0/G1 cell-cycle arrest, cell proliferation, and increased apoptosis. Furthermore, lncRNA H19 expression was significantly related to TNM stage and metastasis (P = 0.012). Overexpression of H19 was negatively correlated with cisplatin-based chemotherapy response in patients. Patients with high H19 expression exhibited a significantly shorter median progression-free survival (PFS) [4.7 months] than the low-expression patients (6.3months) [P = 0.002]. In summary, H19-mediated regulation of cisplatin resistance in human lung adenocarcinoma cells is demonstrated for the first time. H19 could potentially serve as a molecular marker to predict the clinical outcomes of lung adenocarcinoma patients.

  17. Doublet chemotherapy with cisplatin and pemetrexed is associated with a favorable outcome in patients with advanced non-squamous non-small-cell lung cancer who are eligible for bevacizumab and maintenance therapy

    PubMed Central

    Nakashima, Kazuhisa; Murakami, Haruyasu; Omori, Shota; Wakuda, Kazushige; Ono, Akira; Kenmotsu, Hirotsugu; Naito, Tateaki; Endo, Masahiro; Takahashi, Toshiaki

    2016-01-01

    The previous AVAPERL trial demonstrated that induction therapy with first-line cisplatin (CDDP), pemetrexed (PEM) and bevacizumab (BEV), followed by continuation maintenance therapy with PEM+BEV, improved the progression-free survival (PFS) and overall survival (OS) compared with BEV alone (median PFS, 10.2 vs. 6.6 months and median OS, 19.8 vs. 15.9 months, respectively) in patients with advanced non-squamous non-small-cell lung cancer (non-Sq NSCLC). However, those findings were based on selected patients who were eligible for BEV and maintenance therapy. To assess the efficacy of CDDP+PEM as first-line therapy in selected patients depending on their eligibility for BEV and maintenance therapy, consecutive patients with non-Sq NSCLC who received first-line chemotherapy with CDDP+PEM at the Shizuoka Cancer Center (Shizuoka, Japan) between July, 2009 and December, 2013 were retrospectively reviewed. A total of 160 patients were assessed, including 92 who were eligible and 68 who were not eligible for BEV treatment. In the BEV-eligible group, CDDP+PEM treatment followed by maintenance PEM exhibited significantly superior efficacy compared with that in the BEV-ineligible group (median PFS, 5.8 vs. 4.8 months, respectively, P=0.013; and median OS, 21.3 vs. 12.6 months, respectively, P=0.0025). In the BEV-eligible group, 60 patients were suitable for maintenance therapy with PEM (group A) and 32 patients were unsuitable (group B). In the BEV-ineligible group, 31 patients were suitable for maintenance therapy with PEM (group C) and 37 patients were unsuitable (group D). In group A, the median PFS and OS were 6.9 and 31.8 months, respectively, compared with 2.4 and 10.5 months in group B, 6.1 and 18.5 months in group C, and 2.8 and 7.7 months in group D. The PFS and OS in group A were significantly better compared with those in the other groups. Thus, the PFS and OS with CDDP+PEM were favorable among patients with advanced non-Sq NSCLC who were eligible for BEV and

  18. Doublet chemotherapy with cisplatin and pemetrexed is associated with a favorable outcome in patients with advanced non-squamous non-small-cell lung cancer who are eligible for bevacizumab and maintenance therapy.

    PubMed

    Nakashima, Kazuhisa; Murakami, Haruyasu; Omori, Shota; Wakuda, Kazushige; Ono, Akira; Kenmotsu, Hirotsugu; Naito, Tateaki; Endo, Masahiro; Takahashi, Toshiaki

    2016-11-01

    The previous AVAPERL trial demonstrated that induction therapy with first-line cisplatin (CDDP), pemetrexed (PEM) and bevacizumab (BEV), followed by continuation maintenance therapy with PEM+BEV, improved the progression-free survival (PFS) and overall survival (OS) compared with BEV alone (median PFS, 10.2 vs. 6.6 months and median OS, 19.8 vs. 15.9 months, respectively) in patients with advanced non-squamous non-small-cell lung cancer (non-Sq NSCLC). However, those findings were based on selected patients who were eligible for BEV and maintenance therapy. To assess the efficacy of CDDP+PEM as first-line therapy in selected patients depending on their eligibility for BEV and maintenance therapy, consecutive patients with non-Sq NSCLC who received first-line chemotherapy with CDDP+PEM at the Shizuoka Cancer Center (Shizuoka, Japan) between July, 2009 and December, 2013 were retrospectively reviewed. A total of 160 patients were assessed, including 92 who were eligible and 68 who were not eligible for BEV treatment. In the BEV-eligible group, CDDP+PEM treatment followed by maintenance PEM exhibited significantly superior efficacy compared with that in the BEV-ineligible group (median PFS, 5.8 vs. 4.8 months, respectively, P=0.013; and median OS, 21.3 vs. 12.6 months, respectively, P=0.0025). In the BEV-eligible group, 60 patients were suitable for maintenance therapy with PEM (group A) and 32 patients were unsuitable (group B). In the BEV-ineligible group, 31 patients were suitable for maintenance therapy with PEM (group C) and 37 patients were unsuitable (group D). In group A, the median PFS and OS were 6.9 and 31.8 months, respectively, compared with 2.4 and 10.5 months in group B, 6.1 and 18.5 months in group C, and 2.8 and 7.7 months in group D. The PFS and OS in group A were significantly better compared with those in the other groups. Thus, the PFS and OS with CDDP+PEM were favorable among patients with advanced non-Sq NSCLC who were eligible for BEV and

  19. Reduced expression of microRNA-27a modulates cisplatin resistance in bladder cancer by targeting the cystine/glutamate exchanger SLC7A11

    PubMed Central

    Drayton, Ross M; Dudziec, Ewa; Peter, Stefan; Bertz, Simone; Hartmann, Arndt; Bryant, Helen E; Catto, James WF

    2014-01-01

    Purpose Resistance to cisplatin-based chemotherapy is a major obstacle to bladder cancer treatment. We aimed to identify microRNAs that are dysregulated in cisplatin-resistant disease, ascertain how these contribute to a drug resistant phenotype and how this resistance might be overcome. Experimental Design MicroRNA expression in paired cisplatin resistant and sensitive cell lines was measured. Dysregulated microRNAs were further studied for their ability to mediate resistance. The nature of the cisplatin resistant phenotype was established by measurement of cisplatin/DNA adducts and intracellular glutathione. Candidate microRNAs were examined for their ability to (i) mediate resistance and (ii) alter the expression of a candidate target protein (SLC7A11); direct regulation of SLC7A11 was confirmed using a luciferase assay. SLC7A11 protein and mRNA, and microRNA-27a were quantified in patient tumour material. Results A panel of microRNAs were found to be dysregulated in cisplatin resistant cells. MicroRNA-27a was found to target the cystine/glutamate exchanger SLC7A11 and to contribute to cisplatin resistance through modulation of glutathione biosynthesis. In patients, SLC7A11 expression was inversely related to microRNA-27a expression, and those tumors with high mRNA expression or high membrane staining for SLC7A11 experienced poorer clinical outcomes. Resistant cell lines were resensitized by restoring microRNA-27a expression, or reducing SLC7A11 activity with an siRNA or with sulfasalazine. Conclusion Our findings indicate that microRNA-27a negatively regulates SLC7A11 in cisplatin-resistant bladder cancer, and shows promise as a marker for patients likely to benefit from cisplatin-based chemotherapy. SLC7A11 inhibition with sulfasalazine may be a promising therapeutic approach to the treatment of cisplatin-resistant disease. PMID:24516043

  20. Neoadjuvant chemotherapy for bladder cancer.

    PubMed

    Black, Peter C; Brown, Gordon A; Grossman, H Barton; Dinney, Colin P

    2006-11-01

    The 30-45% failure rate after radical cystoprostatectomy mandates that we explore and optimize multimodal therapy to achieve better disease control in these patients. Cisplatin-based multi-agent combination chemotherapy has been used with success in metastatic disease and has therefore also been introduced in patients with high-risk but non-metastatic bladder cancer. There is now convincing evidence that chemotherapy given pre-operatively can improve survival in these patients. In this review we establish the need for peri-operative chemotherapy in bladder cancer patients and summarize the evidence for the efficacy of neoadjuvant chemotherapy. The advantages and disadvantages of neoadjuvant versus adjuvant chemotherapy are discussed, and the main shortcomings of both--treatment-related toxicity and the inability to prospectively identify likely responders--are presented. Finally, a risk-adapted approach to neoadjuvant chemotherapy is presented, whereby the highest risk patients are offered treatment while those unlikely to benefit are spared the treatment-related toxicity.

  1. Feasibility of preoperative combined radiation therapy and chemotherapy with 5-fluorouracil and cisplatin in potentially resectable pancreatic adenocarcinoma: The French SFRO-FFCD 97-04 Phase II trial

    SciTech Connect

    Mornex, Francoise . E-mail: francoise.mornex@chu-lyon.fr; Girard, Nicolas; Scoazec, Jean-Yves; Bossard, Nadine; Ychou, Marc; Smith, Denis; Seitz, Jean-Francois; Valette, Pierre-Jean; Roy, Pascal; Rouanet, Philippe; Ducreux, Michel; Partensky, Christian

    2006-08-01

    Purpose More than 80% of patients who undergo a potentially curative resection for pancreatic cancer develop local or distant recurrence. Neoadjuvant chemoradiotherapy might offer potential benefits regarding local and systemic control and survival. This multi-institutional Phase II trial explored the feasibility of preoperative chemoradiation in this situation. Methods and Materials Treatment consisted of concurrent radiotherapy (50 Gy within 5 weeks), and chemotherapy with 5-fluorouracil (300 mg/m{sup 2}/day, 5 days/week, 5 consecutive weeks) and cisplatin (20 mg/m{sup 2}/day, Days 1-5 and 29-33), followed by surgical resection of the pancreatic tumor in patients without progression. Results A total of 41 patients were enrolled. Of these, 38 (93%) received {>=}47 Gy; 30 patients (73%) received {>=}75% of the prescribed doses of chemotherapy. Surgical resection was performed in 26 patients (63%). Because of local or metastatic progression, 5 patients (12%) did not undergo surgery and 10 underwent surgery without resection of the pancreatic tumor. Operative mortality was 2.8%. Among 40 evaluable patients, 27 were successfully treated (67.5%; 95% CI, 50.9-81.4%). Conclusions Pancreatic cancer is chemo-radiosensitive. The proposed pre-operative scheme is feasible, does not prevent successful surgery, and must be tested on a Phase III setting. Yet, the large proportion of tumor progression during and after chemoradiation justifies the use of more efficient drugs such as Gemcitabine, and optimized radiotherapy including new techniques such as intensity-modulated radiation therapy.

  2. [Preventive effect of polaprezinc suspension dispersed in sodium alginate solution (P-AG) for stomatitis induced by Docetaxel/Cisplatin/Fluorouracil (DCF) chemotherapy in patients with head and neck cancer].

    PubMed

    Sugisaki, Takahito; Kawakami, Kazuyoshi; Nemoto, Maki; Kawata, Keiji; Ishibashi, Michiko; Fujiki, Yukako; Mishima, Yuko; Yokoyama, Masahiro; Takahashi, Shunji; Hatake, Kiyohiko; Hama, Toshihiro

    2011-05-01

    We measured the effectiveness of the prophylactic administration of a polaprezinc suspension dispersed in sodium alginate solution (P-AG) by dividing it into two courses in the same patients, and measured the stomatitis induced by Docetaxel/Cisplatin/Fluorouracil (DCF) chemotherapy. We then evaluated the results. We defined the therapeutic course as the course where P-AG was given therapeutically for stomatitis induced after DCF chemotherapy. We defined the prophylactic course as when P-AG was prophylactically given before any incidences of stomatitis after the therapeutic course. We compared the incidences of stomatitis in the prophylactic courses with those of the therapeutic courses. The incidences of stomatitis that were higher than Grade 1 were 17 out of 17 patients (100%) in the therapeutic course. On the other hand, they were 15 out of 17 patients (88. 2%) in the prophylactic course. Compared with the mean of the Grade of Stomatitis by the Common Terminology Criteria for Adverse Events version 3. 0 (CTCAE v. 3. 0), the maximal Grade of stomatitis significantly decreased in the prophylactic courses compared to those of the therapeutic courses(p<0. 05). Therefore, these results suggested that we were able to decrease the severity of stomatitis by using P-AG prophylactically, as opposed to using P-AG therapeutically.

  3. Development of controlled-release cisplatin dry powders for inhalation against lung cancers.

    PubMed

    Levet, Vincent; Rosière, Rémi; Merlos, Romain; Fusaro, Luca; Berger, Gilles; Amighi, Karim; Wauthoz, Nathalie

    2016-12-30

    The present study focuses on the development of dry powders for inhalation as adjuvant chemotherapy in lung cancer treatment. Cisplatin was chosen as a potential candidate for a local treatment as it remains the main platinum component used in conventional chemotherapies, despite its high and cumulative systemic toxicities. Bulk cisplatin was reduced to submicron sizes using high-pressure homogenization, mixed with a solubilized lipid and/or PEGylated component and then spray-dried to produce controlled-release dry powder formulations. The obtained formulations were characterized for their physicochemical properties (particle size and morphology), aerodynamic performance and release profiles. Cisplatin content and integrity were assessed by electrothermal atomic absorption spectrometry and (195)Pt nuclear magnetic resonance spectroscopy. DPI formulations with cisplatin contents ranging from 48.5 to 101.0% w/w exhibited high fine particle fractions ranging from 37.3% to 51.5% of the nominal dose. Formulations containing cisplatin microcrystals dispersed in solid lipid microparticles based on acceptable triglycerides for inhalation and PEGylated excipients showed a controlled-release for more than 24h and a limited burst effect. These new formulations could provide an interesting approach to increasing and prolonging drug exposure in the lung while minimizing systemic toxicities.

  4. Resveratrol Attenuates Cisplatin Renal Cortical Cytotoxicity by Modifying Oxidative Stress

    PubMed Central

    Valentovic, Monica A.; Ball, John G.; Brown, J. Mike; Terneus, Marcus V.; McQuade, Elizabeth; Van Meter, Stephanie; Hedrick, Hayden M.; Roy, Amy Allison; Williams, Tierra

    2014-01-01

    Cisplatin, a cancer chemotherapy drug, is nephrotoxic. The aim of this study was to investigate whether resveratrol (RES) reduced cisplatin cytotoxicity and oxidative stress. Rat renal cortical slices were pre-incubated 30 min with 0 (VEH, ethanol) or 30 μg/ml RES followed by 60, 90 or 120 min co-incubation with 0, 75, or 150 μg/mL cisplatin. Lactate dehydrogenase (LDH) leakage was unchanged at 60 and 90 min by cisplatin. Cisplatin increased (p<0.05) LDH leakage at 120 min which was protected by RES. Cisplatin induced oxidative stress prior to LDH leakage as cisplatin depressed glutathione peroxidase and superoxide dismutase (SOD) activity, increased lipid peroxidation, protein carbonyls and 4-hydroxynonenal (4-HNE) adducted proteins within 60 min. RES failed to reverse glutathione (GSH) depression by cisplatin. In order to eliminated an extracellular interaction between RES and cisplatin, additional studies (RINSE studies) allowed a 30 min RES uptake into slices, transfer of slices to buffer lacking RES, followed by 120 min cisplatin incubation. RES in the RINSE studies prevented LDH leakage by cisplatin indicating that RES protection was not via a physical interaction with cisplatin in the media. These findings indicate that RES diminished cisplatin in vitro renal toxicity and prevented the development of oxidative stress. PMID:24239945

  5. Mobile Phone Based System Opportunities to Home-based Managing of Chemotherapy Side Effects

    PubMed Central

    Davoodi, Somayeh; Mohammadzadeh, Zeinab; Safdari, Reza

    2016-01-01

    Objective: Applying mobile base systems in cancer care especially in chemotherapy management have remarkable growing in recent decades. Because chemotherapy side effects have significant influences on patient’s lives, therefore it is necessary to take ways to control them. This research has studied some experiences of using mobile phone based systems to home-based monitor of chemotherapy side effects in cancer. Methods: In this literature review study, search was conducted with keywords like cancer, chemotherapy, mobile phone, information technology, side effects and self managing, in Science Direct, Google Scholar and Pub Med databases since 2005. Results: Today, because of the growing trend of the cancer, we need methods and innovations such as information technology to manage and control it. Mobile phone based systems are the solutions that help to provide quick access to monitor chemotherapy side effects for cancer patients at home. Investigated studies demonstrate that using of mobile phones in chemotherapy management have positive results and led to patients and clinicians satisfactions. Conclusion: This study shows that the mobile phone system for home-based monitoring chemotherapy side effects works well. In result, knowledge of cancer self-management and the rate of patient’s effective participation in care process improved. PMID:27482134

  6. BRCA1 epigenetic inactivation predicts sensitivity to platinum-based chemotherapy in breast and ovarian cancer

    PubMed Central

    Stefansson, Olafur A.; Villanueva, Alberto; Vidal, August; Martí, Lola; Esteller, Manel

    2012-01-01

    Germline mutations in the BRCA1 or BRCA2 genes are associated with an increased risk of breast and ovarian cancer development. Both genes are involved in DNA repair, and tumors harboring genetic defects in them are thought to be more sensitive to DNA-damaging agents used in chemotherapy. However, as only a minority of breast and ovarian cancer patients carry BRCA1 or BRCA2 mutations, few patients are likely to benefit from these pharmacogenetic biomarkers. Herein, we show that, in cancer cell lines and xenografted tumors, BRCA1 CpG island promoter hypermethylation-associated silencing also predicts enhanced sensitivity to platinum-derived drugs to the same extent as BRCA1 mutations. Most importantly, BRCA1 hypermethylation proves to be a predictor of longer time to relapse and improved overall survival in ovarian cancer patients undergoing chemotherapy with cisplatin. PMID:23069641

  7. Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialists' Group.

    PubMed Central

    Aabo, K.; Adams, M.; Adnitt, P.; Alberts, D. S.; Athanazziou, A.; Barley, V.; Bell, D. R.; Bianchi, U.; Bolis, G.; Brady, M. F.; Brodovsky, H. S.; Bruckner, H.; Buyse, M.; Canetta, R.; Chylak, V.; Cohen, C. J.; Colombo, N.; Conte, P. F.; Crowther, D.; Edmonson, J. H.; Gennatas, C.; Gilbey, E.; Gore, M.; Guthrie, D.; Yeap, B. Y.

    1998-01-01

    The purpose of this systematic study was to provide an up to date and reliable quantitative summary of the relative benefits of various types of chemotherapy (non-platinum vs platinum, single-agent vs combination and carboplatin vs cisplatin) in the treatment of advanced ovarian cancer. Also, to investigate whether well-defined patient subgroups benefit more or less from cisplatin- or carboplatin-based therapy. Meta-analyses were based on updated individual patient data from all available randomized controlled trials (published and unpublished), including 37 trials, 5667 patients and 4664 deaths. The results suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cisplatin and carboplatin are equally effective. There is no good evidence that cisplatin is more or less effective than carboplatin in any particular subgroup of patients. Images Figure 1 Figure 2 Figure 3 PMID:9836481

  8. MLN4924 Synergistically Enhances Cisplatin-induced Cytotoxicity via JNK and Bcl-xL Pathways in Human Urothelial Carcinoma.

    PubMed

    Ho, I-Lin; Kuo, Kuan-Lin; Liu, Shing-Hwa-; Chang, Hong-Chiang; Hsieh, Ju-Ton; Wu, June-Tai; Chiang, Chih-Kang; Lin, Wei-Chou; Tsai, Yu-Chieh; Chou, Chien-Tso; Hsu, Chen-Hsun; Pu, Yeong-Shiau; Shi, Chung-Sheng; Huang, Kuo-How

    2015-11-23

    Cisplatin-based chemotherapy is the primary treatment for metastatic bladder urothelial carcinoma. However, the response rate is only 40-65%. This study investigated the anti-tumor effect and underlying mechanisms of the combination of cisplatin and the NEDD8-activating enzyme inhibitor MLN4924 in human bladder urothelial carcinoma. The combination of cisplatin and MLN4924 exerted synergistic cytotoxicity on two high-grade bladder urothelial carcinoma cell lines, NTUB1 and T24 (combination index <1). MLN4924 also potentiated the cisplatin-induced apoptosis and activation of caspase-3 and -7, phospho-histone H2A.X and PARP. c-Jun N-terminal kinase (JNK) activation and a down-regulation of B-cell lymphoma-extra large (Bcl-xL) were also observed during cisplatin and MLN4924 treatment. Inhibition of JNK activation partially restored cell viability and Bcl-xL expression. Bcl-xL overexpression also rescued cell viability. MLN4924 significantly potentiated cisplatin-induced tumor suppression in urothelial carcinoma xenograft mice. In summary, MLN4924 synergistically enhanced the anti-tumor effect of cisplatin via an increase in DNA damage, JNK activation and down-regulation of Bcl-xL in urothelial carcinoma cells. These findings provide a new therapeutic strategy for the treatment of bladder cancer.

  9. [50th anniversary of cisplatin].

    PubMed

    Rancoule, Chloé; Guy, Jean-Baptiste; Vallard, Alexis; Ben Mrad, Majed; Rehailia, Amel; Magné, Nicolas

    2017-02-01

    We have just celebrated the 50th anniversary of cisplatin cytotoxic potential discovery. It is time to take stock… and it seems mainly positive. This drug, that revolutionized the treatment of many cancer types, continues to be the most widely prescribed chemotherapy. Despite significant toxicities, resistance mechanisms associated with treatment failures, and unresolved questions about its mechanism of action, the use of this cytotoxic agent remains unwavering. The interest concerning this "old" invincible drug has not yet abated. Indeed many research axes are in the news. New platinum salts agents are tested, new cisplatin formulations are developed to target tumor cells more efficiently, and new combinations are established to increase the cytotoxic potency of cisplatin or overcome the resistance mechanisms.

  10. IL-17A exacerbates cisplatin-based resistance of OVCA via upregulating the expression of ABCG2 and MDR1 through Gli1-mediated Hh signaling.

    PubMed

    Niu, Xiulong; Liu, Wenxing; Wang, Yue; Liu, Xiaomei; Zhang, Hongjian; Li, Zhijun; Li, Hongzhao; Iwakura, Yoichiro; Deng, Weimin

    2016-07-18

    The major obstacle of the tumor chemotherapy, including ovarian cancer (OVCA), is drug resistance. However, the relevance of IL-17A with drug-resistance of OVCA has been poorly elaborated. In this study, we used 2 human OVCA cell lines to investigate the effects of IL-17A on cisplatin (CDDP or DDP)-based resistance in OVCA cells and the underlying mechanisms. Meanwhile, IL-17A-deficient mice and ID8 were used to verify the IL-17A's effects on OVCA chemo-resistance in vivo. Moreover, the relationship between IL-17A level and relevant indices were primarily assessed in ovarian specimens from 55 patients with OVCA. We found that rhIL-17A exacerbated DDP-based resistance of OVCA cells via up-regulating the expression of ABCG2 and MDR1 through Gli1-mediated Hh signal pathway. Animal experiment demonstrated that IL-17A significantly recede DDP-based treatment for ID8 tumor. Similar results were observed in preliminary clinical investigation. Our findings suggest that inhibiting IL-17A/IL-17RA-Gli1 signal may improve the resistance of OVCA to DDP.

  11. Role of ABC transporters in fluoropyrimidine-based chemotherapy response.

    PubMed

    Nies, Anne T; Magdy, Tarek; Schwab, Matthias; Zanger, Ulrich M

    2015-01-01

    Since over 50 years, 5-fluorouracil (5-FU) is in use as backbone of chemotherapy treatment regimens for a wide range of cancers including colon, breast, and head and neck carcinomas. However, drug resistance and severe toxicities such as mucositis, diarrhea, neutropenia, and vomiting in up to 40% of treated patients often lead to dose limitation or treatment discontinuation. Because the oral bioavailability of 5-FU is unpredictable and highly variable, 5-FU is commonly administered intravenously. To overcome medical complications and inconvenience associated with intravenous administration, the oral prodrugs capecitabine and tegafur have been developed. Both fluoropyrimidines are metabolically converted intracellularly to 5-FU, which then needs metabolic activation to exert its damaging activity on RNA and DNA. The low response rates of 10-15% of 5-FU monotherapy can be improved by combination regimens of infusional 5-FU and leucovorin together with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI), thereby increasing response rates to 30-40%. The impact of metabolizing enzymes in the development of fluoropyrimidine toxicity and resistance has been studied in great detail. In addition, membrane drug transporters, which are critical determinants of intracellular drug concentrations, may play a role in occurrence of toxicity and development of resistance against fluoropyrimidine-based therapy as well. This review therefore summarizes current knowledge on the role of drug transporters with particular focus on ATP-binding cassette transporters in fluoropyrimidine-based chemotherapy response.

  12. Syndrome of Inappropriate Secretion of Antidiuretic Hormone Caused by Carboplatin After Switching from Cisplatin in a Metastatic Urethral Cancer Patient.

    PubMed

    Sugiyama, Yosuke; Naiki, Taku; Kondo, Masahiro; Iida, Keitaro; Kondo, Yuki; Tasaki, Yoshihiko; Kataoka, Tomoya; Hotta, Asami; Yasui, Takahiro; Kimura, Kazunori

    2017-05-01

    There is no established chemotherapy regimen in metastatic primary urethral cancer (mPUC). The efficacy of a cisplatin (CDDP)-based regimen has been reported, however, when the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) occurs, the chemotherapy regimen should be changed to another platinum compound. In this report, we describe a 66-year-old woman who was diagnosed as mPUC with, CDDP-induced SIADH. After switching her to CBDCA and careful managing her sodium balance, three courses of the chemotherapy regimen were completed.

  13. Cisplatin Induces Differentiation of Breast Cancer Cells

    PubMed Central

    Prabhakaran, Praseetha; Hassiotou, Foteini; Blancafort, Pilar; Filgueira, Luis

    2013-01-01

    Breast tumors are heterogeneous including cells with stem cell properties and more differentiated cells. This heterogeneity is reflected into the molecular breast cancer subtypes. Breast cancer stem cells are resistant to chemotherapy, thus recent efforts are focusing on identifying treatments that shift them toward a more differentiated phenotype, making them more susceptible to chemotherapy. We examined whether the drug cisplatin induces differentiation in breast cancer cell lines that represent different breast cancer subtypes. We used three cell lines representing triple-negative breast cancers, BT-549 and MDA-MB-231 (claudin-low), and MDA-MB-468 (basal-like), along with estrogen and progesterone receptor positive MCF-7 cells (luminal). Cisplatin was applied at 2.5, 5, 10, and 20 μM, and cell viability and proliferation were measured using MTS and BrdU assays, respectively. The effect of cisplatin on the cellular hierarchy was examined by flow cytometry, immunofluorescence and qRT-PCR. Cisplatin treatment of 10 and 20 μM reduced cell viability by 36–51% and proliferation capacity by 36–67%. Treatment with cisplatin resulted in 12–67% down-regulation of stem cell markers (CD49f, SSEA4) and 10–130% up-regulation of differentiation markers (CK18, SMA, β-tubulin). At the mRNA level, CD49f was down-regulated whilst β-tubulin was up-regulated in the claudin-low cell lines. SSEA4 protein expression decreased upon cisplatin treatment, but SSEA4 mRNA expression increased indicating a differential regulation of cisplatin at the post-transcriptional level. It is concluded that cisplatin reduces breast cancer cell survival and induces differentiation of stem/progenitor cell subpopulations within breast cancer cell lines. These effects indicate the potential of this drug to target specific chemotherapy-resistant cells within a tumor. PMID:23761858

  14. A Retrospective, Multicenter Study of the Tolerance of Induction Chemotherapy With Docetaxel, Cisplatin, and 5-Fluorouracil Followed by Radiotherapy With Concomitant Cetuximab in 46 Cases of Squamous Cell Carcinoma of the Head and Neck

    SciTech Connect

    Buiret, Guillaume; Combe, Claire; Favrel, Veronique; Pommier, Pascal; Martin, Laurent; Ecochard, Rene; Fayette, Jerome; Tartas, Sophie; Ramade, Antoine; Ceruse, Philippe

    2010-06-01

    Purpose: To investigate, in a multicenter study, the tolerance of induction chemotherapy (ICT) and external radiotherapy (ERT) with concomitant cetuximab in the treatment of patients with squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods: Clinical data from 46 patients with Stage III or IV nonmetastatic SCCHN who received docetaxel, cisplatin, and 5-fluorouracil as ICT, followed by ERT with concomitant cetuximab, were retrospectively analyzed. Clinical safety (weight, allergy, mucositis, and dermatitis) and paraclinical safety (levels of hemoglobin, polynuclear neutrophils, and creatinine clearance) were studied. The primary objective was the proportion of patients who completed the protocol. Results: The percentage of patients completing ICT was 73.9%, ERT 93.5%, and cetuximab 69.6%. Induction chemotherapy was better tolerated than that previously reported. The rates of temporary suspensions of radiation (39.1%, mean duration of 13 days) and hospitalization (26.1%) during ERT with concomitant cetuximab were high. Weight loss during treatment (21.4% of patients lost >10% of their body weight), radiodermatitis, and radiomucositis were the main causes of temporary suspension of treatment, although Grade 4 dermatitis was not experienced. There were no allergic reactions to cetuximab. Conclusion: The completed protocol rate for SCCHN patients receiving ICT and ERT with concomitant cetuximab is high and the toxicity acceptable. Future improvements to protocol will be possible through early action and systematic implementation of nutritional support coupled with antibiotic treatment upon the first signs of radiodermatitis. These data could be useful for prospective studies on the safety and efficacy of this protocol.

  15. Optical molecular imaging approach for rapid assessment of response of individual cancer cells to chemotherapy

    NASA Astrophysics Data System (ADS)

    Luo, Zhen; Tikekar, Rohan Vijay; Samadzadeh, Kiana Michelle; Nitin, Nitin

    2012-10-01

    Predicting the response of individual patients to cytotoxic chemotherapy drugs is critical for developing individualized therapies. With this motivation, an optical molecular imaging approach was developed to detect cisplatin induced changes in the uptake and intracellular retention of choline. Intracellular uptake of choline was characterized using a click chemistry reaction between propargyl choline and Alexa-488 azide. Cisplatin induced changes in the uptake of propargyl choline in cells and tumor spheroids were compared with similar measurements using a fluorescent analogue of deoxyglucose and conventional cell viability assays. Uptake and intracellular retention of propargyl choline decreased with an increase in concentration of cisplatin. Intracellular uptake of propargyl choline was significantly reduced within 3 h of incubation with a sub-lethal dose of cisplatin. Results demonstrate that the imaging approach based on propargyl choline was more sensitive in detecting the early response of cancer cells to cisplatin as compared to the imaging based on fluorescent analogue of deoxyglucose and cell viability assays. Imaging measurements in tumor spheroids show a significant decrease in the uptake of propargyl choline following treatment with cisplatin. Overall, the results demonstrate a novel optical molecular imaging approach for rapid measurement of the response of individual cancer cells to cisplatin treatment.

  16. Paclitaxel plus cisplatin vs. 5-fluorouracil plus cisplatin as first-line treatment for patients with advanced squamous cell esophageal cancer

    PubMed Central

    Liu, Ying; Ren, Zhonghai; Yuan, Long; Xu, Shuning; Yao, Zhihua; Qiao, Lei; Li, Ke

    2016-01-01

    Paclitaxel plus cisplatin and 5-fluorouracil plus cisplatin treatments are effective strategies for patients with advanced esophageal squamous cell carcinoma. This study was to evaluate the safety and efficacy of paclitaxel plus cisplatin and 5-fluorouracil plus cisplatin as first-line chemotherapy for patients with advanced esophageal squamous cell carcinoma. A total of 398 patients with advanced esophageal squamous cell carcinoma who received chemotherapy were included and divided into 2 groups: paclitaxel plus cisplatin group and 5-fluorouracil plus cisplatin group. 195 patients received paclitaxel plus cisplatin and 203 patients received 5-fluorouracil plus cisplatin. The objective response rates were 42.5% and 38.4% for paclitaxel plus cisplatin group and 5-fluorouracil plus cisplatin group, respectively (P=0.948). The median progression-free survival was 7.85 months (95% CI, 6.77-8.94 months) for the paclitaxel plus cisplatin group and 6.53 months (95% CI, 5.63-7.43 months) for the 5-fluorouracil plus cisplatin group with significant difference (P=0.02). The median overall survival was 13.46 months (95% CI, 12.01-14.91 months) for the paclitaxel plus cisplatin group and 12.67 months (95% CI, 11.87-13.47 months) for the 5-fluorouracil plus cisplatin group (P=0.204). The first-line chemotherapy of paclitaxel plus cisplatin had better median progression-free survival than 5-fluorouracil plus cisplatin in patients with advanced esophageal squamous cell carcinoma with tolerable toxicities. PMID:27822423

  17. In Silico Oncology: Quantification of the In Vivo Antitumor Efficacy of Cisplatin-Based Doublet Therapy in Non-Small Cell Lung Cancer (NSCLC) through a Multiscale Mechanistic Model

    PubMed Central

    Kolokotroni, Eleni; Dionysiou, Dimitra; Veith, Christian; Kim, Yoo-Jin; Franz, Astrid; Grgic, Aleksandar; Bohle, Rainer M.; Stamatakos, Georgios

    2016-01-01

    The 5-year survival of non-small cell lung cancer patients can be as low as 1% in advanced stages. For patients with resectable disease, the successful choice of preoperative chemotherapy is critical to eliminate micrometastasis and improve operability. In silico experimentations can suggest the optimal treatment protocol for each patient based on their own multiscale data. A determinant for reliable predictions is the a priori estimation of the drugs’ cytotoxic efficacy on cancer cells for a given treatment. In the present work a mechanistic model of cancer response to treatment is applied for the estimation of a plausible value range of the cell killing efficacy of various cisplatin-based doublet regimens. Among others, the model incorporates the cancer related mechanism of uncontrolled proliferation, population heterogeneity, hypoxia and treatment resistance. The methodology is based on the provision of tumor volumetric data at two time points, before and after or during treatment. It takes into account the effect of tumor microenvironment and cell repopulation on treatment outcome. A thorough sensitivity analysis based on one-factor-at-a-time and latin hypercube sampling/partial rank correlation coefficient approaches has established the volume growth rate and the growth fraction at diagnosis as key features for more accurate estimates. The methodology is applied on the retrospective data of thirteen patients with non-small cell lung cancer who received cisplatin in combination with gemcitabine, vinorelbine or docetaxel in the neoadjuvant context. The selection of model input values has been guided by a comprehensive literature survey on cancer-specific proliferation kinetics. The latin hypercube sampling has been recruited to compensate for patient-specific uncertainties. Concluding, the present work provides a quantitative framework for the estimation of the in-vivo cell-killing ability of various chemotherapies. Correlation studies of such estimates with

  18. 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

  19. Sickness behavior induced by cisplatin chemotherapy and radiotherapy in a murine head and neck cancer model is associated with altered mitochondrial gene expression.

    PubMed

    Vichaya, Elisabeth G; Molkentine, Jessica M; Vermeer, Daniel W; Walker, Adam K; Feng, Rebekah; Holder, Gerard; Luu, Katherine; Mason, Ryan M; Saligan, Leo; Heijnen, Cobi J; Kavelaars, Annemieke; Mason, Kathy A; Lee, John H; Dantzer, Robert

    2016-01-15

    The present study was undertaken to explore the possible mechanisms of the behavioral alterations that develop in response to cancer and to cancer therapy. For this purpose we used a syngeneic heterotopic mouse model of human papilloma virus (HPV)-related head and neck cancer in which cancer therapy is curative. Mice implanted or not with HPV+ tumor cells were exposed to sham treatment or a regimen of cisplatin and radiotherapy (chemoradiation). Sickness was measured by body weight loss and reduced food intake. Motivation was measured by burrowing, a highly prevalent species specific behavior. Tumor-bearing mice showed a gradual decrease in burrowing over time and increased brain and liver inflammatory cytokine mRNA expression by 28 days post tumor implantation. Chemoradiation administered to healthy mice resulted in a mild decrease in burrowing, body weight, and food intake. Chemoradiation in tumor-bearing mice decreased tumor growth and abrogated liver and brain inflammation, but failed to attenuate burrowing deficits. PCR array analysis of selected hypoxia and mitochondrial genes revealed that both the tumor and chemoradiation altered the expression of genes involved in mitochondrial energy metabolism within the liver and brain and increased expression of genes related to HIF-1α signaling within the brain. The most prominent changes in brain mitochondrial genes were noted in tumor-bearing mice treated with chemoradiation. These findings indicate that targeting mitochondrial dysfunction following cancer and cancer therapy may be a strategy for prevention of cancer-related symptoms.

  20. Induction chemotherapy in head and neck cancer patients followed by concomitant docetaxel-based radiochemotherapy.

    PubMed

    Mencoboni, M; Grillo-Ruggieri, F; Salami, A; Scasso, F; Rebella, L; Grimaldi, A; Dellepiane, M; Moratti, G; Bruzzone, A; Spigno, F; Ghio, R; Figliomeni, M

    2011-07-01

    Concurrent chemoradiotherapy has become the standard of care for patients with inoperable squamous cell head and neck carcinoma. More recently, induction chemotherapy has been adopted as an approach in the management of these patients. We report the results of a phase II trial associating induction chemotherapy and concomitant chemoradiotherapy in a series of patients with inoperable squamous cell head and neck cancer. Twenty-nine patients with advanced squamous cell carcinoma ineligible for surgery were enrolled. Induction chemotherapy with docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) every 21 days was administered for two cycles. Radiotherapy followed the induction phase. During radiotherapy, docetaxel was administered weekly at the dose of 33 mg/m(2) . Primary end point of the study was feasibility of treatment. Six (18%) patients failed to conclude the treatment schedule. Although response rates in evaluable patients were very high (disease control rate >90%), toxicities were a matter of concern. The reported treatment schedule proved infeasible. However, some modifications in ancillary therapies aimed at exploiting its efficacy could make it practicable.

  1. Hepatitis B virus enhances cisplatin-induced hepatotoxicity via a mechanism involving suppression of glucose-regulated protein of 78 Kda.

    PubMed

    Zhang, Xiaoxue; Zhang, Rui; Yang, HuiOu; Xiang, Qian; Jiang, Qing; He, Qi; Zhang, Ting; Chen, Chen; Zhu, Huifen; Wang, Qiang; Ning, Qin; Li, Yiwu; Lei, Ping; Shen, Guanxin

    2016-07-25

    Cisplatin is a classical platinum-based chemotherapeutic drug used in the treatment of many cancer types, including hepatocellular carcinoma (HCC). The application of cisplatin is significantly limited by its toxicity, which may be affected by various biological factors. Persistence of Hepatitis B virus (HBV) infection leads to HCC development and may be associated with higher incidence of severe hepatitis during chemotherapy. However, whether HBV alters the susceptibility of hepatocytes to cisplatin remains poorly understood. Here, we demonstrate that HBV transfection enhanced cisplatin-induced hepatotoxicity via a mechanism involving suppression of glucose-regulated protein of 78 KDa (Grp78), a major stress-induced chaperone that localizes to the endoplasmic reticulum. Silencing Grp78 gene increased the susceptibility of HepG2 to cisplatin by activating caspase-3. Grp78 expression was down-regulated by HBV infection both in vitro and in liver tissues of patients. We compared the cisplatin sensitivity of hepatoma cells either expressing (HepG2.2.15 cells) or not expressing the entire Hepatitis B Virus genome (HepG2). HepG2.2.15 cells showed increased sensitivity to cisplatin and a higher apoptosis rate. Overexpression of Grp78 counteracted the increase of sensitivity of HepG2.215 cells to cisplatin. Furthermore, we found that HBV disrupted Grp78 synthesis in response to cisplatin stimulation, which may trigger severe and prolonged endoplasmic reticulum (ER) stress that can induce cellular apoptosis. Our findings provide new information into the effect of HBV in the modulation of Grp78 expression, and, consequently on cisplatin-induced hepatotoxicity during viral infection.

  2. Induction chemotherapy with paclitaxel and cisplatin followed by radiotherapy for larynx organ preservation in advanced laryngeal and hypopharyngeal cancer offers moderate late toxicity outcome (DeLOS-I-trial).

    PubMed

    Dietz, Andreas; Rudat, Volker; Dreyhaupt, Jens; Pritsch, Maria; Hoppe, Florian; Hagen, Rudolph; Pfreundner, Leo; Schröder, Ursula; Eckel, Hans; Hess, Markus; Schröder, Michael; Schneider, Petra; Jens, Bünzel; Zenner, Hans P; Werner, Jochen A; Engenhardt-Cabillic, Rita; Vanselow, Bernhard; Plinkert, Peter; Niewald, Marcus; Kuhnt, Thomas; Budach, Wilfried; Flentje, Michael

    2009-08-01

    A prospective multicenter phase-II trial (12 centers) was performed by the German larynx organ preservation group (DeLOS) to evaluate the effect of induction chemotherapy (ICHT) with paclitaxel/cisplatin (TP), followed by accelerated-hyperfractionated (concomitant boost) radiotherapy (RT) in responders. The trial was focused on larynx preservation, tumor control, survival, salvage surgery and late toxicity in patients with advanced larynx/hypopharynx carcinoma eligible for total laryngectomy (LE). Seventy-one patients (40 larynx, 87.5% St. III, IV; 31 hypopharynx, 93.4% St. III, IV) were enrolled into the study and treated with ICHT (200 mg/m(2) paclitaxel, 100 mg/m(2) cisplatin; day 1, 22) according to the DeLOS protocol. Patients with complete or partial tumor response proceeded to RT (69.9 Gy in 5.5 weeks). Non-responders received a LE followed by postoperative RT (56-70 Gy in 5.5-7 weeks). The response rate to ICHT for larynx cancer was 69.6% (7.1% complete, 62.5% partial response) and for hypopharyngeal cancer was 84.3% (6.9% complete, 77.4% partial response). Overall survival after 36 months was 60.3% (95% CI, 48.4-72.2%), after 42 months was 56.5% (95% CI, 44.2-68.8%). Laryngectomy-free survival was as follows: after 36 months, 43.0% (95% CI, 30.9-55.0%); after 42 months, 41.3% (95% CI, 29.3-53.3%). Both parameters did not show different outcomes after distinguishing larynx from hypopharynx. LE was indicated in 15 non-responders after ICHT. Five of the 15 non-responders refused the laryngectomy. Two of the five received RT instead and had no evidence of disease 42 months after RT. Late toxicity (dysphagia III, IV LENT SOMA score in laryngectomy-free survivors: after 6 months, 1.8%; 12 months, 11.4%; 18 months, 14.5%; 24 months, 8.1%; 36 months, 16%) and salvage surgery (4 pharyngocutaneous fistulas in 27 operations) were tolerable. In a large portion of patients eligible for LE, the larynx could be preserved with satisfying functional outcome. Good

  3. Time-Series Modeling and Simulation for Comparative Cost-Effective Analysis in Cancer Chemotherapy: An Application to Platinum-Based Regimens for Advanced Non-small Cell Lung Cancer.

    PubMed

    Chisaki, Yugo; Nakamura, Nobuhiko; Yano, Yoshitaka

    2017-01-01

    The purpose of this study was to propose a time-series modeling and simulation (M&S) strategy for probabilistic cost-effective analysis in cancer chemotherapy using a Monte-Carlo method based on data available from the literature. The simulation included the cost for chemotherapy, for pharmaceutical care for adverse events (AEs) and other medical costs. As an application example, we describe the analysis for the comparison of four regimens, cisplatin plus irinotecan, carboplatin plus paclitaxel, cisplatin plus gemcitabine (GP), and cisplatin plus vinorelbine, for advanced non-small cell lung cancer. The factors, drug efficacy explained by overall survival or time to treatment failure, frequency and severity of AEs, utility value of AEs to determine QOL, the drugs' and other medical costs in Japan, were included in the model. The simulation was performed and quality adjusted life years (QALY) and incremental cost-effectiveness ratios (ICER) were calculated. An index, percentage of superiority (%SUP) which is the rate of the increased cost vs. QALY-gained plots within the area of positive QALY-gained and also below some threshold values of the ICER, was calculated as functions of threshold values of the ICER. An M&S process was developed, and for the simulation example, the GP regimen was the most cost-effective, in case of threshold values of the ICER=$70000/year, the %SUP for the GP are more than 50%. We developed an M&S process for probabilistic cost-effective analysis, this method would be useful for decision-making in choosing a cancer chemotherapy regimen in terms of pharmacoeconomic.

  4. Relationship Between the DPD and TS mRNA Expression and the Response to S-1-Based Chemotherapy and Prognosis in Patients with Advanced Gastric Cancer.

    PubMed

    Shen, Xiao-Ming; Zhou, Chong; Lian, Lian; Li, Li-Qun; Li, Wei; Tao, Min

    2015-04-01

    The aim was to determine changes in dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) mRNAs in the blood of advanced gastric cancer (AGC) patients to see whether these enzymes affected the patients' response to S-1-based chemotherapy and prognosis. For this purpose, pretreatment DPD/TS mRNA expressions were determined in 40 AGC patients using RT-PCR. The patients were then administered with S-1-based regimen (S-1 + cisplatin) and toxicities were recorded. The relationship between the DPD/TS mRNA expressions and the chemotherapy response, drug resistance, and prognosis was analyzed. The data show that DPD mRNA expression correlated significantly with Lauren type while TS mRNA expression correlated with distant metastasis. Patients with higher DPD and/or TS mRNA expression(s) showed poor response, while those with low DPD mRNA expression showed better response to the chemotherapy. Pooled analysis showed that the patients with low DPD/TS mRNA expressions had better therapeutic response. The incidence of bone marrow suppression, diarrhea, and oral mucositis was high in patients with low DPD mRNA expression. Median overall survival (OS) in 40 patients was 13.5 months. It was 17 months for low and 10 months for high DPD (P = 0.044) and TS mRNA expression (P = 0.047). Pooled analysis showed that the patients with both low DPD/TS mRNA expressions had longer OS (P = 0.001). In conclusion, the detection of DPD and/or TS mRNA expression can be used to predict the response to S-1-based chemotherapy, drug resistance, and prognosis in AGC patients as well as to help guide the individualized treatment of gastric cancer.

  5. Nab-paclitaxel-based compared to docetaxel-based induction chemotherapy regimens for locally advanced squamous cell carcinoma of the head and neck

    PubMed Central

    Schell, Amy; Ley, Jessica; Wu, Ningying; Trinkaus, Kathryn; Wildes, Tanya Marya; Michel, Loren; Thorstad, Wade; Gay, Hiram; Lewis, James; Rich, Jason; Diaz, Jason; Paniello, Randal C; Nussenbaum, Brian; Adkins, Douglas R

    2015-01-01

    We previously reported that nab-paclitaxel-based induction chemotherapy (IC) and concurrent chemoradiotherapy resulted in low relapse rates (13%) and excellent survival in head and neck squamous cell carcinoma (HNSCC). We compare the disease-specific survival (DSS) and overall survival (OS) between patients given nab-paclitaxel, cisplatin, and fluorouracil with cetuximab (APF-C) and historical controls given docetaxel, cisplatin, and fluorouracil with cetuximab (TPF-C). Patients with locally advanced HNSCC were treated with APF-C (n = 30) or TPF-C (n = 38). After 3 cycles of IC, patients were scheduled to receive cisplatin concurrent with definitive radiotherapy. T and N classification and smoking history were similar between the two groups and within p16-positive and p16-negative subsets. The median duration of follow-up for living patients in the APF-C group was 43.5 (range: 30–58) months versus 52 (range: 13–84) months for TPF-C. The 2-year DSS for patients treated with APF-C was 96.7% [95% Confidence Interval (CI): 85.2%, 99.8%] and with TPF-C was 77.6% (CI: 62.6%, 89.7%) (P = 0.0004). Disease progression that resulted in death was more frequent in the TPF-C group (39%) compared with the APF-C group (3%) when adjusted for competing risks of death from other causes (Gray's test, P = 0.0004). In p16 positive OPSCC, the 2-year DSS for APF-C was 100% and for TPF-C was 74.6% (CI: 47.4%, 94.6%) (P = 0.0019) and the 2-year OS for APF-C was 94.1% (CI: 65.0%, 99.2%) and for TPF-C was 74.6% (CI: 39.8%, 91.1%) (P = 0.013). In p16 negative HNSCC, the 2-year DSS for APF-C was 91.7% (CI: 67.6%, 99.6%) and for TPF-C was 82.6% (CI: 64.4%, 94.8%) (P = 0.092). A 2-year DSS and OS were significantly better with a nab-paclitaxel-based IC regimen (APF-C) compared to a docetaxel-based IC regimen (TPF-C) in p16-positive OPSCC. PMID:25619559

  6. Biomaterial-based regional chemotherapy: Local anticancer drug delivery to enhance chemotherapy and minimize its side-effects.

    PubMed

    Krukiewicz, Katarzyna; Zak, Jerzy K

    2016-05-01

    Since the majority of anticancer pharmacological agents affect not only cancer tissue but also normal cells, chemotherapy is usually accompanied with severe side effects. Regional chemotherapy, as the alternative version of conventional treatment, leads to the enhancement of the therapeutic efficiency of anticancer drugs and, simultaneously, reduction of toxic effects to healthy tissues. This paper provides an insight into different approaches of local delivery of chemotherapeutics, such as the injection of anticancer agents directly into tumor tissue, the use of injectable in situ forming drug carriers or injectable platforms in a form of implants. The wide range of biomaterials used as reservoirs of anticancer drugs is described, i.e. poly(ethylene glycol) and its copolymers, polyurethanes, poly(lactic acid) and its copolymers, poly(ɛ-caprolactone), polyanhydrides, chitosan, cellulose, cyclodextrins, silk, conducting polymers, modified titanium surfaces, calcium phosphate based biomaterials, silicone and silica implants, as well as carbon nanotubes and graphene. To emphasize the applicability of regional chemotherapy in cancer treatment, the commercially available products approved by the relevant health agencies are presented.

  7. French multicenter phase III randomized study testing concurrent twice-a-day radiotherapy and cisplatin/5-fluorouracil chemotherapy (BiRCF) in unresectable pharyngeal carcinoma: Results at 2 years (FNCLCC-GORTEC)

    SciTech Connect

    Bensadoun, Rene-Jean . E-mail: rene-jean.bensadoun@nice.fnclcc.fr; Benezery, Karen; Dassonville, Olivier; Magne, Nicolas; Poissonnet, Gilles; Ramaioli, Alain; Lemanski, Claire; Bourdin, Sylvain; Tortochaux, Jacques; Peyrade, Frederic; Marcy, Pierre-Yves; Chamorey, Emmanuel Phar; Vallicioni, Jacques; Seng Hang; Alzieu, Claude; Gery, Bernard; Chauvel, Pierre; Schneider, Maurice; Santini, Jose; Demard, Francois; Calais, Gilles

    2006-03-15

    Background: Unresectable carcinomas of the oropharynx and hypopharynx still have a poor long-term prognosis. Following a previous phase II study, this phase III multicenter trial was conducted between November 1997 and March 2002. Methods: Nontreated, strictly unresectable cases were eligible. Twice-daily radiation: two fractions of 1.2 Gy/day, 5 days per week, with no split (D1{sup {yields}}D46). Total tumor doses: 80.4 Gy/46 day (oropharynx), 75.6 Gy/44 day (hypopharynx). Chemotherapy (arm B): Cisplatin 100 mg/m{sup 2} (D1, D22, D43); 5FU, continuous infusion (D1{sup {yields}}D5), 750 mg/m{sup 2}/day cycle 1; 430 mg/m{sup 2}/day cycles 2 and 3. Results: A total of 163 evaluable patients. Grade 3-4 acute mucositis 82.6% arm B/69.5% arm A (NS); Grade 3-4 neutropenia 33.3% arm B/2.4% arm A (p < 0.05). Enteral nutrition through gastrostomy tube was more frequent in arm B before treatment and at 6 months (p < 0.01). At 24 months, overall survival (OS), disease-free survival (DFS), and specific survival (SS) were significantly better in arm B. OS: 37.8% arm B vs. 20.1% arm A (p = 0.038); DFS: 48.2% vs. 25.2% (p = 0.002); SS: 44.5% vs. 30.2% (p 0.021). No significant difference between the two arms in the amount of side effects at 1 and 2 years. Conclusion: For these unresectable cases, chemoradiation provides better outcome than radiation alone, even with an 'aggressive' dose-intensity radiotherapy schedule.

  8. Cisplatin impaired adipogenic differentiation of adipose mesenchymal stem cells.

    PubMed

    Chang, Yu-Hsun; Liu, Hwan-Wun; Chu, Tang-Yuan; Wen, Yao-Tseng; Ding, Dah-Ching

    2017-02-03

    Adipose mesenchymal stem cells (ASCs) were isolated from the adipose tissue and can be induced in vitro to differentiate into osteoblasts, chondroblasts, myocytes, neurons and other cell types. Cisplatin is a commonly used chemotherapy drug for cancer patients. However, the effects of cisplatin on ASC remain elusive. This study found that high-concentration cisplatin affects the viability of ASCs. First, IC50 concentration of cisplatin was evaluated. Proliferation of ASCs assessed by XTT method decreased immediately after cisplatin treatment with various concentrations. ASCs maintained mesenchymal stem cells surface markers evaluating by flow cytometry after cisplatin treatment. Upon differentiation by adding specific chemicals, a significant decrease in adipogenic differentiation (by Oil red staining) and osteogenic differentiation (by Alizarin red staining), and significant chondrogenic differentiation (by Alcian blue staining) were found after cisplatin treatment. Simultaneously, qRT-PCR was also used for evaluating the specific gene expressions after various differentiations. Finally, ASCs from one donor who had received cisplatin showed significantly decreased adipogenic differentiation but increased osteogenic differentiation compared with ASCs derived from one healthy donor. In conclusion, cisplatin affects the viability, proliferation, and differentiation of ASCs both in vitro and in vivo via certain signaling pathway such as p53 and Fas/FasL. The differentiation abilities of ASCs should be evaluated before their transplantation for repairing cisplatin-induced tissue damage.

  9. Neoadjuvant and adjuvant chemotherapy approaches for invasive bladder cancer.

    PubMed

    Raghavan, Derek; Burgess, Earle; Gaston, Kris E; Haake, Michael R; Riggs, Steven B

    2012-10-01

    Deeply invasive bladder cancer, representing approximately 20% of incident cases, is cured by radical cystectomy or radiotherapy in less than 50% of cases. In an effort to improve cure rates, based on objective response rates in metastatic disease of 40%-70% from combination chemotherapy regimens, systemic chemotherapy has been incorporated into programs of definitive treatment for this disease. Several randomized trials and a meta-analysis have confirmed a survival benefit from neoadjuvant chemotherapy followed by definitive local treatment, reflecting both median survival figures and cure rates. Despite several promising phase II trials, no randomized trial of classical adjuvant chemotherapy for bladder cancer has demonstrated an overall survival benefit, despite increments in disease-free survival. Molecular prognostication has been studied in an effort to improve the utility of systemic therapy for invasive non-metastatic bladder cancer, but randomized trials have not shown associated survival benefit. Despite level 1 evidence of a survival benefit from neoadjuvant MVAC (methotrexate, vinblastine, doxorubicin [Adriamycin], cisplatin) or cisplatin, methotrexate, and vinblastine (CMV) chemotherapy, more than 50% of incident cases do not receive such treatment.

  10. Rationally engineered polymeric cisplatin nanoparticle for improved antitumor efficacy

    PubMed Central

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

    2011-01-01

    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) co-polymer, 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 exhibit an IC50 = 0.77 ± 0.11μM comparable to that of free cisplatin (IC50 = 0.44 ± 0.09 μM). The nanoparticles are internalized into the endolysosomal compartment of cancer cells, and releases cisplatin in a pH-dependent manner. Furthermore, the nanoparticles exhibited 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. PMID:21576779

  11. Protective Effect of Tempol against Cisplatin-Induced Ototoxicity

    PubMed Central

    Youn, Cha Kyung; Kim, Jun; Jo, Eu-Ri; Oh, Jeonghyun; Do, Nam Yong; Cho, Sung Il

    2016-01-01

    One of the major adverse effects of cisplatin chemotherapy is hearing loss. Cisplatin-induced ototoxicity hampers treatment because it often necessitates dose reduction, which decreases cisplatin efficacy. This study was performed to investigate the effect of Tempol on cisplatin-induced ototoxicity in an auditory cell line, House Ear Institute-Organ of Corti 1 (HEI-OC1). Cultured HEI-OC1 cells were exposed to 30 μM cisplatin for 24 h with or without a 2 h pre-treatment with Tempol. Cell viability was determined using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and apoptotic cells were identified using terminal deoxynucleotidyl transferase dUTP nick end labeling of nuclei (TUNEL) assay and flow cytometry. The effects of Tempol on cisplatin-induced cleaved poly(ADP-ribose) polymerase, cleaved caspase, and mitochondrial inducible nitric oxide synthase expression were evaluated using western blot analysis. Levels of intracellular reactive oxygen species (ROS) were measured to assess the effects of Tempol on cisplatin-induced ROS accumulation. Mitochondria were evaluated by confocal microscopy, and the mitochondrial membrane potential was measured to investigate whether Tempol protected against cisplatin-induced mitochondrial dysfunction. Cisplatin treatment decreased cell viability, and increased apoptotic features and markers, ROS accumulation, and mitochondrial dysfunction. Tempol pre-treatment before cisplatin exposure significantly inhibited all these cisplatin-induced effects. These results demonstrate that Tempol inhibits cisplatin-induced cytotoxicity in HEI-OC1, and could play a preventive role against cisplatin-induced ototoxicity. PMID:27869744

  12. Protective Effect of Tempol against Cisplatin-Induced Ototoxicity.

    PubMed

    Youn, Cha Kyung; Kim, Jun; Jo, Eu-Ri; Oh, Jeonghyun; Do, Nam Yong; Cho, Sung Il

    2016-11-18

    One of the major adverse effects of cisplatin chemotherapy is hearing loss. Cisplatin-induced ototoxicity hampers treatment because it often necessitates dose reduction, which decreases cisplatin efficacy. This study was performed to investigate the effect of Tempol on cisplatin-induced ototoxicity in an auditory cell line, House Ear Institute-Organ of Corti 1 (HEI-OC1). Cultured HEI-OC1 cells were exposed to 30 μM cisplatin for 24 h with or without a 2 h pre-treatment with Tempol. Cell viability was determined using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and apoptotic cells were identified using terminal deoxynucleotidyl transferase dUTP nick end labeling of nuclei (TUNEL) assay and flow cytometry. The effects of Tempol on cisplatin-induced cleaved poly(ADP-ribose) polymerase, cleaved caspase, and mitochondrial inducible nitric oxide synthase expression were evaluated using western blot analysis. Levels of intracellular reactive oxygen species (ROS) were measured to assess the effects of Tempol on cisplatin-induced ROS accumulation. Mitochondria were evaluated by confocal microscopy, and the mitochondrial membrane potential was measured to investigate whether Tempol protected against cisplatin-induced mitochondrial dysfunction. Cisplatin treatment decreased cell viability, and increased apoptotic features and markers, ROS accumulation, and mitochondrial dysfunction. Tempol pre-treatment before cisplatin exposure significantly inhibited all these cisplatin-induced effects. These results demonstrate that Tempol inhibits cisplatin-induced cytotoxicity in HEI-OC1, and could play a preventive role against cisplatin-induced ototoxicity.

  13. Histone H4 expression is cooperatively maintained by IKKβ and Akt1 which attenuates cisplatin-induced apoptosis through the DNA-PK/RIP1/IAPs signaling cascade

    PubMed Central

    Wang, Ruixue; Zheng, Xuelian; Zhang, Lei; Zhou, Bin; Hu, Huaizhong; Li, Zhiping; Zhang, Lin; Lin, Yong; Wang, Xia

    2017-01-01

    While chromatin remodeling mediated by post-translational modification of histone is extensively studied in carcinogenesis and cancer cell’s response to chemotherapy and radiotherapy, little is known about the role of histone expression in chemoresistance. Here we report a novel chemoresistance mechanism involving histone H4 expression. Extended from our previous studies showing that concurrent blockage of the NF-κB and Akt signaling pathways sensitizes lung cancer cells to cisplatin-induced apoptosis, we for the first time found that knockdown of Akt1 and the NF-κB-activating kinase IKKβ cooperatively downregulated histone H4 expression, which increased cisplatin-induced apoptosis in lung cancer cells. The enhanced cisplatin cytotoxicity in histone H4 knockdown cells was associated with proteasomal degradation of RIP1, accumulation of cellular ROS and degradation of IAPs (cIAP1 and XIAP). The cisplatin-induced DNA-PK activation was suppressed in histone H4 knockdown cells, and inhibiting DNA-PK reduced expression of RIP1 and IAPs in cisplatin-treated cells. These results establish a novel mechanism by which NF-κB and Akt contribute to chemoresistance involving a signaling pathway consisting of histone H4, DNA-PK, RIP1 and IAPs that attenuates ROS-mediated apoptosis, and targeting this pathway may improve the anticancer efficacy of platinum-based chemotherapy. PMID:28139737

  14. Usability and Acceptability of a Web-Based Program for Chemotherapy-Induced Peripheral Neuropathy.

    PubMed

    Tofthagen, Cindy; Kip, Kevin E; Passmore, Denise; Loy, Ian; Berry, Donna L

    2016-07-01

    Chemotherapy-induced neuropathy is a painful and debilitating adverse effect of certain chemotherapy drugs. There have not been any patient-centered, easily accessible Web-based interventions to assist with self-management of chemotherapy-induced neuropathy. The aims of this study were to evaluate usability and acceptability and to estimate an effect size of a Web-based intervention for assessing and managing chemotherapy-induced neuropathy. Participants (N = 14) were instructed to complete the Creativity, Optimism, Planning, and Expert Information for Chemotherapy-Induced Peripheral Neuropathy program and provide verbal responses to the program. Participants completed the Chemotherapy Induced Peripheral Neuropathy Assessment Tool and Post-Study System Usability Questionnaire. Iterative changes were made to the COPE-CIPN. Participants were asked to provide feedback on the revised COPE-CIPN, repeat the Chemotherapy Induced Peripheral Neuropathy Assessment Tool, and evaluate acceptability using the Acceptability e-Scale. The COPE-CIPN demonstrated high usability (mean, 1.98 [SD, 1.12]) and acceptability (mean, 4.40 [SD, 0.52]). Comments indicated that the interface was easy to use, and the information was helpful. While neuropathy symptoms continued to increase in this group of patients receiving neurotoxic chemotherapy, there was a decrease in mean level of interference with activities from 53.71 to 39.29 over 3 to 4 months, which indicated a moderate effect (d = 0.39) size. The COPE-CIPN may be a useful intervention to support self-management of chemotherapy-induced neuropathy.

  15. The natural flavonoid apigenin sensitizes human CD44(+) prostate cancer stem cells to cisplatin therapy.

    PubMed

    Erdogan, Suat; Turkekul, Kader; Serttas, Rıza; Erdogan, Zeynep

    2017-04-01

    Prostate cancer (PCa) is the second most common type of cancer and the fifth leading cause of cancer-related death among men. Development of chemoresistance, tumor relapse and metastasis remain major barriers to effective treatment and all been identified to be associated with cancer stem cells (CSCs). Natural flavonoids such as apigenin have been shown to have the ability to improve the therapeutic efficacy of common chemotherapy agents through CSCs sensitization. Thus, the aim of this study was to evaluate the combination of apigenin with cisplatin on CD44(+) PCa stem cell growth and migration. Platinum-based anti-neoplastic drugs have been used to treat a number of malignancies including PCa. However, acquired resistance and side effects unfortunately have limited cisplatin's use. A CD44(+) subpopulation was isolated from human androgen-independent PC3 PCa cells by using human CD44-PE antibody. IC50 values were determined by MTT test. RT-qPCR, Western blot analyses and image-based cytometer were used to investigate apoptosis, cell cycle and their underlying molecular mechanisms. Cell migration was evaluated by wound healing test. The combination of the IC50 doses of apigenin (15μM) and cisplatin (7.5μM) for 48h significantly enhanced cisplatin's cytotoxic and apoptotic effects through downregulation of Bcl-2, sharpin and survivin; and upregulation of caspase-8, Apaf-1 and p53 mRNA expression. The combined therapy suppressed the phosphorylation of p-PI3K and p-Akt, inhibited the protein expression of NF-κB, and downregulated the cell cycle by upregulating p21, as well as cyclin dependent kinases CDK-2, -4, and -6. Apigenin significantly increased the inhibitory effects of cisplatin on cell migration via downregulation of Snail expression. In conclusion, our study showed the possible therapeutic approach of using apigenin to potentially increase the effects of cisplatin by targeting CSCs subset in prostate cancer.

  16. Plasma chromogranin A marks emesis and serotonin release associated with dacarbazine and nitrogen mustard but not with cyclophosphamide-based chemotherapies.

    PubMed Central

    Cubeddu, L. X.; O'Connor, D. T.; Hoffmann, I.; Parmer, R. J.

    1995-01-01

    Chromogranin A (CgA) is present in high concentrations in enterochromaffin cells, where it is co-localised with serotonin in the storage granules. Plasma CgA has been reported to mark emesis and serotonin release associated with cisplatin treatment. However, it is not known whether plasma CgA could be an indicator of emesis and of serotonin release in patients receiving non-cisplatin chemotherapies. Therefore, in this study we evaluated, in cancer patients, the temporal relationships between the increases in plasma CgA and urinary 5-hydroxyindoleacetic acid (5-HIAA) and the development of vomiting following dacarbazine, nitrogen mustard and cyclophosphamide treatments. Metoclopramide was used as antiemetic. With dacarbazine, nitrogen mustard and cyclophosphamide the median time to the onset of emesis was 2.3, 2.8 and 5.3 h and the duration of intense emesis was 3, 2 and 6 h respectively. Plasma CgA and urinary 5-HIAA increased after dacarbazine- and nitrogen mustard-based chemotherapies, with maximal increases between 4 and 6 h after initiation of drug infusion. The time course for the increases in plasma CgA paralleled that of urinary 5-HIAA and the period of intense emesis. A highly significant (P = 0.0009) positive correlation (r = 0.68) was found between the increases in plasma CgA and in urinary 5-HIAA. Cyclophosphamide treatment was not associated with increases in plasma CgA and in urinary 5-HIAA, despite inducing emesis; this indicates that the increases in CgA and 5-HIAA after dacarbazine and nitrogen mustard are not due to the act of vomiting per se. In summary, plasma CgA is a marker of serotonin release (most likely from enterochromaffin cells) after dacarbazine and nitrogen mustard-based chemotherapies, exocytosis being the most likely mechanism for the release of serotonin. Serotonin released from enterochromaffin cells seems to trigger the emetic response to dacarbazine and nitrogen mustard; however, cyclophosphamide may release serotonin from a

  17. Identification of small molecule inhibitors of ERCC1-XPF that inhibit DNA repair and potentiate cisplatin efficacy in cancer cells.

    PubMed

    Arora, Sanjeevani; Heyza, Joshua; Zhang, Hao; Kalman-Maltese, Vivian; Tillison, Kristin; Floyd, Ashley M; Chalfin, Elaine M; Bepler, Gerold; Patrick, Steve M

    2016-11-15

    ERCC1-XPF heterodimer is a 5'-3' structure-specific endonuclease which is essential in multiple DNA repair pathways in mammalian cells. ERCC1-XPF (ERCC1-ERCC4) repairs cisplatin-DNA intrastrand adducts and interstrand crosslinks and its specific inhibition has been shown to enhance cisplatin cytotoxicity in cancer cells. In this study, we describe a high throughput screen (HTS) used to identify small molecules that inhibit the endonuclease activity of ERCC1-XPF. Primary screens identified two compounds that inhibit ERCC1-XPF activity in the nanomolar range. These compounds were validated in secondary screens against two other non-related endonucleases to ensure specificity. Results from these screens were validated using an in vitro gel-based nuclease assay. Electrophoretic mobility shift assays (EMSAs) further show that these compounds do not inhibit the binding of purified ERCC1-XPF to DNA. Next, in lung cancer cells these compounds potentiated cisplatin cytotoxicity and inhibited DNA repair. Structure activity relationship (SAR) studies identified related compounds for one of the original Hits, which also potentiated cisplatin cytotoxicity in cancer cells. Excitingly, dosing with NSC16168 compound potentiated cisplatin antitumor activity in a lung cancer xenograft model. Further development of ERCC1-XPF DNA repair inhibitors is expected to sensitize cancer cells to DNA damage-based chemotherapy.

  18. Identification of small molecule inhibitors of ERCC1-XPF that inhibit DNA repair and potentiate cisplatin efficacy in cancer cells

    PubMed Central

    Arora, Sanjeevani; Heyza, Joshua; Zhang, Hao; Kalman-Maltese, Vivian; Tillison, Kristin; Floyd, Ashley M.; Chalfin, Elaine M.; Bepler, Gerold; Patrick, Steve M.

    2016-01-01

    ERCC1-XPF heterodimer is a 5′-3′ structure-specific endonuclease which is essential in multiple DNA repair pathways in mammalian cells. ERCC1-XPF (ERCC1-ERCC4) repairs cisplatin-DNA intrastrand adducts and interstrand crosslinks and its specific inhibition has been shown to enhance cisplatin cytotoxicity in cancer cells. In this study, we describe a high throughput screen (HTS) used to identify small molecules that inhibit the endonuclease activity of ERCC1-XPF. Primary screens identified two compounds that inhibit ERCC1-XPF activity in the nanomolar range. These compounds were validated in secondary screens against two other non-related endonucleases to ensure specificity. Results from these screens were validated using an in vitro gel-based nuclease assay. Electrophoretic mobility shift assays (EMSAs) further show that these compounds do not inhibit the binding of purified ERCC1-XPF to DNA. Next, in lung cancer cells these compounds potentiated cisplatin cytotoxicity and inhibited DNA repair. Structure activity relationship (SAR) studies identified related compounds for one of the original Hits, which also potentiated cisplatin cytotoxicity in cancer cells. Excitingly, dosing with NSC16168 compound potentiated cisplatin antitumor activity in a lung cancer xenograft model. Further development of ERCC1-XPF DNA repair inhibitors is expected to sensitize cancer cells to DNA damage-based chemotherapy. PMID:27650543

  19. Targeting Mechanisms of Resistance to Taxane-Based Chemotherapy

    DTIC Science & Technology

    2008-09-01

    family 22 member 3 Hepsin SRY-box 9 Ankyrin repeat family A 2 Baculoviral IAP repeat -containing 2 Hypothetical gene LOC128439 Mitogen-activated...on docetaxel-mediated prostate cancer cell growth inhibition. In summary, genes and pathways that may contribute to chemotherapy resistance...exert cytoprotective effects [6, 9]. Of the cytokine-encoding transcripts that we found to be differentially expressed, Growth Differentiation Factor

  20. eIF4E promotes tumorigenesis and modulates chemosensitivity to cisplatin in esophageal squamous cell carcinoma

    PubMed Central

    Zhao, Hui; Deng, Juan; Long, Ying; Shuai, Meng-ting; Li, Qian; Gu, Huan; Chen, Ya-qi; Leng, Ai-min

    2016-01-01

    Patients with esophageal squamous cell cancer are often diagnosed with advanced diseases that respond poorly to chemotherapy. Overexpression of eIF4E leads to enhance the translation of key malignancy-related proteins and enabling tumor growth and chemoresistance in a variety of human malignancies, but whether it has a role in ESCC remains obscure. We hypothesized that eIF4E promoted ESCC tumorigenesis and facilitated the development of acquired resistance to the cisplatin-based chemotherapy. In this study, we showed that eIF4E expression was increased significantly in clinical ESCC tissues and and ESCC cell lines and its expression level was correlated with lymph node metastasis, TNM stage, as well as overall and disease-free survival of ESCC. We also showed here that knockdown of eIF4E in EC9706 would dramatically reduced cell proliferation, colony formation, migration and invasion, apoptosis in vitro as well as in vivo, and vice versa. Moreover, “weak mRNAs” were demonstrated to be regulated by eIF4E in ESCC, which might interpret the above function. Overexpression of eIF4E decreased the efficacy of cisplatin-induced cell growth inhibition in ESCC cell line and xenograft model (P < 0.05). eIF4E knockdown by shRNA increased cisplatin-induced cytotoxicity in ESCC cell lines, and enhanced chemosensitivity to cisplatin in xenograft tumor models. Furthermore, we found that the PI3K/AKT pathway and Bcl-2/Bax ratio might be responsible for the eIF4E-induced cisplatin resistance in ESCC. Our data collectively show association of eIF4E expression with chemotherapeutic response in ESCC, and suggest that therapeutically targeting eIF4E may be a viable means of improving chemotherapy response in ESCC. PMID:27588477

  1. Tumour chemotherapy strategy based on impulse control theory.

    PubMed

    Ren, Hai-Peng; Yang, Yan; Baptista, Murilo S; Grebogi, Celso

    2017-03-06

    Chemotherapy is a widely accepted method for tumour treatment. A medical doctor usually treats patients periodically with an amount of drug according to empirical medicine guides. From the point of view of cybernetics, this procedure is an impulse control system, where the amount and frequency of drug used can be determined analytically using the impulse control theory. In this paper, the stability of a chemotherapy treatment of a tumour is analysed applying the impulse control theory. The globally stable condition for prescription of a periodic oscillatory chemotherapeutic agent is derived. The permanence of the solution of the treatment process is verified using the Lyapunov function and the comparison theorem. Finally, we provide the values for the strength and the time interval that the chemotherapeutic agent needs to be applied such that the proposed impulse chemotherapy can eliminate the tumour cells and preserve the immune cells. The results given in the paper provide an analytical formula to guide medical doctors to choose the theoretical minimum amount of drug to treat the cancer and prevent harming the patients because of over-treating.This article is part of the themed issue 'Horizons of cybernetical physics'.

  2. Pros and cons of intraperitoneal chemotherapy in the treatment of epithelial ovarian cancer.

    PubMed

    Zeimet, Alain G; Reimer, Daniel; Radl, Alice C; Reinthaller, Alexander; Schauer, Christian; Petru, Edgar; Concin, Nicole; Braun, Stephan; Marth, Christian

    2009-07-01

    Development of the pros and cons of intraperitoneal (IP) chemotherapy in the treatment of epithelial ovarian cancer based on the most prominent data published on the evolution of IP chemotherapy and on experience with this therapeutic strategy in clinical routine. The literature published on IP chemotherapy in ovarian cancer between 1970 and 2008 was identified systematically by computer-based searches in MEDLINE and the Cochrane Library. Furthermore, a preliminary analysis of data recorded during an observational nationwide multicenter study of the Austrian AGO on IP-IV chemotherapy using the GOG-172 treatment regimen was performed. The literature review unequivocally revealed a significantly greater toxicity for IP than for intravenous (IV) cisplatin-based chemotherapy. However, according to a Cochrane meta-analysis, IP-IV administration of chemotherapy is associated with a 21.6% decrease in the risk for death. In agreement with earlier reports, the most frequently mentioned side-effects in the Austria-wide observational study were long-lasting neurotoxicity, abdominal pain, fatigue, gastrointestinal and metabolic toxicities, and catheter-related complications. Most of these toxicities were identified as mirroring the toxicity profile of high-dose IV cisplatin (>or=100 mg/m(2)). In some patients, the classic IP-IV regimen with cisplatin/paclitaxel was changed to an alternative schedule comprising carboplatin AUC 5 (d1) and weekly paclitaxel 60 mg/m(2) (d1, 8, 15) completely administered via the IP route. This treatment was better tolerated and quality of life was significantly less compromised. However, neutropenia and thrombocytopenia were the limiting side-effects of this IP regimen. In cases where optimal cytoreduction with residual disease chemotherapy should be given serious consideration, even at the expense of significantly increased, but manageable toxicity.

  3. Transcriptome Sequencing Reveals Key Pathways and Genes Associated with Cisplatin Resistance in Lung Adenocarcinoma A549 Cells

    PubMed Central

    Fang, Yani; Zhang, Cheng; Wu, Tong; Wang, Qi; Liu, Jinhui; Dai, Penggao

    2017-01-01

    Acquired resistance to cisplatin-based chemotherapy frequently occurs in patients with non-small cell lung cancer, and the underlying molecular mechanisms are not well understood. The aim of this study was to investigate whether a distinct gene expression pattern is associated with acquired resistance to cisplatin in human lung adenocarcinoma. Whole-transcriptome sequencing was performed to compare the genome-wide gene expression patterns of the human lung adenocarcinoma A549 cisplatin-resistant cell line A549/DDP with those of its progenitor cell line A549. A total of 1214 differentially expressed genes (DEGs) were identified, 656 of which were upregulated and 558 were downregulated. Functional annotation of the DEGs in the Kyoto Encyclopedia of Genes and Genomes database revealed that most of the identified genes were enriched in the PI3K/AKT, mitogen-activated protein kinase, actin cytoskeleton regulation, and focal adhesion pathways in A549/DDP cells. These results support previous studies demonstrating that the pathways regulating cell proliferation and invasion confer resistance to chemotherapy. Furthermore, the results proved that cell adhesion and cytoskeleton regulation is associated with cisplatin resistance in human lung cancer. Our study provides new promising biomarkers for lung cancer prognosis and potential therapeutic targets for lung cancer treatment. PMID:28114404

  4. Analysis of risk factors for cisplatin-induced ototoxicity in patients with testicular cancer.

    PubMed Central

    Bokemeyer, C.; Berger, C. C.; Hartmann, J. T.; Kollmannsberger, C.; Schmoll, H. J.; Kuczyk, M. A.; Kanz, L.

    1998-01-01

    This study evaluates the degree and relevance of persisting ototoxicity after cisplatin-based standard-dose chemotherapy for testicular cancer, with emphasis on identification of potential factors for an increased risk of this late sequel. Hearing thresholds of 86 patients with a median age of 31 years (range 21-53 years) and a median follow-up time of 58 months (range 15-159 months) were assessed by conventional pure-tone audiometry. Interviews were conducted evaluating the patients' history with special regard to audiological risk factors, as well as circumstances of ototoxic symptoms. Details concerning treatment and patient variables were extracted retrospectively from the patients' charts. An additional screening programme assessed current body functions, blood parameters and other late toxicities. Symptomatic ototoxicity persisted in 20% of patients (59% tinnitus, 18% hearing loss, 23% both), while 10% had experienced completely reversible ototoxic symptoms for a duration of 1-18 months after treatment. Symptoms were bilateral in 81% of patients. Hearing thresholds were compatible with cisplatin-induced hearing loss in 42% of audiograms performed. Subjective (history) and objective (audiogram) findings were not always consistent. The following statistically significant risk factors for ototoxicity were established: high cumulative dose of cisplatin (P < 0.0001); history of noise exposure (P = 0.006). Additionally, high doses of vincristine (P = 0.001) seemed to result in reversible ototoxic symptoms. No other independent risk factors were identified. In conclusion, persisting ototoxicity represents a clinical sequel for approximately 20% of testicular cancer patients treated at standard dose but may affect more than 50% of patients receiving cumulative doses of cisplatin > 400 mg m(-2). Previous noise exposure may also result in a threefold increased risk for cisplatin ototoxicity. Future studies should use these risk factors as important stratification

  5. Structure Determination of Ornithine-Linked Cisplatin by Infrared Multiple Photon Dissociation Action Spectroscopy

    NASA Astrophysics Data System (ADS)

    He, Chenchen; Kimutai, Bett; Hamlow, Lucas; Roy, Harrison; Nei, Y.-W.; Bao, Xun; Gao, Juehan; Martens, Jonathan K.; Berden, Giel; Oomens, Jos; Maitre, Philippe; Steinmetz, Vincent; McNary, Christopher P.; Armentrout, Peter B.; Chow, C. S.; Rodgers, M. T.

    2016-06-01

    Cisplatin [(NH_3)_2PtCl_2], the first FDA-approved platinum-based anticancer drug, has been widely used in cancer chemotherapy. Its pharmacological mechanism has been identified as its ability to coordinate to genomic DNA with guanine as its major target. Amino acid-linked cisplatin derivatives are being investigated as alternatives for cisplatin that may exhibit altered binding selectivity such as that found for ornithine-linked cisplatin (Ornplatin, [(Orn)PtCl_2]), which exhibits a preference for adenine over guanine in RNA. Infrared multiple photon dissociation (IRMPD) action spectroscopy experiments and complementary electronic structure calculations are performed on a series of Ornplatin complexes to elucidate the nature of binding of the Orn amino acid to the Pt center and how that binding is influenced by the local environment. The complexes examined in the work include: [(Orn-H)PtCl_2]-, [(Orn)PtCl]+, [(Orn)Pt(H_2O)Cl]+, and [(Orn)PtCl_2+Na]+. In contrast to that found previously for the glycine-linked cisplatin complex (Glyplatin), which binds via the backbone amino and carboxylate groups, binding of Orn in these complexes is found to involve both the backbone and sidechain amino groups. Extensive broadening of the IRMPD spectrum for the [(Orn)Pt(H_2O)Cl]+ complex suggests that either multiple structures are contributing to the measured spectrum or strong intra-molecular hydrogen-binding interactions are present. The results for Ornplatin lead to an interesting discussion about the differences in selectivity and reactivity versus cisplatin.

  6. Preventive Effect of Dihydromyricetin against Cisplatin-Induced Nephrotoxicity In Vitro and In Vivo

    PubMed Central

    2016-01-01

    Nephrotoxicity is a frequent severe side effect of cisplatin chemotherapy, limiting its clinical use despite being one of the most potent chemotherapy drugs. Dihydromyricetin is a highly abundant compound purified from the leaves of Ampelopsis grossedentata. Previous studies have demonstrated the anti-inflammatory and antioxidative effects of Dihydromyricetin both in vitro and in vivo, but little is known about the effects of Dihydromyricetin on cisplatin-induced nephrotoxicity and its underlying mechanisms. In the present study, we investigated its potential renoprotective effect and found that Dihydromyricetin ameliorated the renal functional impairment and structural damage caused by cisplatin. Moreover, Dihydromyricetin markedly attenuated cisplatin-induced oxidative stress, as well as protecting against cisplatin-induced inflammation and apoptotic cell death in mouse kidney tissues. These results collectively highlight the potential of DMY as a rational renoprotective agent against cisplatin. PMID:27642358

  7. Electrohydrodynamic encapsulation of cisplatin in poly (lactic-co-glycolic acid) nanoparticles for controlled drug delivery.

    PubMed

    Parhizkar, Maryam; Reardon, Philip J T; Knowles, Jonathan C; Browning, Richard J; Stride, Eleanor; Barbara, Pedley R; Harker, Anthony H; Edirisinghe, Mohan

    2016-10-01

    Targeted delivery of potent, toxic chemotherapy drugs, such as cisplatin, is a significant area of research in cancer treatment. In this study, cisplatin was successfully encapsulated with high efficiency (>70%) in poly (lactic-co-glycolic acid) polymeric nanoparticles by using electrohydrodynamic atomization (EHDA) where applied voltage and solution flow rate as well as the concentration of cisplatin and polymer were varied to control the size of the particles. Thus, nanoparticles were produced with three different drug:polymer ratios (2.5, 5 and 10wt% cisplatin). It was shown that smaller nanoparticles were produced with 10wt% cisplatin. Furthermore, these demonstrated the best sustained release (smallest burst release). By fitting the experimental data with various kinetic models it was concluded that the release is dependent upon the particle morphology and the drug concentration. Thus, these particles have significant potential for cisplatin delivery with controlled dosage and release period that are crucial chemotherapy parameters.

  8. Postoperative Chemotherapy Followed by Conformal Concomitant Chemoradiotherapy in High-Risk Gastric Cancer

    SciTech Connect

    Quero, Laurent; Bouchbika, Zineb; Kouto, Honorine; Baruch-Hennequin, Valerie; Gornet, Jean-Marc; Munoz, Nicolas; Cojean-Zelek, Isabelle; Houdart, Remi; Panis, Yves; Valleur, Patrice; Aparicio, Thomas; Maylin, Claude; Hennequin, Christophe

    2012-06-01

    Purpose: To analyze the efficacy, toxicity, and pattern of relapse after adjuvant cisplatin-based chemotherapy followed by three-dimensional irradiation and concomitant LV5FU2 chemotherapy (high-dose leucovorin and 5-fluorouracil bolus plus continuous infusion) in the treatment of completely resected high-risk gastric cancer. Methods and Materials: This was a retrospective analysis of 52 patients with high-risk gastric cancer initially treated by total/partial gastrectomy and lymphadenectomy between January 2002 and June 2007. Median age was 54 years (range, 36-75 years). Postoperative treatment consisted of 5-fluorouracil and cisplatin chemotherapy. Adjuvant chemotherapy was followed by three-dimensional conformal radiotherapy in the tumor bed and regional lymph nodes at 4500 cGy/25 fractions in association with concomitant chemotherapy. Concomitant chemotherapy consisted of a 2-h infusion of leucovorin (200 mg/m Superscript-Two ) followed by a bolus of 5-fluorouracil (400 mg/m Superscript-Two ) and then a 44-h continuous infusion of 5-fluorouracil (2400-3600 mg/m Superscript-Two ) given every 14 days, for three cycles (LV5FU2 protocol). Results: Five-year overall and disease-free survival were 50% and 48%, respectively. Distant metastases and peritoneal spread were the most frequent sites of relapse (37% each). After multivariate analysis, only pathologic nodal status was significantly associated with disease-free and overall survival. Acute toxicities were essentially gastrointestinal and hematologic. One myocardial infarction and one pulmonary embolism were also reported. Eighteen patients had a radiotherapy program interruption because of acute toxicity. All patients but 2 have completed radiotherapy. Conclusion: Postoperative cisplatin-based chemotherapy followed by conformal radiotherapy in association with concurrent 5-fluorouracil seemed to be feasible and resulted in successful locoregional control.

  9. Adjuvant chemotherapy for early-stage cervical cancer

    PubMed Central

    Asano, Hiroshi; Todo, Yukiharu; Watari, Hidemichi

    2016-01-01

    The aim of this review is to address the current status of adjuvant chemotherapy alone in early-stage cervical cancer treatments in the literature. At present, the therapeutic effect of adjuvant chemotherapy alone after radical surgery (RS) has not yet been established, and radiation therapy (RT) or concurrent chemoradiotherapy (CCRT) is recommended as the standard adjuvant therapy after RS for early-stage cervical cancer in various guidelines. The main purpose of adjuvant therapy after RS, however, should be to reduce extrapelvic recurrence rather than local recurrence, although adjuvant RT or CCRT has survival benefits for patients with intermediate- or high-risk factors for recurrence. Moreover, several studies reported that adjuvant therapies including RT were associated with a higher incidence of complications, such as lymphedema, bowel obstruction and urinary disturbance, and a lower grade of long-term quality of life (QOL) or sexual functioning than adjuvant chemotherapy alone. The effect of adjuvant chemotherapy alone for early-stage cervical cancer with intermediate- or high-risk factors for recurrence were not fully investigated in prospective studies, but several retrospective studies suggest that the adjuvant effects of chemotherapy alone are at least similar to that of RT or CCRT in terms of recurrence rate, disease-free survival, or overall survival (OS) with lower incidence of complications. Whereas cisplatin based combination regimens were used in these studies, paclitaxel/cisplatin (TP) regimen, which is currently recognized as a standard chemotherapy regimen for patients with metastatic, recurrent or persistent cervical cancer by Gynecologic Oncology Group (GOG), had also survival benefit as an adjuvant therapy. Therefore, it may be worth considering a prospective randomized controlled trial (RCT) of adjuvant chemotherapy alone using TP regimen versus adjuvant RT as an alternative adjuvant therapy. Because early-stage cervical cancer is a curable

  10. ERCC1 and the efficacy of cisplatin in patients with resected non-small cell lung cancer.

    PubMed

    Li, Chunhong; Liu, Meiyan; Yan, An; Liu, Wei; Hou, Junjun; Cai, Li; Dong, Xiaoqun

    2014-12-01

    Excision repair cross-complementing gene 1 (ERCC1) protein is proposed as a predictor for cisplatin efficacy in patients with non-small cell lung cancer (NSCLC). However, recent studies declare that ERCC1 is not associated with the response of platinum-based chemotherapy or clinical outcomes. The purpose of this study is to assess whether ERCC1 expression level is linked to cisplatin sensitivity and clinical outcomes in resected NSCLC patients. Paraffin-embedded cancer samples from 112 patients were used for immunohistochemical staining. Cancer cells isolated from fresh tumor tissues were used to determine the sensitivity to cisplatin by MTT assay. The association between ERCC1 expression and cisplatin sensitivity was tested by Spearman's rho test. The correlation of ERCC1 expression with clinicopathologic parameters was evaluated by the chi-square tests. The relationship between variables and survival was assessed by log-rank test. Overall survival (OS) and disease-free survival (DFS) curves were plotted by the Kaplan-Meier method. Cox proportional hazards model was used for multivariate analysis of survival. ERCC1 expression was significantly correlated with the sensitivity of cisplatin in vitro (p < 0.01, r = 0.37). ERCC1 was not associated with OS (p = 0.17) or DFS (p = 0.13) in patients with resected NSCLC. ERCC1 is not a sensible marker for the choice of treatment in clinical patients with resected NSCLC.

  11. 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

  12. Prognostic markers of survival after combined mitotane- and platinum-based chemotherapy in metastatic adrenocortical carcinoma.

    PubMed

    Malandrino, Pasqualino; Al Ghuzlan, Abir; Castaing, Marine; Young, Jacques; Caillou, Bernard; Travagli, Jean-Paul; Elias, Dominique; de Baere, Thierry; Dromain, Clarisse; Paci, Angelo; Chanson, Philippe; Schlumberger, Martin; Leboulleux, Sophie; Baudin, Eric

    2010-09-01

    To progress in the stratification of the first-line therapeutic management of metastatic adrenocortical carcinoma (ACC), we searched for prognostic parameters of survival in patients treated with combined mitotane- and cisplatinum-based chemotherapy as first-line. We retrospectively studied prospectively collected parameters from 131 consecutive patients with metastatic ACC (44 with a tissue specimen available) treated at the Gustave Roussy Institute with mitotane- and platinum-based chemotherapy. Fifty-five patients with clinical, pathological, and morphological data available together with treatment characteristics including detailed follow-up were enrolled. Plasma mitotane levels and ERCC1 protein staining were analyzed. Response was analyzed according to RECIST criteria as well as overall survival (OS) from the start of cisplatinum-based chemotherapy. Parameters impacting on OS were evaluated by univariate analysis, and then analyzed by multivariate analysis. Using a landmark method, OS according to response to chemotherapy was analyzed. Objective response to combined mitotane- and cisplatinum-based chemotherapy was 27.3%. Median OS was 1 year. In the univariate analysis, resection of the primary, time since diagnosis, mitotane monotherapy as single first-line treatment, number of affected organs, plasma mitotane above 14 mg/l, and objective response were predictors of survival. In the multivariate analysis, mitotane level > or =14 mg/l and objective response to platinum-based chemotherapy were found to be independent predictors of survival (P=0.03 and <0.001). Our study suggests a prognostic role for mitotane therapy and objective response to platinum-based chemotherapy.

  13. S-1-Based Chemotherapy versus Capecitabine-Based Chemotherapy as First-Line Treatment for Advanced Gastric Carcinoma: A Meta-Analysis

    PubMed Central

    Wang, Zhi-qiang; Zhang, Dong-sheng; Luo, Hui-yan; Qiu, Miao-zhen; Wang, Feng-hua; Ren, Chao; Zeng, Zhao-lei; Xu, Rui-hua

    2013-01-01

    Background Although both oral fluoropyrimidines were reported effective and safe, doubts exist about whether S-1 or capecitabine is more advantageous in advanced gastric carcinoma (AGC). Herein, we performed a meta-analysis to comprehensively compare the efficacy and safety of S-1-based chemotherapy versus capecitabine-based chemotherapy as first-line treatment for AGC. Methods PubMed/Medline, EmBase, Cochrane library, and China National Knowledge Infrastructure databases were searched for articles comparing S-1-based chemotherapy to capecitabine-based chemotherapy for AGC. Primary outcomes were overall response rate (ORR), time to progression (TTP), overall survival (OS), progression-free probability, and survival probability. Secondary outcomes were toxicities. Fixed-effects model were used and all the results were confirmed by random-effects model. Results Five randomized controlled trials and five cohort studies with 821 patients were included. We found equivalent ORR (38.3% vs. 39.1%, odds ratio [OR] 0.92, 95% confidence interval [CI] 0.69-1.24, P = 0.59), TTP (harzad ratio [HR] 0.98, 95% CI 0.82-1.16, P = 0.79), OS (HR 0.99, 95% CI 0.87-1.13, P = 0.91), progression-free probability (3-month OR 1.02, 95% CI 0.62-1.68, P = 0.94; 6-month OR 1.34, 95% CI 0.88-2.04, P = 0.18) and survival probability (0.5-year OR 0.90, 95% CI 0.61-1.31, P =0.57; 1-year OR 0.97, 95% CI 0.70- 1.33, P = 0.84; 2-year OR 1.15, 95% CI 0.61-2.17, P = 0.66). Equivalent grade 3 to 4 hematological and non-hematological toxicities were found except hand-foot syndrome was less prominent in S-1-based chemotherapy (0.3% vs. 5.9%, OR 0.19, 95% CI 0.06-0.56, P = 0.003). There’re no significant heterogeneity and publication bias. Cumulative analysis found stable time-dependent trend. Consistent results stratified by study design, age, regimen, cycle, country were observed. Conclusion S-1-based chemotherapy was associated with non-inferior antitumor efficacy and better safety profile, compared

  14. MT 2A Phosphorylation by PKC Mu/PKD Influences Chemosensitivity to Cisplatin in Prostate Cancer

    DTIC Science & Technology

    2008-11-01

    reduce MT induction in mice inocu- ated with human or murine bladder tumor cells, hich markedly enhanced the antitumor activity f cisplatin and other...85–98, 1999. B ROLOGY 67 (6), 200611. Kondo Y, Yamagata K, Satoh M, et al: Optimal admin- stration schedule of cisplatin for bladder tumor with...analysis. Chemotherapy and radiation sensitivity assays of cells after treatment with cisplatin or radiation were performed in the presence, or absence, of

  15. Quantitative imaging of platinum based on laser ablation-inductively coupled plasma-mass spectrometry to investigate toxic side effects of cisplatin.

    PubMed

    Köppen, C; Reifschneider, O; Castanheira, I; Sperling, M; Karst, U; Ciarimboli, G

    2015-12-01

    This work presents a quantitative bioimaging method for platinum based on laser ablation-inductively coupled plasma-mass spectrometry and its application for a biomedical study concerning toxic side effects of cisplatin. To trace the histopathology back to cisplatin, platinum was localized and quantified in major functional units of testicle, cochlea, kidney, nerve and brain sections from cisplatin treated mice. The direct consideration of the histology enables precise interpretation of the Pt images and the novel quantitative evaluation approach allows significantly more precise investigations than the pure image. For the first time, platinum was detected and quantified in all major injured structures including organ of Corti of cochlea and seminiferous tubule of testicle. In this way, proximal tubule in kidney, Leydig cells in testicle, stria vascularis and organ of Corti in cochlea and nerve fibers in sciatic nerves are confirmed as targets of cisplatin in these organs. However, the accumulation of platinum in almost all investigated structures also raises questions about more complex pathogenesis including direct and indirect interruption of several biological processes.

  16. Phase II multi-institutional prospective randomised trial comparing S-1+paclitaxel with S-1+cisplatin in patients with unresectable and/or recurrent advanced gastric cancer

    PubMed Central

    Mochiki, E; Ogata, K; Ohno, T; Toyomasu, Y; Haga, N; Fukai, Y; Aihara, R; Ando, H; Uchida, N; Asao, T; Kuwano, H

    2012-01-01

    Background: A combination of S-1 and cisplatin has been shown to be effective with acceptable safety for the first-line treatment of far-advanced gastric cancer in Japan. This is the first randomised phase II trial to compare S-1+paclitaxel with S-1+cisplatin in this setting. Methods: Patients with unresectable and/or recurrent advanced gastric cancer were randomly assigned to receive one of the two regimens: S-1 (40 mg m−2 twice daily) on days 1–14 plus paclitaxel (60 mg m−2) on days 1, 8, and 15 of a 4-week cycle (S-1+paclitaxel) or S-1 (40 mg m−2 twice daily) on days 1–21 plus cisplatin (60 mg m−2) on day 8 of a 5-week cycle (S-1+cisplatin). The primary end point was the response rate (RR). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 83 patients were eligible for safety and efficacy analyses. In the S-1+paclitaxel and S-1+cisplatin groups, RRs (52.3% vs 48.7% P=0.74) and median PFS (9 vs 6 months; P=0.50) were similar. The median OS was similar in the S-1+paclitaxel and S-1+cisplatin groups (16 vs 17 months; P=0.84). The incidence of grade 3 or higher haematological toxicity was 19.0% with S-1+paclitaxel and 19.5% with S-1+cisplatin. The incidence of grade 3 or higher non-haematological toxicity was 14.2% with S-1+paclitaxel and 17.1% with S-1+cisplatin. Conclusion: S-1+paclitaxel was suggested to be a feasible and effective non-platinum-based regimen for chemotherapy in patients with advanced gastric cancer. Our results should be confirmed in multicenter, phase III-controlled clinical trials. PMID:22617130

  17. 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.

  18. Efficacy of carboplatin-based preoperative chemotherapy for triple-negative breast cancer

    PubMed Central

    Wang, Li-Yang; Xie, Hua; Zhou, Hang; Yao, Wen-Xiu; Zhao, Xin; Wang, Yi

    2017-01-01

    Objectives: To evaluate the efficacy and safety of carboplatin-based preoperative chemotherapy in triple-negative breast cancer patients (TNBC). Methods: PubMed, EMBASE, the Web of Science, the Cochrane Library, major clinical trial registries, and abstract collections from major international meetings were systematically searched for relevant randomized controlled trials. Endpoints included rates of pathologic complete response (pCR), overall response (ORR), breast-conserving surgery (BCS) and toxicity. Pooled relative risk (RR) was calculated for each endpoint using a fixed- or random-effect model depending on the heterogeneity among included studies. Results: A total of 5 randomized controlled trials involving 1007 patients were included in the meta-analysis. Carboplatin-based chemotherapy was associated with a pooled pCR rate of 53.3%, which was significantly higher than the rate associated with non-carboplatin therapy (37.8%, RR: 1.41, 95% confidence interval [CI]: 1.23 to 1.62, p<0.00001). Compared with non-carboplatin therapy (48.1%), carboplatin-based chemotherapy increased BCS rate (59.7%, RR: 1.24, 95% CI: 1.06 to 1.46, p=0.007). Carboplatin-based chemotherapy was associated with similar ORR as non-carboplatin therapy. Carboplatin-based chemotherapy was associated with higher incidence of grade 3 or 4 anemia, neutropenia, febrile neutropenia, and thrombocytopenia than non-carboplatin therapy, while the 2 regimens were associated with similar incidence of fatigue, leucopenia, and nausea/vomiting. Conclusion: The available evidence suggests that carboplatin-based preoperative chemotherapy is associated with significantly better pCR and BCS rates than non-carboplatin-based therapy in TNBC patients. PMID:28042625

  19. Risk based neoadjuvant chemotherapy in muscle invasive bladder cancer

    PubMed Central

    Jayaratna, Isuru S.; Navai, Neema

    2015-01-01

    Muscle invasive bladder cancer (MIBC) is an aggressive disease that frequently requires radical cystectomy (RC) to achieve durable cure rates. Surgery is most effective when performed in organ-confined disease, with the best outcomes for those patients with a pT0 result. The goals of neoadjuvant chemotherapy (NC) are to optimize surgical outcomes for a malignancy with limited adjuvant therapies and a lack of effective salvage treatments. Despite level 1 evidence demonstrating a survival benefit, the utilization of NC has been hampered by several issues, including, the inability to predict responders and the perception that NC may delay curative surgery. In this article, we review the current efforts to identify patients that are most likely to derive a benefit from NC, in order to create a risk-adapted paradigm that reserves NC for those who need it. PMID:26816830

  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.

  1. Nanoscale Drug Delivery Platforms Overcome Platinum-Based Resistance in Cancer Cells Due to Abnormal Membrane Protein Trafficking

    PubMed Central

    Xue, Xue; Hall, Matthew D.; Zhang, Qiang; Wang, Paul C.; Gottesman, Michael M.; Liang, Xing-Jie

    2014-01-01

    The development of cellular resistance to platinum-based chemotherapies is often associated with reduced intracellular platinum concentrations. In some models, this reduction is due to abnormal membrane protein trafficking, resulting in reduced uptake by transporters at the cell surface. Given the central role of platinum drugs in the clinic, it is critical to overcome cisplatin resistance by bypassing the plasma membrane barrier to significantly increase the intracellular cisplatin concentration enough to inhibit the proliferation of cisplatin-resistant cells. Therefore, rational design of appropriate nanoscale drug delivery platforms (nDDPs) loaded with cisplatin or other platinum analogs as payloads is a possible strategy to solve this problem. This review will focus on the known mechanism of membrane trafficking in cisplatin-resistant cells, and the development and employment of nDDPs to improve cell uptake of cisplatin. PMID:24219825

  2. Nanoscale drug delivery platforms overcome platinum-based resistance in cancer cells due to abnormal membrane protein trafficking.

    PubMed

    Xue, Xue; Hall, Matthew D; Zhang, Qiang; Wang, Paul C; Gottesman, Michael M; Liang, Xing-Jie

    2013-12-23

    The development of cellular resistance to platinum-based chemotherapies is often associated with reduced intracellular platinum concentrations. In some models, this reduction is due to abnormal membrane protein trafficking, resulting in reduced uptake by transporters at the cell surface. Given the central role of platinum drugs in the clinic, it is critical to overcome cisplatin resistance by bypassing the plasma membrane barrier to significantly increase the intracellular cisplatin concentration enough to inhibit the proliferation of cisplatin-resistant cells. Therefore, rational design of appropriate nanoscale drug delivery platforms (nDDPs) loaded with cisplatin or other platinum analogues as payloads is a possible strategy to solve this problem. This review will focus on the known mechanism of membrane trafficking in cisplatin-resistant cells and the development and employment of nDDPs to improve cell uptake of cisplatin.

  3. p53-Based Strategy to Reduce Hematological Toxicity of Chemotherapy: A Proof of Principle Study

    PubMed Central

    Ha, Chul S.; Michalek, Joel E.; Elledge, Richard; Kelly, Kevin R.; Ganapathy, Suthakar; Su, Hang; Jenkins, Carol A.; Argiris, Athanassios; Swords, Ronan; Eng, Tony Y.; Karnad, Anand; Crownover, Richard L.; Swanson, Gregory P.; Goros, Martin; Pollock, Brad H.; Yuan, Zhi-Min

    2015-01-01

    P53 activation is a primary mechanism underlying pathological responses to DNA-damaging agents such as chemotherapy and radiotherapy. Our recent animal studies showed that low dose arsenic (LDA)-induced transient p53 inhibition selectively protected normal tissues from chemotherapy-induced toxicity. Study objectives were to: 1) define the lowest safe dose of arsenic trioxide that transiently blocks p53 activation in patients and 2) assess the potential of LDA to decrease hematological toxicity from chemotherapy. Patients scheduled to receive minimum 4 cycles of myelosuppressive chemotherapy were eligible. For objective 1, dose escalation of LDA started at 0.005mg/kg/day for 3 days. This dose satisfied objective 1 and was administered before chemotherapy cycles 2, 4 and 6 for objective 2. P53 level in peripheral lymphocytes was measured on day 1 of each cycle by ELISA assay. Chemotherapy cycles 1, 3, and 5 served as the baseline for the subsequent cycles of 2, 4 and 6 respectively. If p53 level for the subsequent cycle was lower (or higher) than the baseline cycle, p53 was defined as “suppressed” (or “activated”) for the pair of cycles. Repeated measures linear models of CBC in terms of day, cycle, p53 activity and interaction terms were used. Twenty-six patients treated with 3 week cycle regimens form the base of analyses. The mean white blood cell, hemoglobin and absolute neutrophil counts were significantly higher in the “suppressed” relative to the “activated” group. These data support the proof of principle that suppression of p53 could lead to protection of bone marrow in patients receiving chemotherapy. PMID:26440706

  4. CD147 and MCT1-potential partners in bladder cancer aggressiveness and cisplatin resistance.

    PubMed

    Afonso, Julieta; Santos, Lúcio L; Miranda-Gonçalves, Vera; Morais, António; Amaro, Teresina; Longatto-Filho, Adhemar; Baltazar, Fátima

    2015-11-01

    The relapsing and progressive nature of bladder tumors, and the heterogeneity in the response to cisplatin-containing regimens, are the major concerns in the care of urothelial bladder carcinoma (UBC) patients. The metabolic adaptations that alter the tumor microenvironment and thus contribute to chemoresistance have been poorly explored in UBC setting. We found significant associations between the immunoexpressions of the microenvironment-related molecules CD147, monocarboxylate transporters (MCTs) 1 and 4, CD44 and CAIX in tumor tissue sections from 114 UBC patients. The presence of MCT1 and/or MCT4 expressions was significantly associated with unfavorable clinicopathological parameters. The incidence of CD147 positive staining significantly increased with advancing stage, grade and type of lesion, and occurrence of lymphovascular invasion. Similar associations were observed when considering the concurrent expression of CD147 and MCT1. This expression profile lowered significantly the 5-year disease-free and overall survival rates. Moreover, when selecting patients who received platinum-based chemotherapy, the prognosis was significantly worse for those with MCT1 and CD147 positive tumors. CD147 specific silencing by small interfering RNAs (siRNAs) in UBC cells was accompanied by a decrease in MCT1 and MCT4 expressions and, importantly, an increase in chemosensitivity to cisplatin. Our results provide novel insights for the involvement of CD147 and MCTs in bladder cancer progression and resistance to cisplatin-based chemotherapy. We consider that the possible cooperative role of CD147 and MCT1 in determining cisplatin resistance should be further explored as a potential theranostics biomarker.

  5. May glutamine addiction drive the delivery of antitumor cisplatin-based Pt(IV) prodrugs?

    PubMed

    Ravera, Mauro; Gabano, Elisabetta; Tinello, Stefano; Zanellato, Ilaria; Osella, Domenico

    2017-02-01

    A small series of Pt(IV) prodrugs containing Gln-like (Gln=glutamine) axial ligands has been designed with the aim to take advantage of the increased demand of Gln showed by some cancer cells (glutamine addiction). In complex 4 the Gln, linked through the α-carboxylic group is recognized by the Gln transporters, in particular by the solute carrier transporter SLC1A5. All compounds showed cellular accumulation, as well as antiproliferative activity, related to their lipophilicity, as already demonstrated for the majority of Pt(IV) prodrugs, that enter cells mainly by passive diffusion. On the contrary, when the Gln concentration in cell medium is near or lower to the physiological value, complex 4 acts as a Trojan horse: it enters SLC1A5-overexpressing cells, where, upon reduction, it releases the active metabolite cisplatin and the Gln-containing ligand, thus preventing any possible extrusion by the L-type amino acid transporter LAT1. This selective mechanism could decrease off-target accumulation of 4 and, consequently, Pt-associated side-effects.

  6. Role of chemotherapy in the management of advanced thymic tumors.

    PubMed

    Evans, Tracey L; Lynch, Thomas J

    2005-01-01

    Chemotherapy has an important role in the treatment of advanced thymic tumors. Early stage tumors are successfully treated with surgery. Locally advanced tumors (Masaoka stage III and IVA) are often treated with combined modality treatment including surgery, radiation, and chemotherapy. For patients with curable thymic tumors, the ability to attain a complete resection is a critical prognostic factor. Locally advanced tumors have a relatively high risk of recurrence and decreased rates of long-term survival. A multimodality approach including induction chemotherapy and postoperative radiation therapy can improve complete resection rates and long-term outcomes. Thymic tumors are chemoresponsive with optimal responses achieved with cisplatin-based combination chemotherapy. Chemotherapy with radiation can result in long-term progression-free survival for patients with locally advanced disease who remain inoperable following induction therapy. Patients with disseminated (stage IVB) thymic tumors can also have significant disease response and palliation of symptoms when treated with chemotherapy. Octreotide and corticosteroids also have shown efficacy. For best results, it is important that thoracic surgeons, radiation oncologists, and medical oncologists work together to obtain the best local control of tumor and optimal treatment of metastases.

  7. Neoadjuvant chemotherapy in muscle-invasive bladder cancer: ready for prime time?

    PubMed

    Pouessel, Damien; Mongiat-Artus, Pierre; Culine, Stéphane

    2013-03-01

    Through a Medline search from January 1, 1998 to February 29, 2012, the literature data supporting the standard use of neoadjuvant or adjuvant chemotherapy in the perioperative setting for muscle-invasive transitional cell carcinoma of the bladder were reviewed. Randomized phase III trials and meta-analyses have shown a significant benefit (level I evidence) in overall survival for neoadjuvant chemotherapy, with a 5% absolute benefit at 5 years, provided cisplatin-based combination regimens are used. Major methodological biases preclude any firm conclusion regarding the routine use of adjuvant therapy. The optimal chemotherapy regimen remains to be determined. Predictive biomarkers are urgently needed in order to determine which patients are more likely to benefit from neoadjuvant chemotherapy.

  8. Pharmacogenomics of platinum-based chemotherapy response in NSCLC: a genotyping study and a pooled analysis

    PubMed Central

    Chen, Juan; Wang, Zhan; Zou, Ting; Cui, Jiajia; Yin, Jiye; Zheng, Wei; Jiang, Wuzhong; Zhou, Honghao; Liu, Zhaoqian

    2016-01-01

    Published data showed inconsistent results about associations of extensively studied polymorphisms with platinum-based chemotherapy response. Our study aimed to provide reliable conclusions of these associations by detecting genotypes of the SNPs in a larger sample size and summarizing a comprehensive pooled analysis. 13 SNPs in 8 genes were genotyped in 1024 NSCLC patients by SequenomMassARRAY. 39 published studies and our study were included in meta-analysis. Patients with GA or GG genotypes of XRCC1 G1196 had better response than AA genotype carriers (Genotyping study: OR = 0.72, 95%CI: 0.53-0.96, P = 0.028; Meta-analysis: OR = 0.74, 95%CI: 0.62-0.89, P = 0.001). Patients carrying CT or TT genotypes of XRCC1 C580T could be more sensitive to platinum-based chemotherapy compared to patients with CC genotype (OR = 0.54, 95%CI: 0.37-0.80, P = 0.002). CC genotype of XRCC3 C18067T carriers showed more resistance to platinum-based chemotherapy when compared to those with CT or TT genotypes (OR = 0.69, 95%CI: 0.52-0.91, P = 0.009). Our study indicated that XRCC1 G1196A/C580T and XRCC3 C18067T should be paid attention for personalized platinum-based chemotherapy in NSCLC patients. PMID:27248474

  9. Anthracycline-based chemotherapy in extraskeletal myxoid chondrosarcoma: a retrospective study

    PubMed Central

    2013-01-01

    Background Extraskeletal myxoid chondrosarcoma (EMC) is a rare subgroup within soft tissue sarcomas. Its sensitivity to chemotherapy is reported to be low. Methods We retrospectively reviewed a series of 11 EMC patients treated as from 2001 within the Italian Rare Cancer Network (RCN) with anthracycline-based chemotherapy. Pathologic diagnosis was centrally reviewed in all cases and confirmed by the presence of the specific chromosomal rearrangements, involving the NR4A3 gene locus on chromosome 9. Results Eleven patients treated with anthracycline-based chemotherapy were included (M/F: 9/2 – mean age: 52 years – site of primary: lower limb/other = 9/2 - metastatic = 11 – front line/ further line = 10/1 – anthracycline as single agent/ combined with ifosfamide = 1/10). Ten patients are evaluable for response. Overall, best response according to RECIST was: partial response (PR) = 4 (40 %), stable disease (SD) = 3, progressive disease (PD) = 3 cases. Median PFS was 8 (range 2–10) months. Conclusions By contrast to what reported so far, anthracycline-based chemotherapy is active in a distinct proportion of EMC patients. PMID:24345066

  10. Potential implications of GRP58 expression and susceptibility of cervical cancer to cisplatin and thymoquinone-based therapy.

    PubMed

    Hafiza, Wan Abd Ghani Wan Nor; Latifah, Saiful Yazan

    2014-01-01

    A new therapeutic approach of looking at the expression of glucose-regulated protein (GRP) 58 as an indication of cisplatin sensitivity may eradicate fruitless treatment and side effects in patients with cervical cancer. Thymoquinone, the bioactive compound in Nigella sativa, has been reported to have an antiproliferative effect on cervical cancer cells. This study compared the cytotoxic effects of cisplatin, a drug commonly used in the treatment of cervical cancer, and thymoquinone in cervical cancer (HeLa and SiHa) cell lines by 3-(4,5-Dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and measured GRP58 expression in the cells by quantitative real-time polymerase chain reaction and Western blotting. Cisplatin had higher antiproliferative activity towards the cervical cancer cell lines than thymoquinone in a dose-dependent and time-dependent manner. However, cisplatin was more toxic to normal 3T3 and Vero cell lines than thymoquinone. The half maximal inhibitory concentration (IC50) of cisplatin in HeLa and SiHa cells at 72 hours was 13.3±2.52 μM and 19.5±2.12 μM, respectively. Meanwhile, the IC50 of thymoquinone in HeLa and SiHa cells was 29.57±5.81 μM and 23.41±1.51 μM, respectively (P<0.05). A significant correlation was found between the cytotoxicity of cisplatin and expression of GRP58, but this relationship was not significant for thymoquinone. Therefore, the response of cervical cancer cells to cisplatin can be predicted on the basis of GRP58 expression.

  11. The renoprotective activity of hesperetin in cisplatin induced nephrotoxicity in rats: Molecular and biochemical evidence.

    PubMed

    Kumar, Mukesh; Dahiya, Vicky; Kasala, Eshvendar Reddy; Bodduluru, Lakshmi Narendra; Lahkar, Mangala

    2017-03-14

    Nephrotoxicity remain a major life-threatening complication in cancer patients on cisplatin chemotherapy. In this study, we investigated the protective effect and possible cellular mechanism of the hesperetin, a naturally-occurring bioflavonoid against cisplatin-induced renal injury in rats. Hesperetin was administered at a dose of 50mg/kg and 100mg/kg orally for 10days and cisplatin (7.5mg/kg, ip) was administered on the 5th day of experiment. Cisplatin induced nephrotoxicity was evidenced by alteration in the level of markers such as blood urea nitrogen, creatinine, serum albumin and severe histopathological changes in kidney. Cisplatin administration also resulted in significant increase in the tissue oxidative stress and inflammatory cytokines. The level of antioxidants enzymes were decreased significantly in the cisplatin administered rats. Hesperetin treatment (50mg/kg and 100mg/kg) normalized the renal function by attenuation of the cisplatin-induced oxidative stress, lipid peroxidation, and inflammatory cytokines and histopathological alterations. On the basis of these experimental findings our present study postulate that co-administration of hesperetin with cisplatin chemotherapy may be promising preventive approach to limit the major mortal side effect of cisplatin.

  12. Origanum majorana Attenuates Nephrotoxicity of Cisplatin Anticancer Drug through Ameliorating Oxidative Stress

    PubMed Central

    Soliman, Amel M.; Desouky, Shreen; Marzouk, Mohamed; Sayed, Amany A.

    2016-01-01

    Despite the fact that cisplatin is an important anticancer drug, its clinical utilization is limited by nephrotoxicity during long term medication. Combined cisplatin chemotherapy with plant extracts can diminish toxicity and enhance the antitumor efficacy of the drug. This study evaluated the effect of Originum majorana ethanolic extract (OMEE) on cisplatin-induced nephrotoxicity. Eighteen male rats were divided into three groups as follows: a control group, a group treated with cisplatin (3 mg/kg body weight), and a group that received both cisplatin and OMEE (500 mg/kg body weight) for 14 days. Cisplatin induced a significant increase in creatinine, urea, uric acid, blood urea nitrogen, malondialdehyde, and nitric oxide levels. However, glutathione, superoxide dismutase, and catalase levels were significantly diminished. Conversely, OMEE significantly modulated the renal and oxidative markers negatively impacted by cisplatin. OMEE significantly reduced the effects of cisplatin-induced changes in renal and oxidative markers, possibly through its free radical scavenging activity. Thus, OMEE may be combined with cisplatin to alleviate nephrotoxicity in cancer chemotherapy. PMID:27164131

  13. Excitatory Hindbrain-Forebrain Communication Is Required for Cisplatin-Induced Anorexia and Weight Loss.

    PubMed

    Alhadeff, Amber L; Holland, Ruby A; Zheng, Huiyuan; Rinaman, Linda; Grill, Harvey J; De Jonghe, Bart C

    2017-01-11

    Cisplatin chemotherapy is commonly used to treat cancer despite severe energy balance side effects. In rats, cisplatin activates nucleus tractus solitarius (NTS) projections to the lateral parabrachial nucleus (lPBN) and calcitonin-gene related peptide (CGRP) projections from the lPBN to the central nucleus of the amygdala (CeA). We demonstrated previously that CeA glutamate receptor signaling mediates cisplatin-induced anorexia and body weight loss. Here, we used neuroanatomical tracing, immunofluorescence, and confocal imaging to demonstrate that virtually all NTS→lPBN and lPBN→CeA CGRP projections coexpress vesicular glutamate transporter 2 (VGLUT2), providing evidence that excitatory projections mediate cisplatin-induced energy balance dysregulation. To test whether lPBN→CeA projection neurons are required for cisplatin-induced anorexia and weight loss, we inhibited these neurons chemogenetically using a retrograde Cre-recombinase-expressing canine adenovirus-2 in combination with Cre-dependent inhibitory Designer Receptors Exclusive Activated by Designer Drugs (DREADDs) before cisplatin treatment. Inhibition of lPBN→CeA neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Using a similar approach, we additionally demonstrated that inhibition of NTS→lPBN neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Together, our data support the view that excitatory hindbrain-forebrain projections are necessary for cisplatin's untoward effects on energy intake, elucidating a key neuroanatomical circuit driving pathological anorexia and weight loss that accompanies chemotherapy treatment.

  14. Origanum majorana Attenuates Nephrotoxicity of Cisplatin Anticancer Drug through Ameliorating Oxidative Stress.

    PubMed

    Soliman, Amel M; Desouky, Shreen; Marzouk, Mohamed; Sayed, Amany A

    2016-05-05

    Despite the fact that cisplatin is an important anticancer drug, its clinical utilization is limited by nephrotoxicity during long term medication. Combined cisplatin chemotherapy with plant extracts can diminish toxicity and enhance the antitumor efficacy of the drug. This study evaluated the effect of Originum majorana ethanolic extract (OMEE) on cisplatin-induced nephrotoxicity. Eighteen male rats were divided into three groups as follows: a control group, a group treated with cisplatin (3 mg/kg body weight), and a group that received both cisplatin and OMEE (500 mg/kg body weight) for 14 days. Cisplatin induced a significant increase in creatinine, urea, uric acid, blood urea nitrogen, malondialdehyde, and nitric oxide levels. However, glutathione, superoxide dismutase, and catalase levels were significantly diminished. Conversely, OMEE significantly modulated the renal and oxidative markers negatively impacted by cisplatin. OMEE significantly reduced the effects of cisplatin-induced changes in renal and oxidative markers, possibly through its free radical scavenging activity. Thus, OMEE may be combined with cisplatin to alleviate nephrotoxicity in cancer chemotherapy.

  15. 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

  16. Dunnione ameliorates cisplatin ototoxicity through modulation of NAD(+) metabolism.

    PubMed

    Kim, Hyung-Jin; Pandit, Arpana; Oh, Gi-Su; Shen, AiHua; Lee, Su-Bin; Khadka, Dipendra; Lee, SeungHoon; Shim, Hyeok; Yang, Sei-Hoon; Cho, Eun-Young; Kwak, Tae Hwan; Choe, Seong-Kyu; Park, Raekil; So, Hong-Seob

    2016-03-01

    Ototoxicity is an important issue in patients receiving cisplatin chemotherapy. Numerous studies have demonstrated that cisplatin-induced ototoxicity is related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD(+)) has emerged as an important regulator of energy metabolism and cellular homeostasis. Here, we demonstrate that the levels and activities of sirtuin-1 (SIRT1) are suppressed by the reduction of intracellular NAD(+) levels in cisplatin-mediated ototoxicity. We provide evidence that the decreases in SIRT1 activity and expression facilitated by increasing poly(ADP-ribose) polymerase-1 (PARP-1) activation and microRNA-34a levels through cisplatin-mediated p53 activation aggravate the associated ototoxicity. Furthermore, we show that the induction of cellular NAD(+) levels using dunnione, which targets intracellular NQO1, prevents the toxic effects of cisplatin through the regulation of PARP-1 and SIRT1 activity. These results suggest that direct modulation of cellular NAD(+) levels by pharmacological agents could be a promising therapeutic approach for protection from cisplatin-induced ototoxicity.

  17. Liposomal cisplatin: a new cisplatin formulation.

    PubMed

    Stathopoulos, George P

    2010-09-01

    Over the last three decades, cisplatin has been one of the most effective cytotoxic agents, but its administration has been hindered by its nephrotoxicity, neurotoxicity and myelo toxicity. Recently, liposomal cisplatin, lipoplatin, has been formulated and tested thoroughly in preclinical (in vitro) and phase I, II and III trials, as documented in the literature. Experiments in animals showed that lipoplatin is less toxic than cisplatin and that it produces tumour reduction. The histological examination of treated tumours from mouse xenografts was consistent with apoptosis in the tumour cells in a mechanism similar to that of cisplatin. Lipoplatin infusion in patients and measurements of platinum levels in tumour specimens showed 10-50 times higher levels in tumours and metastases than in the adjacent normal specimens. A phase I-II study using a combination of lipoplatin and gemcitabine in pretreated patients (with disease progression or stable disease) with advanced pancreatic cancer was conducted. No nephrotoxicity was observed. With lipoplatin monotherapy the dose-limiting toxicity was determined to be 350 mg/m and the maximum tolerated dose 300 mg/m; when used in combination with paclitaxel the dose-limiting toxicity for lipoplatin was 250 mg/m and for paclitaxel 175 mg/m, and the maximum tolerated dose was 200 and 175 mg/m, respectively. In two phase II randomized studies comparing the lipoplatin combination versus the cisplatin combination, it was found that the former was statistically significantly less toxic than the latter, whereas the response rate and survival were similar. Up to now, the data on lipoplatin treatment in malignant tumours are quite impressive, because of the negligible toxicity and because it is equal if not superior to cisplatin with regard to response rate. This review aims to chronologically document publications relevant to liposomal cisplatin to date.

  18. N-acetylcysteine chemoprotection without decreased cisplatin antitumor efficacy in pediatric tumor models.

    PubMed

    Muldoon, Leslie L; Wu, Y Jeffrey; Pagel, Michael A; Neuwelt, Edward A

    2015-02-01

    Decreasing oxidative damage with the antioxidant agent N-acetylcysteine (NAC) can block the side effects of chemotherapy, but may diminish anti-tumor efficacy. We tested the potential for interactions of high dose NAC against a minimally effective cisplatin chemotherapy regimen in rat models of human pediatric cancers. Athymic rats received subcutaneous implantation of human SK-N-AS neuroblastoma cells or intra-cerebellar implantation of human D283-MED medulloblastoma cells. Rats were untreated or treated with cisplatin (3 or 4 mg/kg IV) with or without NAC (1,000 mg/kg IV) 30 min before or 4 h after cisplatin treatment. Blood urea nitrogen (BUN) and tumor volumes were measured. Cisplatin decreased the growth of SK-N-AS neuroblastoma subcutaneous tumors from 17.7 ± 4.9 to 6.4 ± 2.5 fold over baseline 2 weeks after treatment (P < 0.001). Pretreatment with NAC decreased cisplatin efficacy, while 4 h delayed NAC did not significantly affect cisplatin anti-tumor effects (relative tumor volume 6.8 ± 2.0 fold baseline, P < 0.001). In D283-MED medulloblastoma brain tumors, cisplatin decreased final tumor volume to 3.9 ± 2.3 mm(3) compared to untreated tumor volume of 45.9 ± 38.7 (P = 0.008). Delayed NAC did not significantly alter cisplatin efficacy (tumor volume 6.8 ± 8.1 mm(3), P = 0.014 versus control). Cisplatin was minimally nephrotoxic in these models. NAC decreased cisplatin-induced elevations in BUN (P < 0.02). NAC chemoprotection did not alter cisplatin therapy, if delayed until 4 h after chemotherapy. These data support a Phase I/II clinical trial of delayed NAC to reduce ototoxicity in children with localized pediatric cancers.

  19. Induction chemotherapy-based larynx preservation program for locally advanced hypopharyngeal cancer: oncologic and functional outcomes and prognostic factors.

    PubMed

    Bozec, Alexandre; Benezery, Karen; Ettaiche, Marc; Chamorey, Emmanuel; Vandersteen, Clair; Dassonville, Olivier; Poissonnet, Gilles; Riss, Jean-Christophe; Hannoun-Lévi, Jean-Michel; Chand, Marie-Eve; Leysalle, Axel; Saada, Esma; Guigay, Joël; Sudaka, Anne; Demard, François; Santini, José; Peyrade, Frédéric

    2016-10-01

    To evaluate oncologic and functional outcomes and prognostic factors in patients with locally advanced hypopharyngeal cancer included in an induction chemotherapy (ICT)-based larynx preservation program in daily clinical practice. All patients with locally advanced (T3/4, N0-3, M0) hypopharyngeal squamous cell carcinoma, technically suitable for total pharyngo-laryngectomy, treated by docetaxel (75 mg/m(2), day 1), cisplatin (75 mg/m(2), day 1) and 5-fluorouracil (750 mg/m(2)/day, day 1-5) (TPF)-ICT (2-3 cycles) for larynx preservation at our institution between 2004 and 2013, were included in this retrospective study. Prognostic factors of oncologic (overall, cause-specific and recurrence-free survival: OS, SS and RFS) and functional (dysphagia outcome and severity scale, permanent enteral nutrition, larynx preservation) outcomes were assessed in univariate and multivariate analyses. A total of 53 patients (42 men and 11 women, mean age 58.6 ± 8.2 years) were included in this study. Grade 3-4 toxicities were experienced by 17 (32 %) patients during ICT. The rate of poor response (response <50 % without larynx remobilization) to ICT was 10 %. At 5 years, OS, SS and RFS rates were 56, 60 and 54 %, respectively. Four patients required definitive enteral nutrition (permanent enteral tube feeding). The rate of patients alive, disease-free and with a functional larynx at 2 years was 58 %. T4 tumor stage (p = 0.005) and response to ICT <50 % (p = 0.02) were independent prognostic factors of OS. Response to ICT was significantly associated with the risk of permanent enteral nutrition (p = 0.04) and larynx preservation (p = 0.01). In daily clinical practice, a TPF-ICT-based larynx preservation protocol can be used in patients with locally advanced hypopharyngeal cancer with satisfactory results in terms of tolerance, efficacy and oncologic and functional outcomes.

  20. Berberine sensitizes ovarian cancer cells to cisplatin through miR-21/PDCD4 axis.

    PubMed

    Liu, Shiguo; Fang, Yue; Shen, Huiling; Xu, Wenlin; Li, Hao

    2013-09-01

    Recent studies have shown that microRNA-21 (miR-21) contributes to tumor resistance to chemotherapy. Interestingly, we have found that berberine could inhibit miR-21 expression in several cancer cell lines. In this study, we investigated whether berberine could modulate the sensitivity of ovarian cancer cells to cisplatin and explored the mechanism. The cisplatin-resistant SKOV3 cells that were incubated with berberine combined with cisplatin had a significantly lower survival than the cisplatin alone group and enhanced cisplatin-induced apoptosis. Berberine could inhibit miR-21 expression and function in ovarian cancer, as shown by an enhancement of its target PDCD4, an important tumor suppressor in ovarian cancer. The results suggested that berberine could modulate the sensitivity of cisplatin via regulating miR-21/PDCD4 axis in the ovarian cancer cells.

  1. Efficacy of Ginger in Control of Chemotherapy Induced Nausea and Vomiting in Breast Cancer Patients Receiving Doxorubicin-Based Chemotherapy.

    PubMed

    Ansari, Mansour; Porouhan, Pezhman; Mohammadianpanah, Mohammad; Omidvari, Shapour; Mosalaei, Ahmad; Ahmadloo, Niloofar; Nasrollahi, Hamid; Hamedi, Seyed Hasan

    2016-01-01

    Nausea and vomiting are among the most serious side effects of chemotherapy, in some cases leading to treatment interruption or chemotherapy dose reduction. Ginger has long been known as an antiemetic drug, used for conditions such as motion sickness, nausea-vomiting in pregnancy, and post-operation side effects. One hundred and fifty female patients with breast cancer entered this prospective study and were randomized to receive ginger (500 mg ginger powder, twice a day for 3 days) or placebo. One hundred and nineteen patients completed the study: 57 of them received ginger and 62 received ginger for the frst 3 chemotherapy cycles. Mean age in all patients was 48.6 (25-79) years. After 1st chemotherapy, mean nausea in the ginger and control arms were 1.36 (±1.31) and 1.46 (±1.28) with no statistically significant difference. After the 2nd chemotherapy session, nausea score was slightly more in the ginger group (1.36 versus 1.32). After 3rd chemotherapy, mean nausea severity in control group was less than ginger group [1.37 (±1.14), versus 1.42 (±1.30)]. Considering all patients, nausea was slightly more severe in ginger arm. In ginger arm mean nausea score was 1.42 (±0.96) and in control arm it was 1.40 (±0.92). Mean vomiting scores after chemotherapy in ginger arm were 0.719 (±1.03), 0.68 (±1.00) and 0.77 (±1.18). In control arm, mean vomiting was 0.983 (±1.23), 1.03 (±1.22) and 1.15 (±1.27). In all sessions, ginger decreased vomiting severity from 1.4 (±1.04) to 0.71 (±0.86). None of the differences were significant. In those patients who received the AC regimen, vomiting was less severe (0.64±0.87) compared to those who received placebo (1.13±1.12), which was statistically significant (p-value <0.05). Further and larger studies are needed to draw conclusions.

  2. Cisplatin nephrotoxicity: molecular mechanisms

    PubMed Central

    Hanigan, Marie H.; Devarajan, Prasad

    2007-01-01

    Summary Cisplatin is one of the most widely used chemotherapeutic agents for the treatment of several human malignancies. The efficacy of cisplatin is dose dependent, but the significant risk of nephrotoxicity frequently hinders the use of higher doses to maximize its antineoplastic effects. Several advances in our understanding of the biochemical and molecular mechanisms underlying cisplatin nephrotoxicity have recently emerged, and are reviewed in this article. Evidence is presented for distinct mechanisms of cisplatin toxicity in actively dividing tumor cells versus the normally quiescent renal proximal tubular epithelial cells. The unexpected role of gamma-glutamyl transpeptidase in cisplatin nephrotoxicity is elucidated. Recent studies demonstrating the ability of proximal tubular cells to metabolize cisplatin to a nephrotoxin are reviewed. The evidence for apoptosis as a major mechanism underlying cisplatin-induced renal cell injury is presented, along with the data exploring the role of specific intracellular pathways that may mediate the programmed cell death. The information gleaned from this review may provide critical clues to novel therapeutic interventions aimed at minimizing cisplatin-induced nephrotoxicity while enhancing its antineoplastic efficacy. PMID:18185852

  3. Combined Use of Gene Expression Modeling and siRNA Screening Identifies Genes and Pathways Which Enhance the Activity of Cisplatin When Added at No Effect Levels to Non-Small Cell Lung Cancer Cells In Vitro

    PubMed Central

    Leung, Ada W. Y.; Hung, Stacy S.; Backstrom, Ian; Ricaurte, Daniel; Kwok, Brian; Poon, Steven; McKinney, Steven; Segovia, Romulo; Rawji, Jenna; Qadir, Mohammed A.; Aparicio, Samuel; Stirling, Peter C.; Steidl, Christian; Bally, Marcel B.

    2016-01-01

    Platinum-based combination chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC). While cisplatin is effective, its use is not curative and resistance often emerges. As a consequence of microenvironmental heterogeneity, many tumour cells are exposed to sub-lethal doses of cisplatin. Further, genomic heterogeneity and unique tumor cell sub-populations with reduced sensitivities to cisplatin play a role in its effectiveness within a site of tumor growth. Being exposed to sub-lethal doses will induce changes in gene expression that contribute to the tumour cell’s ability to survive and eventually contribute to the selective pressures leading to cisplatin resistance. Such changes in gene expression, therefore, may contribute to cytoprotective mechanisms. Here, we report on studies designed to uncover how tumour cells respond to sub-lethal doses of cisplatin. A microarray study revealed changes in gene expressions that occurred when A549 cells were exposed to a no-observed-effect level (NOEL) of cisplatin (e.g. the IC10). These data were integrated with results from a genome-wide siRNA screen looking for novel therapeutic targets that when inhibited transformed a NOEL of cisplatin into one that induced significant increases in lethality. Pathway analyses were performed to identify pathways that could be targeted to enhance cisplatin activity. We found that over 100 genes were differentially expressed when A549 cells were exposed to a NOEL of cisplatin. Pathways associated with apoptosis and DNA repair were activated. The siRNA screen revealed the importance of the hedgehog, cell cycle regulation, and insulin action pathways in A549 cell survival and response to cisplatin treatment. Results from both datasets suggest that RRM2B, CABYR, ALDH3A1, and FHL2 could be further explored as cisplatin-enhancing gene targets. Finally, pathways involved in repairing double-strand DNA breaks and INO80 chromatin remodeling were enriched in both

  4. Combined Use of Gene Expression Modeling and siRNA Screening Identifies Genes and Pathways Which Enhance the Activity of Cisplatin When Added at No Effect Levels to Non-Small Cell Lung Cancer Cells In Vitro.

    PubMed

    Leung, Ada W Y; Hung, Stacy S; Backstrom, Ian; Ricaurte, Daniel; Kwok, Brian; Poon, Steven; McKinney, Steven; Segovia, Romulo; Rawji, Jenna; Qadir, Mohammed A; Aparicio, Samuel; Stirling, Peter C; Steidl, Christian; Bally, Marcel B

    2016-01-01

    Platinum-based combination chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC). While cisplatin is effective, its use is not curative and resistance often emerges. As a consequence of microenvironmental heterogeneity, many tumour cells are exposed to sub-lethal doses of cisplatin. Further, genomic heterogeneity and unique tumor cell sub-populations with reduced sensitivities to cisplatin play a role in its effectiveness within a site of tumor growth. Being exposed to sub-lethal doses will induce changes in gene expression that contribute to the tumour cell's ability to survive and eventually contribute to the selective pressures leading to cisplatin resistance. Such changes in gene expression, therefore, may contribute to cytoprotective mechanisms. Here, we report on studies designed to uncover how tumour cells respond to sub-lethal doses of cisplatin. A microarray study revealed changes in gene expressions that occurred when A549 cells were exposed to a no-observed-effect level (NOEL) of cisplatin (e.g. the IC10). These data were integrated with results from a genome-wide siRNA screen looking for novel therapeutic targets that when inhibited transformed a NOEL of cisplatin into one that induced significant increases in lethality. Pathway analyses were performed to identify pathways that could be targeted to enhance cisplatin activity. We found that over 100 genes were differentially expressed when A549 cells were exposed to a NOEL of cisplatin. Pathways associated with apoptosis and DNA repair were activated. The siRNA screen revealed the importance of the hedgehog, cell cycle regulation, and insulin action pathways in A549 cell survival and response to cisplatin treatment. Results from both datasets suggest that RRM2B, CABYR, ALDH3A1, and FHL2 could be further explored as cisplatin-enhancing gene targets. Finally, pathways involved in repairing double-strand DNA breaks and INO80 chromatin remodeling were enriched in both

  5. Regulation of the high-affinity copper transporter (hCtr1) expression by cisplatin and heavy metals.

    PubMed

    Liang, Zheng Dong; Long, Yan; Chen, Helen H W; Savaraj, Niramol; Kuo, Macus Tien

    2014-01-01

    Platinum-based antitumor agents have been the mainstay in cancer chemotherapy for many human malignancies. Drug resistance is an important obstacle to achieving the maximal therapeutic efficacy of these drugs. Understanding how platinum drugs enter cells is of great importance in improving therapeutic efficacy. It has been demonstrated that human high-affinity copper transporter 1 (hCtr1) is involved in transporting cisplatin into cells to elicit cytotoxic effects, although other mechanisms may exist. In this communication, we demonstrate that cisplatin transcriptionally induces the expression of hCtr1 in time- and concentration-dependent manners. Cisplatin functions as a competitor for hCtr1-mediated copper transport, resulting in reduced cellular copper levels and leading to upregulated expression of Sp1, which is a positive regulator for hCtr1 expression. Thus, regulation of hCtr1 expression by cisplatin is an integral part of the copper homeostasis regulation system. We also demonstrate that Ag(I) and Zn(II), which are known to suppress hCtr1-mediated copper transport, can also induce hCtr1/Sp1 expression. In contrast, Cd(II), another inhibitor of copper transport, downregulates hCtr1 expression by suppressing Sp1 expression. Collectively, our results demonstrate diverse mechanisms of regulating copper metabolism by these heavy metals.

  6. Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck

    PubMed Central

    Huang, Kie Kyon; Jang, Kang Won; Kim, Sangwoo; Kim, Han Sang; Kim, Sung-Moo; Kwon, Hyeong Ju; Kim, Hye Ryun; Yun, Hwan Jung; Ahn, Myung Ju; Park, Keon Uk; Ramnarayanan, Kalpana; McPherson, John R.; Zhang, Shenli; Rhee, Je-Keun; Vettore, André L.; Das, Kakoli; Ishimoto, Takatsugu; Kim, Joo Hang; Koh, Yoon Woo; Kim, Se Hun; Choi, Eun Chang; Teh, Bin Tean; Rozen, Steven G.; Kim, Tae-Min; Tan, Patrick; Cho, Byoung Chul

    2016-01-01

    Dacomitinib, an irreversible pan-HER inhibitor, had shown modest clinical activity in squamous cell carcinoma of head and neck (SCCHN) patients. Therefore, validated predictive biomarkers are required to identify patients most likely to benefit from this therapeutic option. To characterize the genetic landscape of cisplatin-treated SCCHN genomes and identify potential predictive biomarkers for dacomitinib sensitivity, we performed whole exome sequencing on 18 cisplatin-resistant metastatic SCCHN tumors and their matched germline DNA. Platinum-based chemotherapy elevated the mutation rates of SCCHN compared to chemotherapy-naïve SCCHNs. Cisplatin-treated SCCHN genomes uniquely exhibited a novel mutational signature characterized by C:G to A:T transversions at CCR sequence contexts that may have arisen due to error-prone translesional synthesis. Somatic mutations in REV3L, the gene encoding the catalytic subunit of DNA polymerase ζ involved in translesional synthesis, are significantly enriched in a subset of patients who derived extended clinical benefit to dacomitinib (P = 0.04). Functional assays showed that loss-of-function of REV3L dramatically enhanced the sensitivity of SCCHN cells to dacomitinib by the loss of both translesion synthesis and homologous recombination pathways. Our data suggest that the ‘platinum’ mutational signature and inactivation of REV3L may inform treatment options in patients of recurrent SCCHN. PMID:26790612

  7. Concurrent Chemoradiation With Carboplatin-5-Fluorouracil Versus Cisplatin in Locally Advanced Oropharyngeal Cancers: Is More Always Better?

    SciTech Connect

    Barkati, Maroie; Fortin, Bernard; Soulieres, Denis; Clavel, Sebastien; Despres, Phillipe; Charpentier, Danielle; Tabet, Jean-Claude; Guertin, Louis; Olivier, Marie-Jo; Coulombe, Genevieve; Donath, David; Nguyen-Tan, Phuc Felix

    2010-02-01

    Purpose: The optimal chemotherapy regimen remains undefined in the treatment of locally advanced oropharyngeal cancer by concomitant chemoradiation. This article compares two platinum-based chemotherapy regimens. Methods and Materials: In this retrospective study, we reviewed all consecutive patients treated for Stage III or IVA-B oropharyngeal cancer using either a combination of carboplatin and 5-fluorouracil (5FU) every 3 weeks or high-dose cisplatin every 3 weeks concomitant with definitive radiation therapy. Results: A total of 200 patients were treated with carboplatin-5FU and 53 patients with cisplatin. Median potential follow-up was 43 months. The 3-year overall survival rates for carboplatin-5FU and cisplatin respectively were 79.1% and 74.9% (p = 0.628), the 3-year disease-free survival rates were 76.0% and 71.3% (p = 0.799), and the 3-year locoregional control rates were 88.4% and 94.2% (p = 0.244). Conclusions: We could not demonstrate differences between these two regimens, which both proved efficacious. Polychemotherapy and monochemotherapy therefore seem comparable in this retrospective analysis.

  8. Pharmacogenetic predictors of toxicity to platinum based chemotherapy in non-small cell lung cancer patients.

    PubMed

    Pérez-Ramírez, Cristina; Cañadas-Garre, Marisa; Alnatsha, Ahmed; Villar, Eduardo; Delgado, Juan Ramón; Faus-Dáder, María José; Calleja-Hernández, Miguel Ángel

    2016-09-01

    Platinum-based chemotherapy is the standard treatment for NSCLC patients with EGFR wild-type, and as alternative to failure to EGFR inhibitors. However, this treatment is aggressive and most patients experience grade 3-4 toxicities. ERCC1, ERCC2, ERCC5, XRCC1, MDM2, ABCB1, MTHFR, MTR, SLC19A1, IL6 and IL16 gene polymorphisms may contribute to individual variation in toxicity to chemotherapy. The aim of this study was to evaluate the effect of these polymorphisms on platinum-based chemotherapy in NSCLC patients. A prospective cohorts study was conducted, including 141 NSCLC patients. Polymorphisms were analyzed by PCR Real-Time with Taqman(®) probes and sequencing. Patients with ERCC1 C118T-T allele (p=0.00345; RR=26.05; CI95%=4.33, 515.77) and ERCC2 rs50872-CC genotype (p=0.00291; RR=4.06; CI95%=1.66, 10.65) had higher risk of general toxicity for platinum-based chemotherapy. ERCC2 Asp312Asn G-alelle, ABCB1 C1236T-TT and the IL1B rs12621220-CT/TT genotypes conferred a higher risk to present multiple adverse events. The subtype toxicity analysis also revealed that ERCC2 rs50872-CC genotype (p=0.01562; OR=3.23; CI95%=1.29, 8.82) and IL16 rs7170924-T allele (p=0.01007; OR=3.19; CI95%=1.35, 7.97) were associated with grade 3-4 hematological toxicity. We did not found the influence of ERCC1 C8092A, ERCC2 Lys751Gln, ERCC2 Asp312Asn, ERCC5 Asp1104His, XRCC1 Arg194Trp, MDM2 rs1690924, ABCB1 C3435T, ABCB1 Ala893Ser/Thr, MTHFR A1298C, MTHFR C677T, IL1B rs1143623, IL1B rs16944, and IL1B rs1143627 on platinum-based chemotherapy toxicity. In conclusion, ERCC1 C118T, ERCC2 rs50872, ERCC2 Asp312Asn, ABCB1 C1236T, IL1B rs12621220 and IL16 rs7170924 polymorphisms may substantially act as prognostic factors in NSCLC patients treated with platinum-based chemotherapy.

  9. Sequential chemoradiotherapy with gemcitabine and cisplatin for locoregionally advanced nasopharyngeal carcinoma.

    PubMed

    Gu, Mo-Fa; Liu, Li-Zhi; He, Long-Jun; Yuan, Wen-Xin; Zhang, Rong; Luo, Guang-Yu; Xu, Guo-Liang; Zhang, Hua-Man; Yan, Chao-Xian; Li, Jian-Jun

    2013-01-01

    We investigated a new chemoradiotherapy (CRT) regimen for locoregionally advanced nasopharyngeal carcinoma (NPC). A total of 240 patients were randomly assigned to three different CRT regimens: sequential CRT [1 cycle chemotherapy + Phase I radiotherapy (RT) + 1 cycle chemotherapy + Phase II RT + 2 cycles chemotherapy] with a cisplatin-gemcitabine (GC) regimen (800 mg/m(2) gemcitabine on Days 1 and 8 and 20 mg/m(2) cisplatin on Days 1-5, every 4 weeks) (sGC-RT); sequential chemoradiotherapy with a cisplatin-fluorouracil (PF) regimen (20 mg/m(2) DDP and 500 mg/m(2) 5-FU on Days 1-5, every 4 weeks) (sPF-RT) and cisplatin-based concurrent chemoradiotherapy plus adjuvant PF chemotherapy (Con-RT + PF). The complete response rate was higher in the sGC + RT group than in the other two groups (98.75% vs. 92.50%, p < 0.01). The 3-year overall survival (OS), disease-free survival (DFS) and distant metastasis-free survival (DMFS) rates in the sGC-RT group were significantly higher than those observed in the Con-RT group (OS, 95.0% vs. 76.3%, p < 0.001; DFS, 89.9% vs. 67.5%, p < 0.001; DMFS, 92.5% vs. 76.0%, p = 0.004) and in the sPF + RT group (OS, 95.0% vs. 73.6%, p < 0.001; DFS, 89.9% vs. 63.3%, p < 0.001; DMFS, 92.5% vs. 74.7%, p = 0.002). There were no significant differences in 3-year OS, DFS and MFS rates between the Con-RT and the sPF-RT groups. The GC-RT group experienced more hematologic toxicity, constipation and rash; however, there were no differences in late RT toxicity between the groups. These results demonstrate that a sGC-RT regimen is effective and well tolerated in patients with locoregionally advanced NPC.

  10. 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. PMID:27630935

  11. Intratumoral chemotherapy for lung cancer: re-challenge current targeted therapies

    PubMed Central

    Hohenforst-Schmidt, Wolfgang; Zarogoulidis, Paul; Darwiche, Kaid; Vogl, Thomas; Goldberg, Eugene P; Huang, Haidong; Simoff, Michael; Li, Qiang; Browning, Robert; Turner, Francis J; Le Pivert, Patrick; Spyratos, Dionysios; Zarogoulidis, Konstantinos; Celikoglu, Seyhan I; Celikoglu, Firuz; Brachmann, Johannes

    2013-01-01

    Strategies to enhance the already established doublet chemotherapy regimen for lung cancer have been investigated for more than 20 years. Initially, the concept was to administer chemotherapy drugs locally to the tumor site for efficient diffusion through passive transport within the tumor. Recent advances have enhanced the diffusion of pharmaceuticals through active transport by using pharmaceuticals designed to target the genome of tumors. In the present study, five patients with non-small cell lung cancer epidermal growth factor receptor (EGFR) negative stage IIIa–IV International Union Against Cancer 7 (UICC-7), and with Eastern Cooperative Oncology Group (ECOG) 2 scores were administered platinum-based doublet chemotherapy using combined intratumoral-regional and intravenous route of administration. Cisplatin analogues were injected at 0.5%–1% concentration within the tumor lesion and proven malignant lymph nodes according to pretreatment histological/cytological results and the concentration of systemic infusion was decreased to 70% of a standard protocol. This combined intravenous plus intratumoral-regional chemotherapy is used as a first line therapy on this short series of patients. To the best of our knowledge this is the first report of direct treatment of involved lymph nodes with cisplatin by endobronchial ultrasound drug delivery with a needle without any adverse effects. The initial overall survival and local response are suggestive of a better efficacy compared to established doublet cisplatin–based systemic chemotherapy in (higher) standard concentrations alone according to the UICC 7 database expected survival. An extensive search of the literature was performed to gather information of previously published literature of intratumoral chemo-drug administration and formulation for this treatment modality. Our study shows a favorable local response, more than a 50% reduction, for a massive tumor mass after administration of five sessions of

  12. CT-Based Evaluation of Tumor Volume After Intra-Arterial Chemotherapy of Locally Advanced Carcinoma of the Oral Cavity: Comparison with Clinical Remission Rates

    SciTech Connect

    Rohde, Stefan Turowski, Bernd; Berkefeld, Joachim; Kovacs, Adorjan F.

    2007-02-15

    Purpose. To assess the volume of locally advanced tumors of the oral cavity and the oropharynx before and after intra-arterial (i.a.) chemotherapy by means of computed tomography and to compare these data with clinically determined treatment response of the same patient population. Methods. Eighty-eight patients with histologically proven, advanced carcinoma of the oral cavity and/or the oropharynx (local tumor stages T3/4) received neoadjuvant i.a. chemotherapy with cisplatin as part of a multimodal therapeutic regimen, comprising (1) local chemotherapy, (2) surgery, and (3) combined radio-chemotherapy. Three weeks after the intervention, residual disease was evaluated radiologically by measurement of the tumor volume and clinically by inspection and palpation of the primary tumor according to WHO criteria. Results. Comparison of treatment response according to radiological and clinical criteria respectively revealed complete remission in 5% vs. 8% (p < 0.05), partial remission in 30% vs. 31%, stable disease in 61% vs. 58%, and tumor progression in 5% vs. 2%. Conclusion. Radiological volumetry and clinical evaluation found comparable response rates after local chemotherapy. However, in patients with good response after local treatment, volumetric measurement with CT may help to distinguish between partial and complete remission. Thus, radiological tumor volumetry provides precise and differentiated information about tumor response and should be used as an additional tool in treatment monitoring after local chemotherapy.

  13. Port central venous catheters-associated bloodstream infection during outpatient-based chemotherapy.

    PubMed

    Mauri, Davide; Roumbkou, Sofia; Michalopoulou, Stella; Tsali, Lamprini; Spiliopoulou, Anastasia; Panou, Charalampos; Valachis, Antonis; Panagopoulos, Angelos; Polyzos, Nikolaos P

    2010-12-01

    Central venous catheters (CVCs) are commonly used for the administration of intravenous chemotherapy in outpatient setting. Nevertheless, outbreaks of catheter-associated bloodstream infections had been reported from oncology centers. We describe a large outbreak of CVCs-associated Klebsiella oxytoca bloodstream infection, occurring in an oncology chemotherapy outpatient unit of northern Greece between October 2006 and May 2007. The outbreak involved approximately 10% of the patients with CVCs who were receiving home-based chemotherapy, and it represents the second larger outbreak of CVCs-associated BSIs due to Klebsiella oxytoca in oncology outpatient centers. We retrospectively analyzed the chain of investigations and prophylactic/diagnostic measures taken to eradicate the infection: (1) patients' chart audit, (2) estimation of the infection among asymptomatic patients, (3) implementation of the level of awareness of medical and paramedical personnel, (4) collection of samples from environment, medications and infusion materials, (5) critical appraisal of chemotherapeutical schemes and (6) cooperation with peripheral institutions. The isolation of Klebsiella oxytoca in a chemotherapy solution (infusional 5-FU in dextrose 5% solution within a 48 h pump) from a peripheral General Hospital and the prompt transmission of the data to the chemotherapy center played a key role for the management of the infection cluster. This is the first report that evidenced the detection of Klebsiella oxytoca within a chemotherapeutical preparation. Data transmission from peripheral hospitals to the central institution resulted in an important feedback that allowed a better estimation of the infection cluster and more tailored actions for the eradication of the infection.

  14. mTOR is a Promising Therapeutic Target Both in Cisplatin-Sensitive and Cisplatin-Resistant Clear Cell Carcinoma of the Ovary

    PubMed Central

    Mabuchi, Seiji; Kawase, Chiaki; Altomare, Deborah A.; Morishige, Kenichirou; Sawada, Kenjiro; Hayashi, Masami; Tsujimoto, Masahiko; Yamoto, Mareo; Klein-Szanto, Andres J.; Schilder, Russell J.; Ohmichi, Masahide; Testa, Joseph R.; Kimura, Tadashi

    2009-01-01

    Translational Relevance Clear cell carcinoma (CCC) of the ovary is a distinctive subtype of epithelial ovarian cancer associated with a poorer sensitivity to platinum-based chemotherapy and a worse prognosis than the more common serous adenocarcinoma (SAC). To improve survival, the development of new treatment strategies that target CCC more effectively is necessary. Our results show that mTOR is more frequently activated in CCCs than in SACs. Our data have relevance for the design of future clinical studies of first-line treatment for patients with CCC of the ovary. Moreover, the finding of increased expression of phospho-mTOR and greater sensitivity to RAD001 in cisplatin-resistant CCC cells than in cisplatin-sensitive cells suggests a novel treatment option for patients with recurrent disease after cisplatin-based first-line chemotherapy. Purpose mTOR (mammalian target of rapamycin) plays a central role in cell proliferation and is regarded as a promising target in cancer therapy including for ovarian cancer. This study aims to examine the role of mTOR as a therapeutic target in clear cell carcinoma (CCC) of the ovary which is regarded as aggressive, chemo-resistant histological subtype. Experimental Design Using tissue microarrays of 98 primary ovarian cancers (52 clear cell carcinomas and 46 serous adenocarcinomas), the expression of phospho-mTOR was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTOR inhibition by RAD001 (everolimus) was examined using 2 pairs of cisplatin-sensitive parental (RMG1 and KOC7C) and cisplatin-resistant human CCC cell lines (RMG1-CR and KOC7C-CR) both in vitro and in vivo. Results Immunohistochemical analysis demonstrated mTOR was more frequently activated in CCCs than in serous adenocarcinomas (86.6% vs 50%). Treatment with RAD001 markedly inhibited the growth of both RMG1 and KOC7C cells both in vitro and in vivo. Increased expression of phospho-mTOR was observed in cisplatin-resistant RMG1-CR and KOC7C

  15. Cisplatin promotes mesenchymal-like characteristics in osteosarcoma through Snail

    PubMed Central

    Fang, Shuo; Yu, Ling; Mei, Hongjun; Yang, Jian; Gao, Tian; Cheng, Anyuan; Guo, Weichun; Xia, Kezhou; Liu, Gaiwei

    2016-01-01

    More than 30% of patients with osteosarcoma succumb to pulmonary metastases. Epithelial-mesenchymal transition (EMT) is a biological process by which tumor cells gain an increased capacity for invasiveness and metastasis. A previous study confirmed the phenomenon of EMT in osteosarcoma, a mesenchymal-derived tumor. However, whether chemotherapy affects EMT remains to be elucidated. In the present study, the osteosarcoma cells were exposed to a sublethal dose of cisplatin, and any surviving cells were assumed to be more resistant to cisplatin. In addition, these cells exhibited a more mesenchymal phenotype. Immunofluorescence analysis revealed that the cisplatin treated cells had an increased long/short axis ratio and increased expression of N-cadherin compared with control cells. A panel of EMT-associated genes was subsequently assessed by quantitative PCR and western blot analysis, and they were observed to be significantly upregulated in the cisplatin treated cells. The in vitro wound healing and Transwell assay indicated that the cisplatin treated cells were more prone to migrate and invade. An in vivo assay showed that the cisplatin-treated xenograft had increased expression of EMT-associated genes, and exhibited increased pulmonary lesions compared with the control, which indicated an elevated capacity to metastasize. The expression of Snail was knocked down by specific small interfering RNA, and it was observed that Snail inhibition promoted cisplatin sensitivity, and cisplatin-induced EMT was significantly blocked. Taken together, the results of the present study supported that idea that Snail participates in cisplatin-induced EMT in osteosarcoma cells, and targeting EMT-transcription factors may offer promise for the therapeutics of osteosarcoma. PMID:28105207

  16. Paclitaxel loaded PEGylated gleceryl monooleate based nanoparticulate carriers in chemotherapy.

    PubMed

    Jain, Vikas; Swarnakar, Nitin K; Mishra, Prabhat R; Verma, Ashwni; Kaul, Ankur; Mishra, Anil K; Jain, Narendra K

    2012-10-01

    A PEGylated drug delivery system of paclitaxel (PTX), based on glyceryl monooleate (GMO) was prepared by optimizing various parameters to explore its potential in anticancer therapy. The prepared system was characterized through polarized light microscopy, TEM, AFM and SAXS to reveal its liquid crystalline nature. As GMO based LCNPs exhibit high hemolytic toxicity and faster release of entrapped drug (66.2 ± 2.5% in 24 h), PEGylation strategy was utilized to increase the hemocompatibility (reduction in hemolysis from 60.3 ± 10.2 to 4.4 ± 1.3%) and control the release of PTX (43.6 ± 3.2% released in 24 h). The cytotoxic potential and cellular uptake was assessed in MCF-7 cell lines. Further, biodistribution studies were carried out in EAT (Ehrlich Ascites tumor) bearing mice using (99m)Tc-(Technetium radionuclide) labeled formulations and an enhanced circulation time and tumor accumulation (14 and 8 times, respectively) were observed with PEGylated carriers over plain ones, at 24 h. Finally, tumor growth inhibition experiment was performed and after 15 days, control group exhibited 15 times enhancement in tumor volume, while plain and PEGylated systems exhibited only 8 and 4 times enhancement, respectively, as compared to initial tumor volume. The results suggest that PEGylation enhances the hemocompatibility and efficacy of GMO based system that may serve as an efficient i.v. delivery vehicle for paclitaxel.

  17. Personalized medicine for targeted and platinum-based chemotherapy of lung and bladder cancer

    PubMed Central

    Cimino, George D; Pan, Chong-xian; Henderson, Paul T

    2013-01-01

    The personalized medicine revolution is occurring for cancer chemotherapy. Biomarkers are increasingly capable of distinguishing genotypic or phenotypic traits of individual tumors, and are being linked to the selection of treatment protocols. This review covers the molecular basis for biomarkers of response to targeted and cytotoxic lung and bladder cancer treatment with an emphasis on platinum-based chemotherapy. Platinum derivatives are a class of drugs commonly employed against solid tumors that kill cells by covalent attachment to DNA. Platinum–DNA adduct levels in patient tissues have been correlated to response and survival. The sensitivity and precision of adduct detection has increased to the point of enabling subtherapeutic dosing for diagnostics applications, termed diagnostic microdosing, prior to the initiation of full-dose therapy. The clinical status of this unique phenotypic marker for lung and bladder cancer applications is detailed along with discussion of future applications. PMID:23394702

  18. A Hydrogel-Based Epirubicin Delivery System for Intravesical Chemotherapy.

    PubMed

    Liu, Ching-Wen; Wu, Yu-Tse; Lin, Kai-Jen; Yu, Tsan-Jung; Kuo, Yu-Liang; Chang, Li-Ching

    2016-06-01

    This study aimed to examine the efficacy of epirubicin-loaded gelatin hydrogel (EPI-H) in the treatment of superficial urothelium carcinoma. Hydrogel was prepared by Schiff base-crosslinking of gelatin with glutaraldehyde. EPI-H exhibited high entrapment efficiency (59.87% ± 0.51%). EPI-H also increased epirubicin accumulation in AY-27 cells when compared with the effect of aqueous solutions of epirubicin (EPI-AQ); respective epirubicin-positive cell counts were 69.0% ± 7.6% and 38.3% ± 5.8%. EPI-H also exhibited greater cytotoxicity against AY-27 cells than that of EPI-AQ; IC50 values were 13.1 ± 1.1 and 7.5 ± 0.3 μg/mL, respectively. Cystometrograms showed that EPI-H reduced peak micturition, threshold pressures, and micturition duration, and that it increased bladder compliance more so than EPI-AQ. EPI-H enhanced epirubicin penetration into basal cells of urothelium in vivo, whereas EPI-AQ did so only to the umbrella cells. EPI-H inhibited tumor growth upon intravesical instillation to tumor-bearing bladder of F344 rats, inducing higher levels of caspase-3 expression than that observed with EPI-AQ treatment; the number of caspase-3 positive cells in treated urothelium carcinoma was 13.9% ± 4.0% (EPI-AQ) and 34.1% ± 1.0%, (EPI-H). EPI-H has value as an improved means to administer epirubicin in intravesical instillation treatments for bladder cancer.

  19. 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

  20. Second-line paclitaxel in non-small cell lung cancer initially treated with cisplatin: a study by the European Lung Cancer Working Party

    PubMed Central

    Berghmans, T; Lafitte, J J; Lecomte, J; Alexopoulos, C G; Van Cutsem, O; Giner, V; Efremidis, A; Berchier, M C; Collon, T; Meert, A P; Scherpereel, A; Ninane, V; Leclercq, N; Paesmans, M; Sculier, J P

    2007-01-01

    In the context of a phase III trial comparing in advanced non-small cell lung cancer (NSCLC) sequential to conventional administration of cisplatin-based chemotherapy and paclitaxel, we evaluated the activity of paclitaxel as second-line chemotherapy and investigated any relation of its efficacy with the type of failure after cisplatin. Patients received three courses of induction GIP (gemcitabine, ifosfamide, cisplatin). Non-progressing patients were randomised between three further courses of GIP or three courses of paclitaxel. Second-line paclitaxel was given to patients with primary failure (PF) to GIP and to those progressing after randomisation to further GIP (secondary failure or SF). One hundred sixty patients received second-line paclitaxel. Response rates were 7.7% for PF and 11.6% for SF (P=0.42). Median survival times (calculated from paclitaxel start) were 4.1 and 7.1 months for PF and SF (P=0.002). In multivariate analysis, three variables were independently associated with better survival: SF (hazard ratio (HR)=1.55, 95% confidence interval (CI) 1.08–2.22; P=0.02), normal haemoglobin level (HR=1.56, 95% CI 1.08–2.26; P=0.02) and minimal weight loss (HR=1.79, 95% CI 1.26–2.55; P=0.001). Paclitaxel in NSCLC patients, whether given for primary or for SF after cisplatin-based chemotherapy, demonstrates activity similar to other drugs considered active as second-line therapy. PMID:17473825

  1. Zidovudine-based lytic-inducing chemotherapy for Epstein-Barr virus-related lymphomas.

    PubMed

    Bayraktar, Ulas Darda; Diaz, Luis A; Ashlock, Brittany; Toomey, Ngoc; Cabral, Lisa; Bayraktar, Soley; Pereira, Denise; Dittmer, Dirk P; Ramos, Juan Carlos

    2014-04-01

    Treatment of Epstein-Barr virus (EBV)-related lymphomas with lytic-inducing agents is an attractive targeted approach for eliminating virus-infected tumor cells. Zidovudine (AZT) is an excellent substrate for EBV-thymidine kinase: it can induce EBV lytic gene expression and apoptosis in primary EBV+ lymphoma cell lines. We hypothesized that the combination of AZT with lytic-inducing chemotherapy agents would be effective in treating EBV+ lymphomas. We report a retrospective analysis of 19 patients with aggressive EBV+ non-Hodgkin lymphoma, including nine cases of acquired immune deficiency syndrome-associated primary central nervous system lymphoma (AIDS-PCNSL) treated with AZT-based chemotherapy. Our results demonstrate that high-dose AZT-methotrexate is efficacious in treating highly aggressive systemic EBV+ lymphomas in the upfront setting. In primary EBV+ lymphoma cell lines, the combination of AZT with hydroxyurea resulted in synergistic EBV lytic induction and cell death. Further, AZT-hydroxyurea treatment resulted in dramatic responses in patients with AIDS-PCNSL. The combination of AZT with chemotherapy, especially lytic-inducing agents, should be explored further in clinical trials for the treatment of EBV-related lymphomas.

  2. Zidovudine-based lytic-inducing chemotherapy for Epstein–Barr virus-related lymphomas

    PubMed Central

    Bayraktar, Ulas Darda; Diaz, Luis A.; Ashlock, Brittany; Toomey, Ngoc; Cabral, Lisa; Bayraktar, Soley; Pereira, Denise; Dittmer, Dirk P.; Ramos, Juan Carlos

    2014-01-01

    Treatment of Epstein–Barr virus (EBV)-related lymphomas with lytic-inducing agents is an attractive targeted approach for eliminating virus-infected tumor cells. Zidovudine (AZT) is an excellent substrate for EBV-thymidine kinase: it can induce EBV lytic gene expression and apoptosis in primary EBV+ lymphoma cell lines. We hypothesized that the combination of AZT with lytic-inducing chemotherapy agents would be effective in treating EBV+ lymphomas. We report a retrospective analysis of 19 patients with aggressive EBV+ non-Hodgkin lymphoma, including nine cases of acquired immune deficiency syndrome-associated primary central nervous system lymphoma (AIDSPCNSL) treated with AZT-based chemotherapy. Our results demonstrate that high-dose AZT–methotrexate is efficacious in treating highly aggressive systemic EBV+ lymphomas in the upfront setting. In primary EBV+ lymphoma cell lines, the combination of AZT with hydroxyurea resulted in synergistic EBV lytic induction and cell death. Further, AZT–hydroxyurea treatment resulted in dramatic responses in patients with AIDSPCNSL. The combination of AZT with chemotherapy, especially lytic-inducing agents, should be explored further in clinical trials for the treatment of EBV-related lymphomas. PMID:23837493

  3. Optimizing glioblastoma temozolomide chemotherapy employing lentiviral-based anti-MGMT shRNA technology.

    PubMed

    Viel, Thomas; Monfared, Parisa; Schelhaas, Sonja; Fricke, Inga B; Kuhlmann, Michael T; Fraefel, Cornel; Jacobs, Andreas H

    2013-03-01

    Despite treatments combining surgery, radiation-, and chemotherapy, patients affected by glioblastoma (GBM) have a limited prognosis. Addition of temozolomide (TMZ) to radiation therapy is the standard therapy in clinical application, but effectiveness of TMZ is limited by the tumor's overexpression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). The goal of this study was to use the highly specific and efficient RNA interference (RNAi) pathway to modulate MGMT expression to increase TMZ efficiency in chemotherapy resistant GBM. Using lentiviral-based anti-MGMT small hairpin RNA (shRNA) technology we observed a specific inhibition of the MGMT expression in GBM cell lines as well as in subcutaneous tumors. Tumor growth inhibition was observed following TMZ treatment of xenografts with low MGMT expression in contrast to xenografts with high MGMT expression. Bioluminescence imaging (BLI) measurements indicated that luciferase and shRNA-expressing lentiviruses were able to efficiently transduce the GBM xenografts in vivo. Treatment combining injection of a lentivirus expressing an anti-MGMT shRNA and TMZ induced a reduction of the size of the tumors, in contrast with treatment combining the lentivirus expressing the control shRNA and TMZ. Our data suggest that anti-MGMT shRNA therapy could be used in combination with TMZ chemotherapy in order to improve the treatment of resistant GBM.

  4. Systematic Review: Generating Evidence-Based Guidelines on the Concurrent Use of Dietary Antioxidants and Chemotherapy or Radiotherapy

    PubMed Central

    Nakayama, Akiko; Alladin, Karen P.; Igbokwe, Obianuju; White, Jeffrey D.

    2013-01-01

    The risk–benefit ratio for concurrent use of dietary antioxidants with chemotherapy or radiation therapy is a controversial topic. In this review, the medical literature on concurrent antioxidant use with chemotherapy or radiotherapy was assessed and further steps for generating evidence-based guidelines are suggested. The clinical cancer research community should cooperate and focus new studies on the use of a specific combination of antioxidant and chemotherapy or radiotherapy, and determine optimal doses for a specific cancer setting. Mechanistic studies on the interaction between antioxidants and conventional cancer therapy could lead to novel biomarkers for assessing dose adequacy. PMID:22085269

  5. Nuclear COMMD1 Is Associated with Cisplatin Sensitivity in Ovarian Cancer

    PubMed Central

    Wisman, G. Bea A.; Duiker, Evelien; Reyners, Anna K. L.; van der Zee, Ate G. J.; van de Sluis, Bart; van Vugt, Marcel A. T. M.

    2016-01-01

    Copper metabolism MURR1 domain 1 (COMMD1) protein is a multifunctional protein, and its expression has been correlated with patients’ survival in different types of cancer. In vitro studies revealed that COMMD1 plays a role in sensitizing cancer cell lines to cisplatin, however, the mechanism and its role in platinum sensitivity in cancer has yet to be established. We evaluated the role of COMMD1 in cisplatin sensitivity in A2780 ovarian cancer cells and the relation between COMMD1 expression and response to platinum-based therapy in advanced stage high-grade serous ovarian cancer (HGSOC) patients. We found that elevation of nuclear COMMD1 expression sensitized A2780 ovarian cancer cells to cisplatin-mediated cytotoxicity. This was accompanied by a more effective G2/M checkpoint, and decreased protein expression of the DNA repair gene BRCA1, and the apoptosis inhibitor BCL2. Furthermore, COMMD1 expression was immunohistochemically analyzed in two tissue micro-arrays (TMAs), representing a historical cohort and a randomized clinical trial-based cohort of advanced stage HGSOC tumor specimens. Expression of COMMD1 was observed in all ovarian cancer samples, however, specifically nuclear expression of COMMD1 was only observed in a subset of ovarian cancers. In our historical cohort, nuclear COMMD1 expression was associated with an improved response to chemotherapy (OR = 0.167; P = 0.038), although this association could not be confirmed in the second cohort, likely due to sample size. Taken together, these results suggest that nuclear expression of COMMD1 sensitize ovarian cancer to cisplatin, possibly by modulating the G2/M checkpoint and through controlling expression of genes involved in DNA repair and apoptosis. PMID:27788210

  6. Ammonium tetrathiomolybdate treatment targets the copper transporter ATP7A and enhances sensitivity of breast cancer to cisplatin

    PubMed Central

    Wong, Ada Hang-Heng; Vazquez-Ortiz, Guelaguetza; Chen, Weiping; Xu, Xiaoling; Deng, Chu-Xia

    2016-01-01

    Cisplatin is an effective breast cancer drug but resistance often develops over prolonged chemotherapy. Therefore, we performed a candidate approach RNAi screen in combination with cisplatin treatment to identify molecular pathways conferring survival advantages. The screen identified ATP7A as a therapeutic target. ATP7A is a copper ATPase transporter responsible for intercellular movement and sequestering of cisplatin. Pharmaceutical replacement for ATP7A by ammonium tetrathiomolybdate (TM) enhanced cisplatin treatment in breast cancer cells. Allograft and xenograft models in athymic nude mice treated with cisplatin/TM exhibited retarded tumor growth, reduced accumulation of cancer stem cells and decreased cell proliferation as compared to mono-treatment with cisplatin or TM. Cisplatin/TM treatment of cisplatin-resistant tumors reduced ATP7A protein levels, attenuated cisplatin sequestering by ATP7A, increased nuclear availability of cisplatin, and subsequently enhanced DNA damage and apoptosis. Microarray analysis of gene ontology pathways that responded uniquely to cisplatin/TM double treatment depicted changes in cell cycle regulation, specifically in the G1/S transition. These findings offer the potential to combat platinum-resistant tumors and sensitize patients to conventional breast cancer treatment by identifying and targeting the resistant tumors' unique molecular adaptations. PMID:27806319

  7. Phase I Study of Everolimus in Combination with Gemcitabine and Split-Dose Cisplatin in Advanced Urothelial Carcinoma

    PubMed Central

    Abida, Wassim; Milowsky, Matthew I.; Ostrovnaya, Irina; Gerst, Scott R.; Rosenberg, Jonathan E.; Voss, Martin H.; Apolo, Andrea B.; Regazzi, Ashley M.; McCoy, Asia S.; Boyd, Mariel E.; Bajorin, Dean F.

    2016-01-01

    Background: Cisplatin-based combination chemotherapy is standard first-line treatment for patients with advanced urothelial carcinoma (UC). Molecular profiling studies reveal that the PI3K/AKT/mTOR pathway is altered in a significant percentage of UCs. Objective: We conducted a phase I trial to evaluate the feasibility of combining the mTOR inhibitor everolimus with gemcitabine and split-dose cisplatin (GC) in advanced UC in the first-line setting. Methods: Patients received gemcitabine 800 mg/m2 and cisplatin 35 mg/m2 on days 1 and 8 of 21-day cycles for a total of 6 cycles in combination with everolimus at increasing dose levels (DL1:5 mg QOD, DL2:5 mg daily, DL3:10 mg daily) following a standard 3+3 design. Responses were assessed every 2 cycles. Patients with at least stable disease (SD) continued everolimus until progression. Goals were to establish dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) for the combination. Results: 12 patients were enrolled, 3 at DL1, 3 at DL2, and an additional 6 at DL1 *(DL1 following de-escalation). 3/3 patients at DL2 had DLTs during cycle 1. 2/8 evaluable patients at DL1/DL1 * had DLTs during cycle 1. DLTs were primarily hematologic. Further toxicities, also primarily hematologic, were observed during later treatment cycles, leading to 8 chemotherapy dose reductions overall. Partial responses were observed in 4/10 evaluable patients, and SD in 5/10. Median overall survival was 10.8 months (95% CI 6.9, not reached). Conclusions: The maximum tolerated dose was reached at the lowest dose level, 5 mg QOD, for everolimus in combination with gemcitabine and split-dose cisplatin in advanced UC. The regimen was limited by hematologic toxicity. PMID:27376132

  8. Protective effects of acetyl-L-carnitine on cisplatin cytotoxicity and oxidative stress in neuroblastoma.

    PubMed

    Altun, Zekiye Sultan; Güneş, Dilek; Aktaş, Safiye; Erbayraktar, Zübeyde; Erbayrktar, Zübeyde; Olgun, Nur

    2010-03-01

    The most widely used platinum-derived drug is cisplatin in neuroblastoma (NB) chemotherapy, which is severely neurotoxic. Acetyl-L-Carnitine (ALC) is a natural occurring compound with a neuroprotective activity in several experimental paradigms. The aim of this study was to determine the effects of ALC on cisplatin induced cytotoxicity and oxidative stress in NB cells. SH-SY5Y (N-Myc negative) and KELLY (N-Myc positive) human NB cell lines were used. Cisplatin induced apoptosis was assessed by using a Cell Death Detection ELISA(PLUS) kit. Lipid peroxidation levels were determined by HPLC analysis. Glutathione levels were determined spectrophotometrically. ALC was used prophylactic or after cisplatin application. The level of cisplatin doses were determined in both type of NB cells at which 50% cell death occurred along with synchronized apoptosis induced. Prophylactic 10 and 50 micromol of ALC concentrations were decreased cisplatin induced lipid peroxidation compared to controls that normally exhibited apoptosis especially in SH-SY5Y cells. Cisplatin caused oxidative stress through decreasing glutathione levels in both cell types. ALC were effectively inhibited the increase in cisplatin induced oxidized glutathione and lipid peroxidation formation in NB cells. We suggested that prophylactic ALC would be a useful agent for cisplatin induced toxicity in NB cells.

  9. A phase II study of STEALTH cisplatin (SPI-77) in patients with advanced non-small cell lung cancer.

    PubMed

    Kim, E S; Lu, C; Khuri, F R; Tonda, M; Glisson, B S; Liu, D; Jung, M; Hong, W K; Herbst, R S

    2001-12-01

    Cisplatin-based chemotherapy improves survival in appropriately selected patients with stage IV non-small cell lung cancer (NSCLC). However, cisplatin-based regimens have well-known dose-related toxicities, particularly renal insufficiency and neurotoxicity. On the basis of prior preclinical and phase I studies, we initiated a phase II study of SPI-77 (STEALTH) Liposomal Cisplatin) in patients with stage IIIB and IV NSCLC who failed previous treatment with platinum. Disease in all subjects had progressed during therapy, failed to respond, or progressed within 3 months after discontinuing the platinum-based chemotherapy. Between January and June 1999, 13 patients were enrolled at our institution. Patient characteristics included: seven women, six men; median age, 61 years; median Karnofsky performance status, 80%; median number of prior chemotherapy regimens, two (range, 1-3). All patients had adequate hepatic and renal function. SPI-77 was administered at a dose of 260 mg/m(2) IV every 3 weeks. A median of two cycles (range 1-6) were given; the total number of cycles was 35. Among the 12 patients evaluable for response, two had (17%) stable disease and ten (83%) had progressive disease. The median survival was 24.3 weeks, and the median follow-up was 43.9 weeks. Toxicity could be evaluated in all subjects. Moderate anemia (46% of cycles, or=grade 3) with minimal granulocytopenia and thrombocytopenia (26% of cycles grade 1; 0% of cycles, >or=grade 2) were the most notable manifestations of myelosuppression. Grade 3 nonhematological toxicities included dyspnea (8%), fatigue (8%), and pain (8%). There were no grade 4 toxicities. These data suggest that this liposomal cisplatin formulation does not have appreciable activity in this population of patients with NSCLC who had received prior platinum-based chemotherapy. The lack of encouraging results from SPI-77 use in other phase I and II studies resulted in early closure of this trial by the

  10. Biological activity of a series of cisplatin-based aliphatic bis(carboxylato) Pt(IV) prodrugs: how long the organic chain should be?

    PubMed

    Zanellato, Ilaria; Bonarrigo, Ilaria; Colangelo, Donato; Gabano, Elisabetta; Ravera, Mauro; Alessio, Manuela; Osella, Domenico

    2014-11-01

    The biological properties of a series of cisplatin-based Pt(IV) prodrug candidates, namely trans,cis,cis-[Pt(carboxylato)2Cl2(NH3)2], where carboxylato=CH3(CH2)nCOO(-) [(1), n=0; (2), n=2; (3), n=4; (4), n=6] having a large interval of lipophilicity are discussed. The stability of the complexes was tested in different pH conditions (i.e. from 1.0 to 9.0) to simulate the hypothetical conditions for an oral route of administration, showing a high stability (>90%). The transformation into their active Pt(II) metabolites was demonstrated in the presence of ascorbic acid, with a pseudo-first order kinetics, the half-time of which smoothly decreases as the chain length of carboxylic acid increases. Their antiproliferative activity has been evaluated in vitro on a large panel of human cancer cell lines. As expected, the potency increases with the chain length: 3 and 4 resulted by far more active than cisplatin on all cell lines of about one or two orders of magnitude, respectively. Both complexes retained their activity also on cisplatin-resistant cell line, and exhibited a progressive increase of the selectivity compared with non-tumor cells. These results were confirmed with more prolonged treatment (up to 14days) studied on multicellular tumor spheroids (MCTSs). In this case the Pt(IV) complexes exert a protracted antiproliferative action, even if the drug is removed from the culture medium. Finally, in a time-course experiment of the total platinum evaluation in mice blood (after a single oral administration of the title complexes), 2 gave the best results, representing a good compromise between lipophilicity and water solubility, that increase and decrease respectively on passing from 1 to 4.

  11. von Willebrand Factor-Rich Platelet Thrombi in the Liver Cause Sinusoidal Obstruction Syndrome following Oxaliplatin-Based Chemotherapy

    PubMed Central

    Nishigori, Naoto; Matsumoto, Masanori; Koyama, Fumikazu; Hayakawa, Masaki; Hatakeyayama, Kinta; Ko, Saiho; Fujimura, Yoshihiro; Nakajima, Yoshiyuki

    2015-01-01

    Oxaliplatin-based chemotherapy is widely used to treat advanced colorectal cancer (CRC). Sinusoidal obstruction syndrome (SOS) due to oxaliplatin is a serious type of chemotherapy-associated liver injury (CALI) in CRC patients. SOS is thought to be caused by the sinusoidal endothelial cell damage, which results in the release of unusually-large von Willebrand factor multimers (UL-VWFMs) from endothelial cells. To investigate the pathophysiology of CALI after oxaliplatin-based chemotherapy, we analyzed plasma concentration of von Willebrand factor (VWF) and the distribution of VWFMs in CRC patients. Twenty-three patients with advanced CRC who received oxaliplatin-based chemotherapy with (n = 6) and without (n = 17) bevacizumab were analyzed. CALI (n = 6) and splenomegaly (n = 9) were found only in patients who did not treated with bevacizumab. Plasma VWF antigen (VWF:Ag) and serum aspartate aminotransferase (AST) levels increased after chemotherapy only in patients without bevacizumab. VWFM analysis in patients who did not receive bevacizumab showed the presence of UL-VWFMs and absence of high molecular weight VWFMs during chemotherapy, especially in those with CALI. In addition, plasma VWF:Ag and AST levels increased after chemotherapy in patients with splenomegaly (n = 9), but not in patients without splenomegaly (n = 14). Histological findings in the liver tissue of patients who did not receive bevacizumab included sinusoidal dilatation and microthrombi in the sinusoids. Many microthrombi were positive for both anti-IIb/IIIa and anti-VWF antibodies. Plasma UL-VWFM levels might be increased by damage to endothelial cells as a result of oxaliplatin-based chemotherapy. Bevacizumab could prevent CALI and splenomegaly through inhibition of VWF-rich platelet thrombus formation. PMID:26580395

  12. High expression of TIMP-1 in human breast cancer tissues is a predictive of resistance to paclitaxel-based chemotherapy.

    PubMed

    Zhu, Dongliang; Zha, Xiaoming; Hu, Meiling; Tao, Aidi; Zhou, Hangbo; Zhou, Xiaojun; Sun, Yujie

    2012-12-01

    For breast cancer patients with lymph node metastasis, paclitaxel is the first-line chemotherapy drug. Clinical studies showed that some patients with breast cancer were insensitive to paclitaxel, which led to chemotherapy failure. Today, no validated markers exist for the prediction of chemotherapy sensitivity in this patient group. Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to protect against apoptosis. Epidemiological studies have also associated elevated tumor tissue TIMP-1 levels with a poor response to cyclophosphamide/methotrexate/5-fluorouracil and anthracycline-based chemotherapy. Additionally, our previous study proved that TIMP-1 significantly decreased the sensitivity of breast cancer cells to paclitaxel-induced apoptosis by enhancing degradation of cyclin B1. These data imply that TIMP-1 may be a useful predictive biomarker for chemotherapy resistance. In this retrospective study, we investigated the association between expression levels of TIMP-1 protein in the primary tumor and objective response to paclitaxel-based chemotherapy in 99 patients with breast cancer. With Kaplan-Meier survival analysis, the patients with high TIMP-1 levels were found to have significantly worse 5-year DFS (71.1 %) than the patients with low levels (88.5 %; P = 0.020). Similarly, the patients with high TIMP-1 levels had significantly worse 5-year OS (78.9 %) than patients with low levels (96.7 %; P = 0.004). In Cox's univariate and multivariate analyses, TIMP-1 was prognostic for both DFS and OS. Our data showed that elevated tumor tissue TIMP-1 levels were significantly associated with a poor response to paclitaxel-based chemotherapy, and TIMP-1 might be a potential biomarker for predicting response of breast cancer patients to paclitaxel-based chemotherapy.

  13. The effects of nabumetone, a cyclooxygenase-2 inhibitor, on cisplatin-induced 5-hydroxytryptamine release from the isolated rat ileum.

    PubMed

    Kudo, C; Minami, M; Hirafuji, M; Endo, T; Hamaue, N; Akita, K; Murakami, T; Kawaguchi, H

    2001-01-01

    In order to elucidate 5-HT release influenced by PGE2 in the background of the anticancer drug-induced emesis, the effect of nabumetone, a COX-2 inhibitor, on the release of 5-HT from the isolated rat ileum was investigated. PGE2 produced a concentration-dependent increase (10(-9) to 10 M) and decrease (10(-8) to 10(-6) M) in 5-HT release. Arachidonic acid also demonstrated a similar bell-shaped 5-HT release. The arachidonic acid-induced 5-HT release at 3 x 10(-6) M (313.04 +/- 25.90%) was significantly inhibited by the concomitant perfusion with BRL10720 (10(-6) M) (161.98 +/- 19.4%, p<0.01), an active metabolite of nabumetone, or indomethacin (3 x 10(-7) M)(190.01 +/- 16.19%, p<0.05). BRL10720 (10(-6) M)(428.57 +/- 51.72%, p<0.05) significantly inhibited the increase in 5-HT release induced by cisplatin (10(-6) M)(748.56 +/- 136.31%), suggesting that PGE2would be involved in cisplatin-induced 5-HT release. The increase in 5-HT release from the isolated ileum 72 hrs after cisplatin administration, in a delayed-emesis animal model, was significantly inhibited by the in vivo 3-day administration of nabumetone or BRL10720, but was not affected by the 3-day administration of dexamethasone. After 72 hours, however, the in vivo 3-days administration of nabumetone, BRL10720 or dexamethasone had no effect on the increase in ileal 5-HT levels induced by cisplatin. The use of COX-2 inhibitors to ameliorate delayed emesis induced by cisplatin-based anticancer chemotherapy has been proposed. On the other hand, there is a possibility that dexamethasone works through a mechanism other than 5-HT release in delayed emesis.

  14. Effects of neo-adjuvant chemotherapy for oesophago-gastric cancer on neuro-muscular gastric function.

    PubMed

    Sung, E Z H; Arasaradnam, R P; Jarvie, E M; James, S; Goodyear, S J; Borman, R A; Snead, D; Sanger, G J; Nwokolo, C U

    2012-12-01

    Delayed gastric emptying symptoms are often reported after chemotherapy. This study aims to characterise the effects of chemotherapy on gastric neuro-muscular function. Patients undergoing elective surgery for oesophago-gastric cancer were recruited. Acetylcholinesterase, nNOS, ghrelin receptor and motilin expressions were studied in gastric sections from patients receiving no chemotherapy (n = 3) or oesophageal (n = 2) or gastric (n = 2) chemotherapy. A scoring system quantified staining intensity (0-3; no staining to strong). Stomach sections were separately suspended in tissue baths for electrical field stimulation (EFS) and exposure to erythromycin or carbachol; three patients had no chemotherapy; four completed cisplatin-based chemotherapy within 6 weeks prior to surgery. AChE expression was markedly decreased after chemotherapy (scores 2.3 ± 0.7, 0.5 ± 0.2 and 0 ± 0 in non-chemotherapy, oesophageal- and gastric-chemotherapy groups (p < 0.03 each) respectively. Ghrelin receptor and motilin expression tended to increase (ghrelin: 0.7 ± 0.4 vs 2.0 ± 0.4 and 1.2 ± 0.2 respectively; p = 0.04 and p = 0.2; motilin: 0.7 ± 0.5 vs 2.2 ± 0.5 and 2.0 ± 0.7; p = 0.06 and p = 0.16). Maximal contraction to carbachol was 3.7 ± 0.7 g and 1.9 ± 0.8 g (longitudinal muscle) and 3.4 ± 0.4 g and 1.6 ± 0.6 (circular) in non-chemotherapy and chemotherapy tissues respectively (p < 0.05 each). There were loss of AChE and reduction in contractility to carbachol. The tendency for ghrelin receptors to increase suggests an attempt to upregulate compensating systems. Our study offers a mechanism by which chemotherapy markedly alters neuro-muscular gastric function.

  15. SNRFCB: sub-network based random forest classifier for predicting chemotherapy benefit on survival for cancer treatment.

    PubMed

    Shi, Mingguang; He, Jianmin

    2016-04-01

    Adjuvant chemotherapy (CTX) should be individualized to provide potential survival benefit and avoid potential harm to cancer patients. Our goal was to establish a computational approach for making personalized estimates of the survival benefit from adjuvant CTX. We developed Sub-Network based Random Forest classifier for predicting Chemotherapy Benefit (SNRFCB) based gene expression datasets of lung cancer. The SNRFCB approach was then validated in independent test cohorts for identifying chemotherapy responder cohorts and chemotherapy non-responder cohorts. SNRFCB involved the pre-selection of gene sub-network signatures based on the mutations and on protein-protein interaction data as well as the application of the random forest algorithm to gene expression datasets. Adjuvant CTX was significantly associated with the prolonged overall survival of lung cancer patients in the chemotherapy responder group (P = 0.008), but it was not beneficial to patients in the chemotherapy non-responder group (P = 0.657). Adjuvant CTX was significantly associated with the prolonged overall survival of lung cancer squamous cell carcinoma (SQCC) subtype patients in the chemotherapy responder cohorts (P = 0.024), but it was not beneficial to patients in the chemotherapy non-responder cohorts (P = 0.383). SNRFCB improved prediction performance as compared to the machine learning method, support vector machine (SVM). To test the general applicability of the predictive model, we further applied the SNRFCB approach to human breast cancer datasets and also observed superior performance. SNRFCB could provide recurrent probability for individual patients and identify which patients may benefit from adjuvant CTX in clinical trials.

  16. Cisplatin-induced mitochondrial dysfunction is associated with impaired cognitive function in rats

    PubMed Central

    Lomeli, Naomi; Di, Kaijun; Czerniawski, Jennifer; Guzowski, John F.; Bota, Daniela A.

    2017-01-01

    Purpose Chemotherapy-related cognitive impairment (CRCI) is commonly reported following the administration of chemotherapeutic agents and comprises a wide variety of neurological problems. No effective treatments for CRCI are currently available. Here we examined the mechanisms involving cisplatin-induced hippocampal damage following cisplatin administration in a rat model and in cultured rat hippocampal neurons and neural stem/progenitor cells (NSCs). We also assessed the protective effects of the antioxidant, N-acetylcysteine in mitigating these damages. Experimental design Adult male rats received 6 mg/kg cisplatin in the acute studies. In chronic studies, rats received 5 mg/kg cisplatin or saline injections once per week for 4 weeks. N-acetylcysteine (250 mg/kg/day) or saline was administered for five consecutive days during cisplatin treatment. Cognitive testing was performed 5 weeks after treatment cessation. Cisplatin-treated cultured hippocampal neurons and NSCs were examined for changes in mitochondrial function, oxidative stress production, caspase-9 activation, and neuronal dendritic spine density. Results Acute cisplatin treatment reduced dendritic branching and spine density, and induced mitochondrial degradation. Rats receiving the chronic cisplatin regimen showed impaired performance in contextual fear conditioning, context object discrimination, and novel object recognition tasks compared to controls. Cisplatin induced mitochondrial DNA damage, impaired respiratory activity, increased oxidative stress, and activated caspase-9 in cultured hippocampal neurons and NSCs. N-acetylcysteine treatment prevented free radical production, ameliorated apoptotic cellular death and dendritic spine loss, and partially reversed the cisplatin-induced cognitive impairments. Conclusions Our results suggest that mitochondrial dysfunction and increased oxidative stress are involved in cisplatin-induced cognitive impairments. Therapeutic agents, such as N

  17. [Neoadjuvant or Adjuvant Chemotherapy for Bladder Cancer?].

    PubMed

    Hupe, M C; Kramer, M W; Kuczyk, M A; Merseburger, A S

    2015-05-01

    Advanced urothelial carcinoma of the bladder is associated with a high metastatic potential. Life expectancy for metastatic patients is poor and rarely exceeds more than one year without further therapy. Neoadjuvant chemotherapy can decrease the tumour burden while reducing the risk of death. Adjuvant chemotherapy has been discussed controversially. Patients with lymph node-positive metastases seem to benefit the most from adjuvant chemotherapy. In selected patients, metastasectomy can prolong survival. In metastastic patients, the combination of gemcitabine and cisplatin has become the new standard regimen due to a lower toxicity in comparison to the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). For second-line treatment, vinflunine is the only approved therapeutic agent.

  18. Chromosome 17 Centromere Duplication and Responsiveness to Anthracycline-Based Neoadjuvant Chemotherapy in Breast Cancer12

    PubMed Central

    Tibau, Ariadna; López-Vilaró, Laura; Pérez-Olabarria, Maitane; Vázquez, Tania; Pons, Cristina; Gich, Ignasi; Alonso, Carmen; Ojeda, Belén; Ramón y Cajal, Teresa; Lerma, Enrique; Barnadas, Agustí; Escuin, Daniel

    2014-01-01

    Human epidermal growth factor receptor 2 (HER2) and topoisomerase II alpha (TOP2A) genes have been proposed as predictive biomarkers of sensitivity to anthracycline chemotherapy. Recently, chromosome 17 centromere enumeration probe (CEP17) duplication has also been associated with increased responsiveness to anthracyclines. However, reports are conflicting and none of these tumor markers can yet be considered a clinically reliable predictor of response to anthracyclines. We studied the association of TOP2A gene alterations, HER2 gene amplification, and CEP17 duplication with response to anthracycline-based neoadjuvant chemotherapy in 140 patients with operable or locally advanced breast cancer. HER2 was tested by fluorescence in situ hybridization and TOP2A and CEP17 by chromogenic in situ hybridization. Thirteen patients (9.3%) achieved pathologic complete response (pCR). HER2 amplification was present in 24 (17.5%) of the tumors. TOP2A amplification occurred in seven tumors (5.1%). CEP17 duplication was detected in 13 patients (9.5%). CEP17 duplication correlated with a higher rate of pCR [odds ratio (OR) 6.55, 95% confidence interval (95% CI) 1.25-34.29, P = .026], and analysis of TOP2A amplification showed a trend bordering on statistical significance (OR 6.97, 95% CI 0.96-50.12, P = .054). TOP2A amplification and CEP17 duplication combined were strongly associated with pCR (OR 6.71, 95% CI 1.66-27.01, P = .007). HER2 amplification did not correlate with pCR. Our results suggest that CEP17 duplication predicts pCR to primary anthracycline-based chemotherapy. CEP17 duplication, TOP2A amplifications, and HER2 amplifications were not associated with prognosis. PMID:25379022

  19. Chromosome 17 centromere duplication and responsiveness to anthracycline-based neoadjuvant chemotherapy in breast cancer.

    PubMed

    Tibau, Ariadna; López-Vilaró, Laura; Pérez-Olabarria, Maitane; Vázquez, Tania; Pons, Cristina; Gich, Ignasi; Alonso, Carmen; Ojeda, Belén; Ramón y Cajal, Teresa; Lerma, Enrique; Barnadas, Agustí; Escuin, Daniel

    2014-10-01

    Human epidermal growth factor receptor 2 (HER2) and topoisomerase II alpha (TOP2A) genes have been proposed as predictive biomarkers of sensitivity to anthracycline chemotherapy. Recently, chromosome 17 centromere enumeration probe (CEP17) duplication has also been associated with increased responsiveness to anthracyclines. However, reports are conflicting and none of these tumor markers can yet be considered a clinically reliable predictor of response to anthracyclines. We studied the association of TOP2A gene alterations, HER2 gene amplification, and CEP17 duplication with response to anthracycline-based neoadjuvant chemotherapy in 140 patients with operable or locally advanced breast cancer. HER2 was tested by fluorescence in situ hybridization and TOP2A and CEP17 by chromogenic in situ hybridization. Thirteen patients (9.3%) achieved pathologic complete response (pCR). HER2 amplification was present in 24 (17.5%) of the tumors. TOP2A amplification occurred in seven tumors (5.1%). CEP17 duplication was detected in 13 patients (9.5%). CEP17 duplication correlated with a higher rate of pCR [odds ratio (OR) 6.55, 95% confidence interval (95% CI) 1.25-34.29, P = .026], and analysis of TOP2A amplification showed a trend bordering on statistical significance (OR 6.97, 95% CI 0.96-50.12, P = .054). TOP2A amplification and CEP17 duplication combined were strongly associated with pCR (OR 6.71, 95% CI 1.66-27.01, P = .007). HER2 amplification did not correlate with pCR. Our results suggest that CEP17 duplication predicts pCR to primary anthracycline-based chemotherapy. CEP17 duplication, TOP2A amplifications, and HER2 amplifications were not associated with prognosis.

  20. Bisphenol A and estradiol are equipotent in antagonizing cisplatin-induced cytotoxicity in breast cancer cells.

    PubMed

    LaPensee, Elizabeth W; LaPensee, Christopher R; Fox, Sejal; Schwemberger, Sandy; Afton, Scott; Ben-Jonathan, Nira

    2010-04-28

    Resistance to chemotherapy is a major problem facing breast cancer patients. Cisplatin, a highly effective DNA-damaging drug, has shown only little success in breast cancer treatment. We are reporting that low nanomolar doses of bisphenol A (BPA) or estradiol antagonize cisplatin cytotoxicity in breast cancer cells, with their effects not mediated via classical estrogen receptors. Although both compounds increase the expression of Bcl-2, a Bcl-2 inhibitor completely blocked the protective effects of BPA while only partially affecting those of estradiol. Blockade of BPA and E2 actions should sensitize ER-negative breast tumors to anti-cancer drugs and allow for the inclusion of cisplatin in treatment regimens.

  1. Cisplatin and bleomycin-induced acute peripheral-vascular stenosis in patient with testicular cancer

    PubMed Central

    Ozkan, Tayyar Alp; Aydin, Ufuk; Ay, Derih; Cebeci, I. Oguz Ozden

    2016-01-01

    After cisplatin and bleomycin-containing chemotherapy (CTx) for testicular cancer, part of the patients may develop acute or long-term cardiovascular toxicity. In the present case, we reported that a 58-year-old male patient presenting with testicular tumors who developed acute peripheral arterial disease during combination CTx with bleomycin, etoposide, and cisplatin. Superficial femoral artery occlusion not responded to structure thrombolytic and anticoagulators treatment. Left lower extremity was amputated below knee. In patients with high risk of cardiovascular disease, prophylactic anticoagulation may be recommended. The risk of causing factors of thromboembolism in patients with testicular cancer under cisplatin and bleomycin-containing CTx should be evaluated. PMID:28057998

  2. Prolactin confers resistance against cisplatin in breast cancer cells by activating glutathione-S-transferase.

    PubMed

    LaPensee, Elizabeth W; Schwemberger, Sandy J; LaPensee, Christopher R; Bahassi, El Mustapha; Afton, Scott E; Ben-Jonathan, Nira

    2009-08-01

    Resistance to chemotherapy is a major obstacle for successful treatment of breast cancer patients. Given that prolactin (PRL) acts as an anti-apoptotic/survival factor in the breast, we postulated that it antagonizes cytotoxicity by chemotherapeutic drugs. Treatment of breast cancer cells with PRL caused variable resistance to taxol, vinblastine, doxorubicin and cisplatin. PRL prevented cisplatin-induced G(2)/M cell cycle arrest and apoptosis. In the presence of PRL, significantly less cisplatin was bound to DNA, as determined by mass spectroscopy, and little DNA damage was seen by gamma-H2AX staining. PRL dramatically increased the activity of glutathione-S-transferase (GST), which sequesters cisplatin in the cytoplasm; this increase was abrogated by Jak and mitogen-activated protein kinase inhibitors. PRL upregulated the expression of the GSTmu, but not the pi, isozyme. A GST inhibitor abrogated antagonism of cisplatin cytotoxicity by PRL. In conclusion, PRL confers resistance against cisplatin by activating a detoxification enzyme, thereby reducing drug entry into the nucleus. These data provide a rational explanation for the ineffectiveness of cisplatin in breast cancer, which is characterized by high expression of both PRL and its receptor. Suppression of PRL production or blockade of its actions should benefit patients undergoing chemotherapy by allowing for lower drug doses and expanded drug options.

  3. Chemotherapy for Testicular Cancer

    MedlinePlus

    ... main drugs used to treat testicular cancer are: Cisplatin Etoposide (VP-16) Bleomycin Ifosfamide (Ifex ® ) Paclitaxel (Taxol ® ) ... cancer are: BEP (or PEB): bleomycin, etoposide, and cisplatin EP: etoposide and cisplatin (also known as EP) ...

  4. Nutritional status and feeding-tube placement in patients with locally advanced hypopharyngeal cancer included in an induction chemotherapy-based larynx preservation program.

    PubMed

    Bozec, Alexandre; Benezery, Karen; Chamorey, Emmanuel; Ettaiche, Marc; Vandersteen, Clair; Dassonville, Olivier; Poissonnet, Gilles; Riss, Jean-Christophe; Hannoun-Lévi, Jean-Michel; Chand, Marie-Eve; Leysalle, Axel; Saada, Esma; Sudaka, Anne; Haudebourg, Juliette; Hebert, Christophe; Falewee, Marie-Noelle; Demard, François; Santini, José; Peyrade, Frédéric

    2016-09-01

    The objective of the study is to evaluate the nutritional status and determine its impact on clinical outcomes in patients with locally advanced hypopharyngeal cancer included in an induction chemotherapy (ICT)-based larynx preservation program without prophylactic feeding-tube placement. All patients with locally advanced (T3/4, N0-3, M0) hypopharyngeal squamous cell carcinoma, technically suitable for total pharyngolaryngectomy, treated by docetaxel, cisplatin and 5-fluorouracil (TPF)-ICT for larynx preservation at our institution between 2004 and 2013, were included in this retrospective study. Patients' nutritional status was closely monitored. Enteral nutrition was used if and when a patient was unable to sustain per-oral nutrition and hydration. The impact of nutritional status on clinical outcomes was investigated in univariate and multivariate analysis. A total of 53 patients (42 men and 11 women, mean age = 58.6 ± 8.2 years) were included in this study. Six (11.3 %) patients had lost more than 10 % of their usual body weight before therapy. Compared with patients' usual weight, the mean maximum patient weight loss during therapeutic management was 8.7 ± 4.5 kg. Enteral nutrition was required in 17 patients (32 %). We found no influence of the tested nutritional status-related factors on response to ICT, toxicity of ICT, overall, cause-specific and recurrence-free survival, and on post-therapeutic swallowing outcome. Maximum weight loss was significantly associated with a higher risk of enteral tube feeding during therapy (p = 0.03) and of complications (grade ≥3, p = 0.006) during RT. Without prophylactic feeding-tube placement, approximately one-third of the patients required enteral nutrition. There was no significant impact of nutritional status on oncologic or functional outcomes.

  5. Meta-analysis Exploring the Effectiveness of S-1-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer.

    PubMed

    Sun, Xin; Sun, Li; Zhang, Shu-Ling; Xiong, Zhi-Cheng; Ma, Jie-Tao; Han, Cheng-Bo

    2017-01-01

    S-1 is a new oral fluoropyrimidine formulation that comprises tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. S-1 is designed to enhance antitumor activity and to reduce gastrointestinal toxicity. Several studies have demonstrated that both S-1 monotherapy and S-1 combination regimens showed encouraging efficacies and mild toxicities in the treatment of lung squamous cell carcinoma and adenocarcinoma. However, it is unclear whether S-1 can be used as standard care in advanced non-small cell lung cancer (NSCLC). The purpose of this meta-analysis was to assess the efficacy and safety of S-1-based chemotherapy, compared with standard chemotherapy, in patients with locally advanced or metastatic NSCLC. Thirteen randomized controlled trials (RCTs) involving 2,134 patients with a similar ratio of different pathological types were included. In first-line or second-line chemotherapy, compared with standard chemotherapy, S-1-based chemotherapy showed similar efficacy in terms of median overall survival (mOS), median progression free survival (mPFS), and objective response rate (ORR) (all P > 0.1), and significantly reduced the incidence of grade ≥ 3 hematological toxicities. In patients with locally advanced NSCLC receiving concurrent chemoradiotherapy, compared with standard chemoradiotherapy, significantly improved survival in the S-1-based chemotherapy was noted in terms of mOS and mPFS (risk radio [RR] = 1.289, P = 0.009; RR = 1.289, P = 0.000, respectively) with lower incidence of grade ≥ 3 neutropenia (RR = 0.453, P = 0.000). The present meta-analysis demonstrates that S-1-based chemotherapy shows similar benefits in advanced NSCLC and improves survival in locally advanced NSCLC, compared with standard treatment.

  6. Combined Cancer Photothermal-Chemotherapy Based on Doxorubicin/Gold Nanorod-Loaded Polymersomes

    PubMed Central

    Liao, JinFeng; Li, WenTing; Peng, JinRong; Yang, Qian; Li, He; Wei, YuQuan; Zhang, XiaoNing; Qian, ZhiYong

    2015-01-01

    Gold nanorods (GNRs) are well known in photothermal therapy based on near-infrared (NIR) laser absorption of the longitudinal plasmon band. Herein, we developed an effective stimulus system -- GNRs and doxorubicin co-loaded polymersomes (P-GNRs-DOX) -- to facilitate co-therapy of photothermal and chemotherapy. DOX can be triggered to release once the polymersomes are corrupted under local hyperthermic condition of GNRs induced by NIR laser irradiation. Also, the cytotoxicity of GNRs caused by the residual cetyltrimethylacmmonium bromide (CTAB) was reduced by shielding the polymersomes. The GNRs-loaded polymersomes (P-GNRs) can be efficiently taken up by the tumor cells. The distribution of the nanomaterial was imaged by IR-820 and quantitatively analyzed by ICP-AES. We studied the ablation of tumor cells in vitro and in vivo, and found that co-therapy offers significantly improved therapeutic efficacy (tumors were eliminated without regrowth.) compared with chemotherapy or photothermal therapy alone. By TUNEL immunofluorescent staining of tumors after NIR laser irradiation, we found that the co-therapy showed more apoptotic tumor cells than the other groups. Furthermore, the toxicity study by pathologic examination of the heart tissues demonstrated a lower systematic toxicity of P-GNRs-DOX than free DOX. Thus, the chemo-photothermal treatment based on polymersomes loaded with DOX and GNRs is a useful strategy for maximizing the therapeutic efficacy and minimizing the dosage-related side effects in the treatment of solid tumors. PMID:25699095

  7. Combination studies of platinum(II)-based metallointercalators with buthionine-S,R-sulfoximine, 3-bromopyruvate, cisplatin or carboplatin.

    PubMed

    Garbutcheon-Singh, K Benjamin; Harper, Benjamin W J; Myers, Simon; Aldrich-Wright, Janice R

    2014-01-01

    With current chemotherapeutic treatment regimes often limited by adverse side effects, the synergistic combination of complexes with anticancer activity appears to offer a promising strategy for effective cancer treatment. This work investigates the anti-proliferative activity using a combination therapy approach where metallointercalators of the type [Pt(IL)(AL)](2+) (where IL is the intercalating ligand and AL is the ancillary ligand) are used in combination with currently approved anticancer drugs cisplatin and carboplatin and organic molecules buthionine-S,R-sulfoximine and 3-bromopyruvate. Synergistic relationships were observed, indicating a potential to decrease dose-dependent toxicity and improve therapeutic efficacy.

  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. Pemirolast reduces cisplatin-induced kaolin intake in rats.

    PubMed

    Tatsushima, Yoko; Egashira, Nobuaki; Matsushita, Naohiro; Kurobe, Kentaro; Kawashiri, Takehiro; Yano, Takahisa; Oishi, Ryozo

    2011-07-01

    Emesis is the most feared side effect in patients who are undergoing cancer chemotherapy. In particular, cisplatin causes severe acute and delayed emesis. Although early vomiting is well controlled by 5-hydroxytryptamine 3 (5-HT(3)) receptor antagonists, delayed-phase vomiting is not sufficiently controlled. Substance P is thought to be involved in the development of emesis, and tachykinin NK(1) receptor antagonists can inhibit delayed vomiting. We previously have reported that substance P is involved in the paclitaxel-induced hypersensitivity reaction in rats, and anti-allergic agent pemirolast reduces these reactions via inhibition of substance P release. In the present study, we investigated the effect of pemirolast on cisplatin-induced kaolin intake, which is an index of nausea/vomiting in the rat. Cisplatin (5 mg/kg, i.p.) induced kaolin intake and reduced normal feed intake from days 1 to 5 after injection. Cisplatin-induced kaolin intake was significantly reduced by co-administration of ondansetron (2 mg/kg, i.p.), a 5-HT(3) receptor antagonist, and dexamethasone (2 mg/kg, i.p.) from days 1 to 5. Similarly, pemirolast (10 mg/kg, p.o.) and the tachykinin NK(1) receptor antagonist aprepitant (10 and 30 mg/kg, p.o.) significantly reduced cisplatin-induced kaolin intake on days 3 and 4. Moreover, pemirolast at the same dose significantly reversed the cisplatin-induced increase in the cerebrospinal fluid level of substance P in rats. These results suggest that substance P is involved in cisplatin-induced kaolin intake in rats, and pemirolast reduces kaolin intake by inhibition of substance P release.

  10. Cisplatin pharmacogenetics, DNA repair polymorphisms, and esophageal cancer outcomes

    PubMed Central

    Bradbury, Penelope A.; Kulke, Matthew H.; Heist, Rebecca S.; Zhou, Wei; Ma, Clement; Xu, Wei; Marshall, Ariela L.; Zhai, Rihong; Hooshmand, Susanne M.; Asomaning, Kofi; Su, Li; Shepherd, Frances A.; Lynch, Thomas J.; Wain, John C.; Christiani, David C.; Liu, Geoffrey

    2011-01-01

    Objectives Genetic variations or polymorphisms within genes of the nucleotide excision repair (NER) pathway alter DNA repair capacity. Reduced DNA repair (NER) capacity may result in tumors that are more susceptible to cisplatin chemotherapy, which functions by causing DNA damage. We investigated the potential predictive significance of functional NER single nucleotide polymorphisms in esophageal cancer patients treated with (n = 262) or without (n = 108) cisplatin. Methods Four NER polymorphisms XPD Asp312Asn; XPD Lys751Gln, ERCC1 8092C/A, and ERCC1 codon 118C/T were each assessed in polymorphism–cisplatin treatment interactions for overall survival (OS), with progression-free survival (PFS) as a secondary endpoint. Results No associations with ERCC1 118 were found. Polymorphism–cisplatin interactions were highly significant in both OS (P = 0.002, P = 0.0001, and P < 0.0001) and PFS (P = 0.006, P = 0.008, and P = 0.0007) for XPD 312, XPD 751, and ERCC1 8092, respectively. In cisplatin-treated patients, variant alleles of XPD 312, XPD 751, and ERCC1 8092 were each associated with significantly improved OS (and PFS): adjusted hazard ratios of homozygous variants versus wild-type ranged from 0.22 [95% confidence interval (CI): 0.1–0.5] to 0.31 (95% CI: 0.1–0.7). In contrast, in patients who did not receive cisplatin, variant alleles of XPD 751 and ERCC1 8092 had significantly worse survival, with adjusted hazard ratios of homozygous variants ranging from 2.47 (95% CI: 1.1–5.5) to 3.73 (95% CI: 1.6–8.7). Haplotype analyses affirmed these results. Conclusion DNA repair polymorphisms are associated with OS and PFS, and if validated may predict for benefit from cisplatin therapy in patients with esophageal cancer. PMID:19620936

  11. Paris Saponin I Sensitizes Gastric Cancer Cell Lines to Cisplatin via Cell Cycle Arrest and Apoptosis

    PubMed Central

    Song, Shuichuan; Du, Leiwen; Jiang, Hao; Zhu, Xinhai; Li, Jinhui; Xu, Ji

    2016-01-01

    Background Dose-related toxicity is the major restriction of cisplatin and cisplatin-combination chemotherapy, and is a challenge for advanced gastric cancer treatment. We explored the possibility of using Paris saponin I as an agent to sensitize gastric cancer cells to cisplatin, and examined the underlying mechanism. Material/Methods Growth inhibition was detected by MTT assay. The cell cycle and apoptosis were detected using flow cytometry and Annexin V/PI staining. The P21waf1/cip1, Bcl-2, Bax, and caspase-3 protein expression were detected using Western blot analysis. Results The results revealed that PSI sensitized gastric cancer cells to cisplatin, with low toxicity. The IC50 value of cisplatin in SGC-7901 cell lines was decreased when combined with PSI. PSI promoted cisplatin-induced G2/M phase arrest and apoptosis in a cisplatin concentration-dependent manner. Bcl-2 protein expression decreased, but Bax, caspase-3, and P21waf1/cip1 protein expression increased with PSI treatment. Conclusions The underlying mechanism of Paris saponin I may be related to targeting the apoptosis pathway and cell cycle blocking, which suggests that PSI is a potential therapeutic sensitizer for cisplatin in treating gastric cancer. PMID:27755523

  12. Dexamethasone loaded nanoparticles exert protective effects against Cisplatin-induced hearing loss by systemic administration.

    PubMed

    Sun, Changling; Wang, Xueling; Chen, Dongye; Lin, Xin; Yu, Dehong; Wu, Hao

    2016-04-21

    Ototoxicity is one of the most important adverse effects of cisplatin chemotherapy. As a common treatment of acute sensorineural hearing loss, systemic administration of steroids was demonstrated ineffective against cisplatin-induced hearing loss (CIHL) in published studies. The current study aimed to evaluate the potential protective effect of dexamethasone (DEX) encapsulated in polyethyleneglycol-coated polylactic acid (PEG-PLA) nanoparticles (DEX-NPs) against cisplatin-induced hearing loss following systemic administration. DEX was fabricated into PEG-PLA nanoparticles using emulsion and evaporation technique as previously reported. DEX or DEX-NPs was administered intraperitoneally to guinea pigs 1h before cisplatin administration. Auditory brainstem response (ABR) threshold shifts were measured at four frequencies (4, 8, 16, and 24kHz) 1 day before and three days after cisplatin injection. Cochlear morphology was examined to evaluate inner ear injury induced by cisplatin exposure. A single dose of DEX-NPs 1h before cisplatin treatment resulted in a significant preservation of the functional and structural properties of the cochlea, which was equivalent to the effect of multidose (3 days) DEX injection. In contrast, no significant protective effect was observed by single dose injection of DEX. The results of histological examination of the cochleae were consistent with the functional measurements. In conclusion, a single dose DEX-NPs significantly attenuated cisplatin ototoxicity in guinea pigs after systemic administration at both histological and functional levels indicating the potential therapeutic benefits of these nanoparticles for enhancing the delivery of DEX in acute sensorineural hearing loss.

  13. Tobacco mosaic virus-based protein nanoparticles and nanorods for chemotherapy delivery targeting breast cancer

    PubMed Central

    Bruckman, Michael A.; Czapar, Anna E.; VanMeter, Allen; Randolph, Lauren N.; Steinmetz, Nicole F.

    2016-01-01

    Drug delivery systems are required for drug targeting to avoid adverse effects associated with chemotherapy treatment regimes. Our approach is focused on the study and development of plant virus-based materials as drug delivery systems; specifically, this work focuses on the tobacco mosaic virus (TMV). Native TMV forms a hollow, high aspect-ratio nanotube measuring 300 × 18 nm with a 4 nm-wide central channel. Heat-transformation can be applied to TMV yielding spherical nanoparticles (SNPs) measuring ~50 nm in size. While bioconjugate chemistries have been established to modify the TMV rod, such methods have not yet been described for the SNP platform. In this work, we probed the reactivity of SNPs toward bioconjugate reactions targeting lysine, glutamine/aspartic acid, and cysteine residues. We demonstrate functionalization of SNPs using these chemistries yielding efficient payload conjugation. In addition to covalent labeling techniques, we developed encapsulation techniques, where the cargo is loaded into the SNP during heat-transition from rod-to-sphere. Finally, we developed TMV and SNP formulations loaded with the chemotherapeutic doxorubicin, and we demonstrate the application of TMV rods and spheres for chemotherapy delivery targeting breast cancer. PMID:26941034

  14. Tobacco mosaic virus-based protein nanoparticles and nanorods for chemotherapy delivery targeting breast cancer.

    PubMed

    Bruckman, Michael A; Czapar, Anna E; VanMeter, Allen; Randolph, Lauren N; Steinmetz, Nicole F

    2016-06-10

    Drug delivery systems are required for drug targeting to avoid adverse effects associated with chemotherapy treatment regimes. Our approach is focused on the study and development of plant virus-based materials as drug delivery systems; specifically, this work focuses on the tobacco mosaic virus (TMV). Native TMV forms a hollow, high aspect-ratio nanotube measuring 300×18nm with a 4nm-wide central channel. Heat-transformation can be applied to TMV yielding spherical nanoparticles (SNPs) measuring ~50nm in size. While bioconjugate chemistries have been established to modify the TMV rod, such methods have not yet been described for the SNP platform. In this work, we probed the reactivity of SNPs toward bioconjugate reactions targeting lysine, glutamine/aspartic acid, and cysteine residues. We demonstrate functionalization of SNPs using these chemistries yielding efficient payload conjugation. In addition to covalent labeling techniques, we developed encapsulation techniques, where the cargo is loaded into the SNP during heat-transition from rod-to-sphere. Finally, we developed TMV and SNP formulations loaded with the chemotherapeutic doxorubicin, and we demonstrate the application of TMV rods and spheres for chemotherapy delivery targeting breast cancer.

  15. Cancer Chemotherapy

    MedlinePlus

    ... controlled way. Cancer cells keep growing without control. Chemotherapy is drug therapy for cancer. It works by killing the cancer ... It depends on the type and amount of chemotherapy you get and how your body reacts. Some ...

  16. The influence of active hexose correlated compound (AHCC) on cisplatin-evoked chemotherapeutic and side effects in tumor-bearing mice

    SciTech Connect

    Hirose, Aya; Sato, Eri; Fujii, Hajime; Sun Buxiang; Nishioka, Hiroshi . E-mail: nishioka@aminoup.co.jp; Aruoma, Okezie I. . E-mail: okezie.aruoma@touro.edu

    2007-07-15

    Cisplatin (cis-diaminedichloroplatinum (II) or CDDP) (a widely used platinum-containing anticancer drug) is nephrotoxic and has a low percentage of tolerance in patients during chemotherapy. The active hexose correlated compound (AHCC) is an extract of Basidiomycotina marketed as a supplement for cancer patients due to its nutrients and fibre content and its ability to strengthen and optimize the capacity of the immune system. The possibility that AHCC could reduce the side effects of cisplatin was assessed in the tumor-bearing BALB/cA mice on the basis of the ability to ameliorate the cisplatin-induced body weight loss, anorexia, nephrotoxicity and hematopoietic toxicity. Although cisplatin (8 mg/kg body weight) reduced the size and weight of the solid tumors, supplementation with AHCC significantly enhanced cisplatin-induced antitumor effect in both the size (p < 0.05) and weight (p < 0.05). Food intake in the cisplatin-treated mice were decreased following commencement of treatment and this remained low compared with the cisplatin-untreated group (control) throughout the experiment period. Supplementation with AHCC increased the food intake in the cisplatin-treated mice. The blood urea nitrogen and serum creatinine concentrations, and the ratio of blood urea nitrogen to serum creatinine were significantly increased in the cisplatin alone treated group compared to the control group. Their increased levels were mitigated by supplementation with AHCC (100 mg/kg body weight) in the cisplatin-treated group. AHCC was also able to modulate the suppression of bone marrow due to cisplatin and the improvement was statistically significant. The histopathological examination of the kidney revealed the presence of cisplatin-induced damage and this was modulated by AHCC treatment. The potential for AHCC to ameliorate the cisplatin-evoked toxicity as well as the chemotherapeutic effect could have beneficial economic implications for patients undergoing chemotherapy with

  17. Diastolic Dysfunction Following Anthracycline-Based Chemotherapy in Breast Cancer Patients: Incidence and Predictors

    PubMed Central

    González, Iria; Del Castillo, Silvia; Muñiz, Javier; Morales, Luis J.; Moreno, Fernando; Jiménez, Rosa; Cristóbal, Carmen; Graupner, Catherine; Talavera, Pedro; Curcio, Alejandro; Martínez, Paula; Guerra, Juan A.; Alonso, Joaquín J.

    2015-01-01

    Introduction. Cardiotoxicity represents a major limitation for the use of anthracyclines or trastuzumab in breast cancer patients. Data from longitudinal studies of diastolic dysfunction (DD) in this group of patients are scarce. The objective of the present study was to assess the incidence, evolution, and predictors of DD in patients with breast cancer treated with anthracyclines. Methods. This analytical, observational cohort study comprised 100 consecutive patients receiving anthracycline-based chemotherapy (CHT) for breast cancer. All patients underwent clinical evaluation, echocardiogram, and measurement of cardiac biomarkers at baseline, end of anthracycline-based CHT, and at 3 months and 9 months after anthracycline-based CHT was completed. Fifteen patients receiving trastuzumab were followed with two additional visits at 6 and 12 months after the last dose of anthracycline-based CHT. A multivariate analysis was performed to find variables related to the development of DD. Fifteen of the 100 patients had baseline DD and were excluded from this analysis. Results. At the end of follow-up (median: 12 months, interquartile range: 11.1–12.8), 49 patients (57.6%) developed DD. DD was persistent in 36 (73%) but reversible in the remaining 13 patients (27%). Four patients developed cardiotoxicity (three patients had left ventricular systolic dysfunction and one suffered a sudden cardiac death). None of the patients with normal diastolic function developed systolic dysfunction during follow-up. In the logistic regression model, body mass index (BMI) and age were independently related to the development of DD, with the following odds ratio values: BMI: 1.19 (95% confidence interval [CI]: 1.04–1.36), and age: 1.12 (95% CI: 1.03–1.19). Neither cardiac biomarkers nor remaining clinical variables were predictors of DD. Conclusion. Development of diastolic dysfunction after treatment with anthracycline or anthracycline- plus trastuzumab chemotherapy is common. BMI

  18. Dihydroartemisinin potentiates the anticancer effect of cisplatin via mTOR inhibition in cisplatin-resistant ovarian cancer cells: involvement of apoptosis and autophagy

    SciTech Connect

    Feng, Xue; Li, Ling; Jiang, Hong; Jiang, Keping; Jin, Ye; Zheng, Jianhua

    2014-02-14

    Highlights: • Phosphorylation of mTOR is abnormal activation in SKOV3/DDP ovarian cancer cells. • Downregulation of mTOR by DHA helps to sensitize the SKOV3/DDP cells to chemotherapy. • DHA has the potential of induce autophagy in cancer cells. - Abstract: Dihydroartemisinin (DHA) exhibits anticancer activity in tumor cells but its mechanism of action is unclear. Cisplatin (DDP) is currently the best known chemotherapeutic available for ovarian cancer. However, tumors return de novo with acquired resistance over time. Mammalian target of rapamycin (mTOR) is an important kinase that regulates cell apoptosis and autophagy, and its dysregulation has been observed in chemoresistant human cancers. Here, we show that compared with control ovarian cancer cells (SKOV3), mTOR phosphorylation was abnormally activated in cisplatin-resistant ovarian cancer cells (SKOV3/DDP) following cisplatin monotherapy. Treatment with cisplatin combined with DHA could enhance cisplatin-induced proliferation inhibition in SKOV3/DDP cells. This mechanism is at least partially due to DHA deactivation of mTOR kinase and promotion of apoptosis. Although autophagy was also induced by DHA, the reduced cell death was not found by suppressing autophagic flux by Bafilomycin A1 (BAF). Taken together, we conclude that inhibition of cisplatin-induced mTOR activation is one of the main mechanisms by which DHA dramatically promotes its anticancer effect in cisplatin-resistant ovarian cancer cells.

  19. Combining TBP-based rOFFGEL-IEF with FASP and nLC-ESI-LTQ-MS/MS for the analysis of cisplatin-binding proteins in rat kidney.

    PubMed

    Moraleja, I; Moreno-Gordaliza, E; Mena, M L; Gómez-Gómez, M M

    2014-03-01

    In this work, a methodology based on a reducing IEF separation in combination with a FASP tryptic digestion able to maintain the integrity of cisplatin-protein complexes has been developed. The method is based on OFFGEL-IEF under conditions provided by the thiol-free reducing agent TBP, which allowed the separation of cisplatin-binding proteins in liquid fractions. The FASP procedure is applied as an intermediate stage between the IEF separation and MS analysis where the proteins are retained and concentrated in a commercially available ultrafiltration device. The filter unit acts as a proteomic reactor for detergent removal, buffer exchange, chemical modification (reduction and alkylation) and protein digestion. Finally, purified peptides are recovered by centrifugation. This procedure provides efficiencies comparable to standard in-solution digestion and the risk of platinum-complexes loss is minimized due to the fact that reagents employed along the process are subsequently eliminated before the following step. The stability of platinum-protein complexes under the FASP tryptic digestion, either using TBP or DTT as reducing agents, was maintained, allowing the identification of several platinum-containing peptides from cisplatin-HSA. This methodology was applied to the separation of platinum-enriched protein fractions obtained by SEC-ICP-MS in a kidney tissue extract from a rat treated with cisplatin, followed by further identification by nLC-ESI-LTQ-MS/MS after FASP tryptic digestion of selected platinum-containing liquid fractions.

  20. Nephroprotective effect of vanillic acid against cisplatin induced nephrotoxicity in wistar rats: a biochemical and molecular study.

    PubMed

    Sindhu, Ganapathy; Nishanthi, Emayavaramban; Sharmila, Ramalingam

    2015-01-01

    Cisplatin is one of the extensively used anticancer drugs against various cancers. Dosage dependent nephrotoxicity is the major problem in cisplatin chemotherapy. Cisplatin induced nephrotoxicity results in the depletion of renal antioxidant defence system. Our present study is aimed to investigate the nephroprotective effect of vanilic acid to against cisplatin induced nephrotoxicity in male wistar rats. Elevated levels of serum creatinine, blood urea nitrogen, serum uric acid and reduced antioxidant status were observed as indicatives of nephrotoxicity in cisplatin (7mg/kg bw) alone administered rats. Animals which are pre-treated with vanillic acid (50mg/kg and 100mg/kg) restored the elevated levels of renal function markers and reduced antioxidant status to near normalcy when compared to cisplatin alone treated animals. Cisplatin induced lipid peroxidation was markedly reduced by oral administration of vanillic acid at a high dose. The findings in the present study suggest that vanillic acid is a potential antioxidant that reduce cisplatin nephrotoxicity and can be as a combinatorial regimen in cancer chemotherapy.

  1. Intraperitoneal chemotherapy for gastric cancer with peritoneal disease: experience from Singapore and Japan.

    PubMed

    Kono, Koji; Yong, Wei-Peng; Okayama, Hirokazu; Shabbir, Asim; Momma, Tomoyuki; Ohki, Shinji; Takenoshita, Seiichi; So, Jimmy

    2017-03-01

    Among advanced gastric cancer cases, peritoneal dissemination is a life-threatening mode of metastasis, and any strategy to control peritoneal metastasis will significantly improve treatment outcomes. Since intraperitoneal administration of anticancer drugs can induce an extremely high concentration of drugs in the peritoneal cavity, intraperitoneal chemotherapy would appear to be a reasonable and promising strategy to control the peritoneal dissemination. However, it has been reported in the past that intraperitoneal administration of mitomycin C or cisplatin resulted in no significant clinical effects against peritoneal metastasis of gastric cancer. In contrast, intraperitoneal paclitaxel is expected to remain inside the peritoneal cavity due to its large molecular weight and fat solubility, leading to a high concentration of the drug in the peritoneal cavity. In fact, promising results in several phase II clinical trials using intraperitoneal paclitaxel have been reported, including a median survival time of 16.2-24.6 months and a 1-year overall survival rate of 69-78 %. Thereafter, a phase III randomized control study (PHOENIX-GC trial) with intraperitoneal paclitaxel plus systemic S-1 and intravenous paclitaxel in comparison to systemic S-1 plus cisplatin was conducted in Japan. Moreover, a phase II clinical trial of combination chemotherapy of intraperitoneal paclitaxel with systemic capecitabine plus oxaliplatin is currently ongoing in Singapore. In this review, based on clinical experience from Singapore and Japan, the clinical significance of intraperitoneal chemotherapy for gastric cancer with peritoneal disease is discussed.

  2. Hindbrain GLP-1 receptor mediation of cisplatin-induced anorexia and nausea

    PubMed Central

    De Jonghe, Bart C.; Holland, Ruby; Olivos, Diana R.; Rupprecht, Laura E.; Kanoski, Scott E.; Hayes, Matthew R.

    2016-01-01

    While chemotherapy-induced nausea and vomiting is clinically controlled in the acute (<24h) phase following treatment, the anorexia, nausea, fatigue, and other illness-type behaviors during the delayed phase (>24h) of chemotherapy are largely uncontrolled. As the hindbrain glucagon-like peptide-1 (GLP-1) system contributes to energy balance and mediates aversive and stressful stimuli, here we examine the hypothesis that hindbrain GLP-1 signaling mediates aspects of chemotherapy-induced nausea and reductions in feeding behavior in rats. Specifically, hindbrain GLP-1 receptor (GLP-1R) blockade, via 4th intracerebroventricular (ICV) exendin-(9-39) injections, attenuates the anorexia, body weight reduction, and pica (nausea-induced ingestion of kaolin clay) elicited by cisplatin chemotherapy during the delayed phase (48hr) of chemotherapy-induced nausea. Additionally, the present data provide evidence that the central GLP-1-producing preproglucagon neurons in the nucleus tractus solitarius (NTS) of the caudal brainstem are activated by cisplatin during the delayed phase of chemotherapy-induced nausea, as cisplatin led to a significant increase in c-Fos immunoreactivity in NTS GLP-1-immunoreactive neurons. These data support a growing body of literature suggesting that the central GLP-1 system may be a potential pharmaceutical target for adjunct anti-emetics used to treat the delayed-phase of nausea and emesis, anorexia, and body weight loss that accompany chemotherapy treatments. PMID:26522737

  3. Hindbrain GLP-1 receptor mediation of cisplatin-induced anorexia and nausea.

    PubMed

    De Jonghe, Bart C; Holland, Ruby A; Olivos, Diana R; Rupprecht, Laura E; Kanoski, Scott E; Hayes, Matthew R

    2016-01-01

    While chemotherapy-induced nausea and vomiting are clinically controlled in the acute (<24 h) phase following treatment, the anorexia, nausea, fatigue, and other illness-type behaviors during the delayed phase (>24 h) of chemotherapy are largely uncontrolled. As the hindbrain glucagon-like peptide-1 (GLP-1) system contributes to energy balance and mediates aversive and stressful stimuli, here we examine the hypothesis that hindbrain GLP-1 signaling mediates aspects of chemotherapy-induced nausea and reductions in feeding behavior in rats. Specifically, hindbrain GLP-1 receptor (GLP-1R) blockade, via 4th intracerebroventricular (ICV) exendin-(9-39) injections, attenuates the anorexia, body weight reduction, and pica (nausea-induced ingestion of kaolin clay) elicited by cisplatin chemotherapy during the delayed phase (48 h) of chemotherapy-induced nausea. Additionally, the present data provide evidence that the central GLP-1-producing preproglucagon neurons in the nucleus tractus solitarius (NTS) of the caudal brainstem are activated by cisplatin during the delayed phase of chemotherapy-induced nausea, as cisplatin led to a significant increase in c-Fos immunoreactivity in NTS GLP-1-immunoreactive neurons. These data support a growing body of literature suggesting that the central GLP-1 system may be a potential pharmaceutical target for adjunct anti-emetics used to treat the delayed-phase of nausea and emesis, anorexia, and body weight loss that accompany chemotherapy treatments.

  4. Over-expression of Skp2 is associated with resistance to preoperative doxorubicin-based chemotherapy in primary breast cancer

    PubMed Central

    Davidovich, Shirly; Ben-Izhak, Ofer; Shapira, Ma'anit; Futerman, Boris; Hershko, Dan D

    2008-01-01

    Introduction Preoperative chemotherapy is often used in patients with locally advanced breast cancer. However, commonly used clinical and pathological parameters are poor predictors of response to this type of therapy. Recent studies have suggested that altered regulation of the cell cycle in cancer may be involved in resistance to chemotherapy. Over-expression of the ubiquitin ligase Skp2 results in loss of the cell cycle inhibitor p27Kip1 and is associated with poor prognosis in early breast cancer. The purpose of the present study was to examine the role of these proteins as predictors of clinical outcome and response to chemotherapy in locally advanced breast cancer. Methods The expression levels of Skp2 and p27Kip1 were determined by immunohistochemistry both before and after preoperative chemotherapy in 40 patients with locally advanced breast cancer. All patients were treated with cyclophosphamide/doxorubicin (adriamycin)/5-fluorouracil (CAF) and some patients received additional treatment with docetaxel. Expression data were compared with patients' clinical and pathological features, clinical outcome, and response to chemotherapy. Results Skp2 expression before preoperative chemotherapy was inversely related to p27Kip1 levels, tumor grade, and expression of estrogen and progesterone receptors. Both Skp2 and p27Kip1 were found to be accurate prognostic markers for disease-free and overall survival. High preoperative expression of Skp2 was associated with resistance to CAF therapy in 94% of patients (P < 0.0001) but not with resistance to docetaxel. Conclusion Skp2 expression may be a useful marker for predicting response to doxorubicin-based preoperative chemotherapy and clinical outcome in patients with locally advanced breast cancer. PMID:18644126

  5. Liposomal cisplatin combined with gemcitabine in pretreated advanced pancreatic cancer patients: a phase I-II study.

    PubMed

    Stathopoulos, George P; Boulikas, Teni; Vougiouka, Maria; Rigatos, Sotirios K; Stathopoulos, John G

    2006-05-01

    The present trial is a phase I-II study based on a new liposomal cisplatin (lipoplatin). Previous preclinical and clinical data (phase I pharmacokinetics) led to the investigation of a combined treatment modality involving lipoplatin and gemcitabine. The gemcitabine dose was kept standard at 1000 mg/m2 and the lipoplatin dose was escalated from 25 mg/m2 to 125 mg/m2. The treatment was administered to advanced pretreated pancreatic cancer patients who were refractory to previous chemotherapy which included gemcitabine. Lipoplatin at 125 mg/m2 was defined as dose limiting toxicity (DLT) and 100 mg/m2 as the maximum tolerated dose (MTD) in combination with 1000 mg/m2 of gemcitabine. Preliminary objective response rate data showed a partial response in 2/24 patients (8.3%), disease stability in 14 patients (58.3%) for a median duration of 3 months (range 2-7 months) and clinical benefit in 8 patients (33.3%). Liposomal cisplatin is a non-toxic alternative agent to bare cisplatin. In combination with gemcitabine, it has an MTD of 100 mg/m2 and shows promising efficacy in refractory pancreatic cancer.

  6. Metformin Prevents Cisplatin-Induced Cognitive Impairment and Brain Damage in Mice

    PubMed Central

    Zhou, Wenjun; Kavelaars, Annemieke; Heijnen, Cobi J.

    2016-01-01

    Rationale Chemotherapy-induced cognitive impairment, also known as ‘chemobrain’, is now widely recognized as a frequent adverse side effect of cancer treatment that often persists into survivorship. There are no drugs available to prevent or treat chemotherapy-induced cognitive deficits. The aim of this study was to establish a mouse model of cisplatin-induced cognitive deficits and to determine the potential preventive effects of the anti-diabetic drug metformin. Results Treatment of C57/BL6J mice with cisplatin (cumulative dose 34.5mg/kg) impaired performance in the novel object and place recognition task as well as in the social discrimination task indicating cognitive deficits. Co-administration of metformin prevented these cisplatin-induced cognitive impairments. At the structural level, we demonstrate that cisplatin reduces coherency of white matter fibers in the cingulate cortex. Moreover, the number of dendritic spines and neuronal arborizations as quantified on Golgi-stained brains was reduced after cisplatin treatment. Co-administration of metformin prevented all of these structural abnormalities in cisplatin-treated mice. In contrast to what has been reported in other models of chemobrain, we do not have evidence for persistent microglial or astrocyte activation in the brains of cisplatin-treated mice. Finally, we show that co-administration of metformin also protects against cisplatin-induced peripheral neuropathy. Conclusion In summary, we show here for the first time that treatment of mice with cisplatin induces cognitive deficits that are associated with structural abnormalities in the brain. Moreover, we present the first evidence that the widely used and safe anti-diabetic drug metformin protects against these deleterious effects of cancer treatment. In view of the ongoing clinical trials to examine the potential efficacy of metformin as add-on therapy in patients treated for cancer, these findings should allow rapid clinical translation. PMID

  7. Knockdown of NAPA using short-hairpin RNA sensitizes cancer cells to cisplatin: implications to overcome chemoresistance.

    PubMed

    Wu, Zchong-Zcho; Chao, Chuck C-K

    2010-09-15

    Cisplatin is a widely used anti-cancer drug which targets DNA in replicating cells. In the present study, we found that NAPA--a protein found in the endoplasmic reticulum (ER) and implicated in protein trafficking--protects cells against cisplatin. Accordingly, knockdown of NAPA using lentivirus-encoded shRNA (shNAPA) induced ER stress similar to cisplatin treatment in HEK293 cells. A low dose of cisplatin also elicited a mild ER stress response associated with the accumulation of the protective proteins BiP and NAPA. Remarkably, knockdown of NAPA induced apoptosis and enhanced cisplatin-induced cytotoxicity/apoptosis, thereby sensitizing cancer cells to cisplatin. On the other hand, overexpression of NAPA increased resistance to cisplatin by reducing cisplatin-induced ER stress and apoptosis. The modulatory effects of shNAPA required the tumor suppressor p53 since the effects of NAPA knockdown were reduced by the p53 inhibitor PFT-alpha and in H1299 cells which are p53-null. A partial reversal of cisplatin resistance was also observed in cisplatin-resistant HeLa cells following knockdown of NAPA. Our results also indicated that calpain is required for ER-mediated apoptosis. Importantly, combined cisplatin/shNAPA treatment suppressed tumor growth in vivo in xenograph experiments performed in nude mice. Taken together, these observations suggest that NAPA represents a target of cisplatin, and that knockdown of NAPA may improve cisplatin-based cancer therapy.

  8. Puerarin attenuates cisplatin-induced rat nephrotoxicity: The involvement of TLR4/NF-κB signaling pathway

    PubMed Central

    Ma, Xu; Yan, Lei; Zhu, Qing; Shao, Fengmin

    2017-01-01

    inhibition but promotion effect on the antitumor activity of cisplatin. Puerarin might be a promising adjuvant agent for cisplatin chemotherapy. PMID:28182789

  9. Platinum-containing compound platinum pyrithione is stronger and safer than cisplatin in cancer therapy

    PubMed Central

    Zang, Dan; Lan, Xiaoying; Liao, Siyan; Yang, Changshan; Zhang, Peiquan; Wu, Jinjie; Li, Xiaofen; Liu, Ningning; Liao, Yuning; Huang, Hongbiao; Shi, Xianping; Jiang, Lili; Liu, Xiuhua; He, Zhimin; Wang, Xuejun; Liu, Jinbao

    2017-01-01

    DNA is the well-known molecular target of current platinum-based anticancer drugs; consequently, their clinical use is severely restricted by their systemic toxicities and drug resistance originating from non-selective DNA damage. Various strategies have been developed to circumvent the shortcomings of platinum-based chemotherapy but the inherent problem remains unsolved. Here we report that platinum pyrithione (PtPT), a chemically well-characterized synthetic complex of platinum, inhibits proteasome function and thereby exhibits greater and more selective cytotoxicity to multiple cancer cells than cisplatin, without showing discernible DNA damage both in vitro and in vivo. Moreover, unlike the classical proteasome inhibitor bortezomib/Velcade which inhibits the proteasome via blocking the peptidase activity of 20S proteasomes, PtPT primarily deactivates 26S proteasome-associated deubiquitinases USP14 and UCHL5. Furthermore, PtPT can selectively induce cytotoxicity and proteasome inhibition in cancer cells from leukemia patients but not peripheral blood mononuclear cells from healthy humans. In nude mice, PtPT also remarkably inhibited tumor xenograft growth, without showing the adverse effects that were induced by cisplatin. Hence, we have discovered a new platinum-based anti-tumor agent PtPT which targets 26S proteasome-associated deubiquitinases rather than DNA in the cell and thereby exerts safer and more potent anti-tumor effects, identifying a highly translatable new platinum-based anti-cancer strategy. PMID:27381943

  10. Efficacy of crizotinib and pemetrexed-based chemotherapy in Chinese NSCLC patients with ROS1 rearrangement

    PubMed Central

    Li, Wei; Li, Xuefei; Zhao, Sha; Liu, Xiaozhen; Jia, Yijun; Yang, Hui; Ren, Shengxiang; Zhou, Caicun

    2016-01-01

    Background ROS1 rearrangement is a novel molecular subgroup of non-small-cell lung cancer (NSCLC). This study aimed to investigate the efficacy of crizotinib and pemetrexed-based chemotherapy in Chinese NSCLC patients with ROS1 rearrangement. Results A total of 2309 patients received ROS1 fusion detection and 51(2.2%) patients had ROS1 rearrangement. There was no significant difference between ROS1 fusion-positive and fusion-negative cohorts in demographic data. For the ROS1 fusion-positive patients, crizotinb-treated group had a higher overall response rate (ORR, 80.0%), disease control rate (DCR, 90.0%) and longer progression-free survival (PFS, 294 days) compared with the rates in pemetrexed-treated group (ORR, 40.8%; DCR, 71.4%; PFS, 179 days) and non-pemetrexed-treated group (ORR, 25.0%; DCR, 47.7%; PFS, 110 days). Besides, ORR, DCR and PFS were similar in three major ROS1 fusion partners. For the first-line treatment, patients received pemetrexed had a significant longer PFS than those received non-pemetrexed chemotherapy (209 vs. 146 days, P = 0.0107). In pemetrexed-treated cohorts, ROS1-positive patients with low TS expression had a statistically significant longer PFS than those with high TS expression (184 vs. 110 days, P = 0.0105). Materials and methods We retrospectively identified patients with NSCLC who were screened for ROS1 fusion using multiplex reverse transcription-polymerase chain reaction (RT-PCR) from October 2013 to February 2016. The thymidylate synthase (TS) mRNA levels were tested using quantitative real-time RT-PCR. Conclusions Crizotinib was also highly active at treating Chinese NSCLC patients with ROS1 rearrangement. TS expression could predict the efficacy of pemetrexed-based therapy in ROS1 fusion-positive patients. PMID:27738334

  11. Successful transfer of frozen-thawed embryos obtained after subtotal colectomy for colorectal cancer and before fluorouracil-based chemotherapy.

    PubMed

    Azem, Foad; Amit, Ami; Merimsky, Ofer; Lessing, Joseph B

    2004-04-01

    Background. Fertility preservation is applied to patients with cancer who may be rendered sterile from chemotherapy or radiotherapy. Fluorouracil is considered as having almost no effect on human reproductive function, although clinical data defining infertility risk is negligible. Case. Controlled ovarian stimulation, in vitro fertilization (IVF), and embryo freezing were performed before fluorouracil-based chemotherapy in a 28-year-old woman who underwent subtotal colectomy for colorectal cancer (CRC). Three years later, when the clinical and hormonal analysis confirmed ovarian failure, two thawed embryos were transferred to the uterus. She gave birth at term to a 3200g infant. Discussion. Women with good prognosis who wish to bear children in the future should be offered fertility preservation options before chemotherapy, even if the likelihood of permanent ovarian failure appears to be negligible.

  12. 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.

  13. Examining the Effects of Exercise Training on Tumor Response to Nithracycline-Based Chemotherapy

    DTIC Science & Technology

    2005-08-01

    quality of life in breast cancer patients during adjuvant chemotherapy . An essential precursor to these... Exercise is becoming readily accepted as a beneficial adjunct therapy to maintain or enhance quality of life in breast cancer patients during adjuvant ... exercise as a supportive intervention for breast cancer patients during conventional adjuvant chemotherapy

  14. Cannabidiol attenuates cisplatin-induced nephrotoxicity by decreasing oxidative/nitrosative stress, inflammation, and cell death.

    PubMed

    Pan, Hao; Mukhopadhyay, Partha; Rajesh, Mohanraj; Patel, Vivek; Mukhopadhyay, Bani; Gao, Bin; Haskó, György; Pacher, Pál

    2009-03-01

    The platinum compound cisplatin is one of the most potent chemotherapy agents available to treat various malignancies. Nephrotoxicity is a common complication of cisplatin chemotherapy, which involves increased oxidative and nitrosative stress, limiting its clinical use. In this study, we have investigated the effects of a nonpsychoactive cannabinoid cannabidiol, which was reported to exert antioxidant effects and has recently been approved for the treatment of inflammation, pain, and spasticity associated with multiple sclerosis in patients in a mouse model of cisplatin-induced nephropathy. Cisplatin induced increased expression of superoxide-generating enzymes RENOX (NOX4) and NOX1, enhanced reactive oxygen species generation, inducible nitric-oxide synthase expression, nitrotyrosine formation, apoptosis (caspase-3/7 activity, DNA fragmentation, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining), poly(ADP-ribose) polymerase activity, and inflammation (tumor necrosis factor-alpha and interleukin-1beta) in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum blood urea nitrogen and creatinine levels) 72 h after the administration of the drug. Treatment of mice with cannabidiol markedly attenuated the cisplatin-induced oxidative/nitrosative stress, inflammation, and cell death in the kidney, and it improved renal function. Thus, our results suggest that cannabidiol may represent a promising new protective strategy against cisplatin-induced nephrotoxicity.

  15. MicroRNA-451 sensitizes lung cancer cells to cisplatin through regulation of Mcl-1.

    PubMed

    Cheng, Dezhi; Xu, Yi; Sun, Changzheng; He, Zhifeng

    2016-12-01

    As one of the most widely used chemotherapy drugs for lung cancer, chemoresistance of cisplatin (DPP) is one of the major hindrances in treatment of this malignancy. The microRNAs (miRNAs) have been identified to mediate chemotherapy drug resistance. MiR-451 as a tumor suppressor has been evaluated its potential effect on the sensitivity of cancer cells to DDP. However, the role of miR-451 in regulatory mechanism of chemosensitivity in lung cancer cells is still largely unknown. In this study, we first constructed a cisplatin-resistant A549 cell line (A549/DPP) accompanied with a decreased expression of miR-451 and an increased expression of Mcl-1in the drug resistant cells compared with the parental cells. Exogenous expression of miR-451 level in A549/DPP was found to sensitize their reaction to the treatment of cisplatin, which coincides with reduced expression of Mcl-1. Interestingly, Mcl-1 knockdown in A549/DPP cells increased the chemosensitivity to DPP, suggesting the dependence of Mcl-1 regulation in miR-451 activity. Moreover, miR-451 can restore cisplatin treatment response in cisplatin-resistant xenografts in vivo, while Mcl-1 protein levels were decreased. Thus, these findings provided that in lung cancer cells, tumor suppressor miR-451 enhanced DPP sensitivity via regulation of Mcl-1 expression, which could be served as a novel therapeutic target for the treatment of chemotherapy resistant in lung cancer.

  16. [An effective case of hepatic arterial infusion chemotherapy based on biochemical modulation for hepatic recurrence of non-functioning islet cell carcinoma of the pancreas].

    PubMed

    Nishijima, K; Ohta, T; Elnemr, A; Yi, S; Ninomiya, I; Kitagawa, H; Fushida, S; Nishimura, G; Fujimura, T; Kayahara, M; Shimizu, K; Miwa, K

    2000-10-01

    A 55-year-old man had a metastasis in segment 3 of the liver 5 months after surgery for non-functioning islet cell carcinoma of the pancreas. The metastatic lesion increased in size in a short period, and other liver micro-metastases that could not be detected by imaging may exist, so hepatic arterial infusion chemotherapy was scheduled for 3 months. The patient underwent hepatic arterial infusion chemotherapy of 5-fluorouracil (250 mg/day/body for 5 days/week) and adriamycin (10 mg/day/body for 2 days/week) and cisplatin (10 mg/day/body for 5 days/week) and he was put on Leucovorin 30 mg/day as a biochemical modulator of 5-FU and tamoxifen 40 mg/day as a biochemical modulator of ADM. A total 6,000 mg of 5-FU, 100 mg of ADM and 240 mg of CDDP had been administered, until hepatic arterial infusion chemotherapy was discontinued because of complicated gastric ulcer. Three months later, the size of the metastatic liver tumor was reduced remarkably and no other metastasis was detected on CT scan, so he underwent partial hepatectomy of the metastatic lesion. No recurrence was found and he has survived in good physical condition during the follow-up period of 5 months after the second operation.

  17. [Construction of optimal combined chemotherapy of anti-tumor drugs based on chronotherapy].

    PubMed

    To, Hideto

    2006-06-01

    Metastatic breast cancer (MBC) is almost always incurable, and the median survival is of the order on 18-24 months. Combination therapy with adriamycin (ADR) and docetaxel (DOC) is more effective against MBC than the previous therapy due to differences between their mechanisms. However, the combination of ADR and DOC induces severe adverse effects, limiting its clinical use in many patients with MBC. The biologic functions of most living organisms are organized along an approximate 24 h time cycle or circadian rhythm. Chronotherapy is defined as the administration of medications using biological rhythms to optimize the therapeutic outcomes and/or control adverse effects. To decrease adverse effects, many antitumor drugs have been particularly studied in humans and animals. The toxicities of ADR and DOC have also been found to depend on dosing-time in animals and humans. This study was to establish the most suitable dosing schedule to relieve severe adverse effects and improve antitumor effects by considering a chronopharmacological approach, dosing-interval and dosing-sequence to the combination chemotherapy of ADR and DOC in mice. In the results, we demonstrate that the dosing schedule based on dosing-sequence, dosing-interval and dosing-time not only significantly reduced leukopenia and toxic death but also significantly increased the inhibition rate of tumor growth compared with the dosing schedule without an interval between each injection, commonly used in clinical practice. These findings suggest that the therapeutic index of combined chemotherapy can be improved by choosing an optimal dosing-schedule (dosing-interval, dosing-sequence and dosing-time).

  18. PTEN overexpression improves cisplatin-resistance of human ovarian cancer cells through upregulating KRT10 expression

    SciTech Connect

    Wu, Huijuan; Wang, Ke; Liu, Wenxin; Hao, Quan

    2014-02-07

    Highlights: • Overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin. • KRT10 is a downstream molecule of PTEN involved in the resistance-reversing effect. • Overexpression of KRT10 enhanced the chemosensitivity of C13K cells to cisplatin. - Abstract: Multi-drug resistance (MDR) is a common cause of the failure of chemotherapy in ovarian cancer. PTEN, a tumor suppressor gene, has been demonstrated to be able to reverse cisplatin-resistance in ovarian cancer cell line C13K. However, the downstream molecules of PTEN involved in the resistance-reversing effect have not been completely clarified. Therefore, we screened the downstream molecules of PTEN and studied their interactions in C13K ovarian cancer cells using a 3D culture model. Firstly, we constructed an ovarian cancer cell line stably expressing PTEN, C13K/PTEN. MTT assay showed that overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin, but not to paclitaxel. Then we examined the differently expressed proteins that interacted with PTEN in C13K/PTEN cells with or without cisplatin treatment by co-immunoprecipitation. KRT10 was identified as a differently expressed protein in cisplatin-treated C13K/PTEN cells. Further study confirmed that cisplatin could induce upregulation of KRT10 mRNA and protein in C13K/PTEN cells and there was a directly interaction between KRT10 and PTEN. Forced expression of KRT10 in C13K cells also enhanced cisplatin-induced proliferation inhibition and apoptosis of C13K cells. In addition, KRT10 siRNA blocked cisplatin-induced proliferation inhibition of C13K/PTEN cells. In conclusion, our data demonstrate that KRT10 is a downstream molecule of PTEN which improves cisplatin-resistance of ovarian cancer and forced KRT10 overexpression may also act as a therapeutic method for overcoming MDR in ovarian cancer.

  19. MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β.

    PubMed

    Hao, Jielu; Lou, Qiang; Wei, Qingqing; Mei, Shuqin; Li, Lin; Wu, Guangyu; Mi, Qing-Sheng; Mei, Changlin; Dong, Zheng

    2017-03-17

    Nephrotoxicity is a major adverse effect of cisplatin-mediated chemotherapy in cancer patients. The pathogenesis of cisplatin-induced nephrotoxicity remains largely unclear, making it difficult to design effective renoprotective approaches. Here, we have examined the role of microRNAs (miRNAs) in cisplatin-induced nephrotoxicity. We show that cisplatin nephrotoxicity was not affected by overall depletion of both beneficial and detrimental miRNAs from kidney proximal tubular cells in mice in which the miRNA-generating enzyme Dicer had been conditionally knocked out. To identify miRNAs involved in cisplatin nephrotoxicity, we used microarray analysis to profile miRNA expression and identified 47 up-regulated microRNAs and 20 down-regulated microRNAs in kidney cortical tissues. One up-regulated miRNA was miR-375, whose expression was also induced in cisplatin-treated renal tubular cells. Interestingly, inhibition of miR-375 decreased cisplatin-induced apoptosis, suggesting that miR-375 is a cell-damaging or pro-apoptotic agent. Blockade of P53 or NF-κB attenuated cisplatin-induced miR-375 expression, supporting a role of P53 and NF-κB in miR-375 induction. We also identified hepatocyte nuclear factor 1 homeobox B (HNF-1β) as a key downstream target of miR-375. Of note, we further demonstrated that HNF-1β protected renal cells against cisplatin-induced apoptosis. Together, these results suggest that upon cisplatin exposure, P53 and NF-κB collaboratively induce miR-375 expression, which, in turn, represses HNF-1β activity, resulting in renal tubular cell apoptosis and nephrotoxicity.

  20. Cisplatin Inhibits Bone Healing During Distraction Osteogenesis

    PubMed Central

    Stine, Kimo C.; Wahl, Elizabeth C.; Liu, Lichu; Skinner, Robert A.; Schilden, Jaclyn Vander; Bunn, Robert C.; Montgomery, Corey O.; Suva, Larry J.; Aronson, James; Becton, David L.; Nicholas, Richard W.; Swearingen, Christopher J.; Lumpkin, Charles K.

    2014-01-01

    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 (2mg/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 5 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

  1. A proteomic kinetic analysis of IGROV1 ovarian carcinoma cell line response to cisplatin treatment.

    PubMed

    Le Moguen, Karen; Lincet, Hubert; Marcelo, Paulo; Lemoisson, Edwige; Heutte, Natacha; Duval, Marilyne; Poulain, Laurent; Vinh, Joëlle; Gauduchon, Pascal; Baudin, Bruno

    2007-11-01

    Ovarian cancer is one of the leading causes of mortality by gynecological cancer. Despite good response to surgery and initial chemotherapy, essentially based on cisplatin (cis-diamino-dichloro-platinum(II) (CDDP)) compounds, frequent recurrences with chemoresistance acquisition are responsible for poor prognosis. Several mechanisms have been described as implicated in CDDP resistance, however they are not sufficient to exhaustively account for this resistance emergence. We applied a proteomic approach based on 2-DE coupled with MS (MALDI-TOF/TOF) to identify proteins associated with chemoresistance induced by CDDP. A kinetic analysis of IGROV1 cell behavior following treatment with CDDP and subsequent statistical analysis revealed time and/or concentration-dependent modifications in protein expression. We evidenced events such as decreased amino-acid and nucleotide synthesis potentially associated with cell cycle blockade, and variations that may be related to resistance acquisition, such as possible enhanced glycolysis and increased proliferating potential. Moreover, overexpressions of aldehyde dehydrogenase 1 and both cytokeratins 8 and 18 were consistent with our previous findings, demonstrating that expression of these proteins was increased in cisplatin-resistant IGROV1-R10 as compared to IGROV1 parental cells. Identification of such proteins could allow improved understanding of the mechanisms leading to cell death or survival and, thus, to the acquisition of chemoresistance.

  2. Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer

    PubMed Central

    Pötter, Richard; Georg, Petra; Dimopoulos, Johannes C.A.; Grimm, Magdalena; Berger, Daniel; Nesvacil, Nicole; Georg, Dietmar; Schmid, Maximilian P.; Reinthaller, Alexander; Sturdza, Alina; Kirisits, Christian

    2011-01-01

    Background To analyse the overall clinical outcome and benefits by applying protocol based image guided adaptive brachytherapy combined with 3D conformal external beam radiotherapy (EBRT) ± chemotherapy (ChT). Methods Treatment schedule was EBRT with 45–50.4 Gy ± concomitant cisplatin chemotherapy plus 4 × 7 Gy High Dose Rate (HDR) brachytherapy. Patients were treated in the “protocol period” (2001–2008) with the prospective application of the High Risk CTV concept (D90) and dose volume constraints for organs at risk including biological modelling. Dose volume adaptation was performed with the aim of dose escalation in large tumours (prescribed D90 > 85 Gy), often with inserting additional interstitial needles. Dose volume constraints (D2cc) were 70–75 Gy for rectum and sigmoid and 90 Gy for bladder. Late morbidity was prospectively scored, using LENT/SOMA Score. Disease outcome and treatment related late morbidity were evaluated and compared using actuarial analysis. Findings One hundred and fifty-six consecutive patients (median age 58 years) with cervix cancer FIGO stages IB–IVA were treated with definitive radiotherapy in curative intent. Histology was squamous cell cancer in 134 patients (86%), tumour size was >5 cm in 103 patients (66%), lymph node involvement in 75 patients (48%). Median follow-up was 42 months for all patients. Interstitial techniques were used in addition to intracavitary brachytherapy in 69/156 (44%) patients. Total prescribed mean dose (D90) was 93 ± 13 Gy, D2cc 86 ± 17 Gy for bladder, 65 ± 9 Gy for rectum and 64 ± 9 Gy for sigmoid. Complete remission was achieved in 151/156 patients (97%). Overall local control at 3 years was 95%; 98% for tumours 2–5 cm, and 92% for tumours >5 cm (p = 0.04), 100% for IB, 96% for IIB, 86% for IIIB. Cancer specific survival at 3 years was overall 74%, 83% for tumours 2–5 cm, 70% for tumours >5 cm, 83% for IB, 84% for IIB, 52% for IIIB. Overall

  3. Upregulation of microRNA-524-5p enhances the cisplatin sensitivity of gastric cancer cells by modulating proliferation and metastasis via targeting SOX9

    PubMed Central

    Zhou, Jin; Sun, Qing; Liang, Hansi; Gao, Ling

    2017-01-01

    Cisplatin-based chemotherapy is the most commonly used treatment regimen for gastric cancer (GC), however, the resistance to cisplatin represents the key limitation for the therapeutic efficacy. Aberrant expression of MiR-524-5p appears to be involves in tumorigenesis and chemoresistance. However, the mechanism by which miR-524-5p mediates effects of cisplatin treatment in GC remains poorly understood. Expressions of MiR-524-5p was detected in GC tissues and cell lines by qRT-PCR. Cell proliferation was observed by MTT assay; Cell migration was detected by transwell migration and invasion assay. The targeting protein of miR-524-5p was identified by luciferase reporter assay and western blot. We found that downregulation of miR-524-5p in GC tissues and cell lines. SC-M1 and AZ521 cells resistant to cisplatin expressed low levels of miR-524-5p in comparison to the sensitive parental cells. Overexpression of miR-524-5p expression in SC-M1 and AZ521 cells inhibited cell proliferation, migration, and invasion, and conferred sensitivity to cisplatin-resistant GC cells. Subsequently, we identified SOX9 as a functional target protein of miR-524-5p and found that SOX9 overexpression could counteracts the chemosensitizing effects of miR-524-5p. These results provide novel insight into the regulation of GC tumorigenesis and progression by miRNAs. Restoration of miR-524-5p may have therapeutic potential against GC. PMID:27880941

  4. Serum APE1 as a predictive marker for platinum-based chemotherapy of non-small cell lung cancer patients

    PubMed Central

    Dai, Nan; Guan, Wei; Shan, Jinlu; Yang, Xueqin; Zhong, Zhaoyang; Qing, Yi; Jin, Feng; Chen, Chuan; Yang, Yuxin; Wang, Hongyi; Baugh, Laura; Tell, Gianluca; Wilson, David M.; Li, Mengxia; Wang, Dong

    2016-01-01

    Purpose To define the role of the DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1) in predicting the prognosis and chemotherapeutic response of non-small cell lung cancer patients receiving platinum-containing chemotherapy. Results Our investigations found that serum APE1 level was significantly elevated in 229 of 412 NSCLC patients and correlated with its level in tissue (r2 = 0.639, p < 0.001). The elevated APE1 level in both tissue and serum of patients prior to chemotherapy was associated with worse progression-free survival (HR: 2.165, p < 0.001, HR: 1.421, p = 0.012), but not with overall survival. After 6 cycles of chemotherapy, a low APE1 serum level was associated with better overall survival (HR: 0.497, p = 0.010). Experimental Design We measured APE1 protein levels in biopsy tissue from 172 NSCLC patients and sera of 412 NSCLC patients receiving platinum-based chemotherapy by immunohistochemistry and a newly established sensitive and specific enzyme-linked immunosorbent assay, respectively. APE1 levels in sera of 523 healthy donors were also determined as control. Conclusions Our studies indicate that APE1 is a biomarker for predicting prognosis and therapeutic efficacy in NSCLC. The chemotherapy-naïve serum APE1 level, which correlated with its tissue level inversely associated with progression-free survival of platinum-containing doublet chemotherapy, whereas post-treatment serum APE1 level was inversely associated with overall survival. PMID:27813497

  5. Cost-effectiveness of chemotherapy combined with thoracic radiotherapy versus chemotherapy alone for limited stage small cell lung cancer: A population-based propensity-score matched analysis

    PubMed Central

    Chien, Chun-Ru; Hsia, Te-Chun; Chen, Chih-Yi

    2014-01-01

    Background The addition of thoracic radiotherapy improves the outcome of limited stage small cell lung cancer (LS-SCLC), however, the cost-effectiveness of this process has never been reported. We aimed to estimate the short-term cost-effectiveness of chemotherapy combined with thoracic radiotherapy (C-TRT) versus chemotherapy alone (C/T) for LS-SCLC patients from the payer's perspective (Taiwan National Health Insurance). Methods We identified LS-SCLC patients diagnosed within 2007–2009 through a comprehensive population-based database containing cancer and death registries, and reimbursement data. The duration of interest was one year within diagnosis. We included potential confounding covariables through literature searching and our own experience, and used a propensity score to construct a 1:1 population for adjustment. We used a net benefit (NB) approach to evaluate the cost-effectiveness at various willingness-to-pay (WTP) levels. Sensitivity analysis regarding potential unmeasured confounder(s) was performed. Results Our study population constituted 74 patients. The mean cost (2013 USD) and survival (year) was higher for C-TRT (42 439 vs. 28 357; 0.94 vs. 0.88). At the common WTP level (50 000 USD/life-year), C-TRT was not cost effective (incremental NB − 11 082) and the probability for C-TRT to be cost effective (i.e. positive net benefit) was 0.005. The result was moderately sensitive to potential unmeasured confounder(s) in sensitivity analysis. Conclusions We provide evidence that when compared to C/T, C-TRT is effective in improving survival, but is not cost-effective in the short-term at a common WTP level from a payer's perspective. This information should be considered by clinicians when discussing thoracic radiotherapy with their LS-SCLC patients. PMID:26767048

  6. Integrating Chemotherapy into the Management of Oligometastatic Colorectal Cancer: Evidence based Approach Using Clinical Trial Findings

    PubMed Central

    Semrad, Thomas J.; Fahrni, Ana Rodriguez; Gong, I-Yeh; Khatri, Vijay P.

    2015-01-01

    Purpose With the use of case presentations, we present a review of the role of systemic chemotherapy in oligometastatic colorectal cancer and suggest ways to integrate clinical research findings into the interdisciplinary management of this potentially curable subset of patients. Methods This educational review discusses the role of chemotherapy in the management of oligometastatic metastatic colorectal cancer. Results In initially resectable oligometastatic colorectal cancer, the goal of chemotherapy is to eradicate micrometastatic disease. Perioperative 5-fluorouracil and oxaliplatin along with surgical resection can result in 5-year survival rates as high as 57%. With the development of increasingly successful chemotherapy regimens, attention is being paid to the use of chemotherapy to convert patients with initially unresectable metastasis into patients with a chance of surgical cure. The choice of chemotherapy regimen requires consideration of the goals of therapy and assessment of both tumor and patient-specific factors. Discussion Herein we discuss the choice and timing of chemotherapy in patients with initially resectable and borderline resectable metastatic colorectal cancer. Coordinated multidisciplinary care of such patients can optimize survival outcomes and result in the cure of patients with this otherwise lethal disease. PMID:26100816

  7. Does hyperthermic intraoperative chemotherapy lead to improved outcomes in patients with ovarian cancer? A single center cohort study in 111 consecutive patients

    PubMed Central

    2012-01-01

    Background For recurrent disease or primary therapy of advanced ovarian cancer, cytoreductive surgery (CRS) followed by adjuvant chemotherapy is a therapeutic option. The aim of this study was to evaluate the outcome for patients with epithelial ovarian cancer treated with hyperthermic intraoperative chemotherapy (HIPEC) and completeness of cytoreduction (CC). Methods Data were retrospectively collected from 111 patients with recurrent or primary ovarian cancer operated with the contribution of visceral surgical oncologists between 1991 and 2006 in a tertiary referral hospital. Results Ninety patients received CRS and 21 patients CRS plus HIPEC with cisplatin. Patients with complete cytoreduction (CC0) were more likely to receive HIPEC. Overall, 19 of 21 patients (90.5 %) with HIPEC and 33 of 90 patients (36.7 %) with CRS had a complete cytoreduction (P < 0.001). Incomplete cytoreduction was associated with worse survival rates with a hazard ratio (HR) of 4.4 (95%CI: 2.3-8.4) for CC1/2 and 6.0 (95%CI: 2.9-12.3) for CC3 (P < 0.001). In a Cox-regression limited to 52 patients with CC0 a systemic concomitant chemotherapy (HR 0.3, 95%CI: 0.1-0.96, P = 0.046) but not HIPEC (HR 0.98 with 95 % CI 0.32 to 2.97, P = 0.967) improved survival. Two patients (9.5 %) developed severe renal failure after HIPEC with absolute cisplatin dosages of 90 and 95 mg. Conclusions Completeness of cytoreduction was proved to be crucial for long-term outcome. HIPEC procedures in ovarian cancer should be performed in clinical trials to compare CRS, HIPEC and systemic chemotherapy against CRS with systemic chemotherapy. Concerning the safety of HIPEC with cisplatin, the risk of persistent renal failure must be considered when dosage is based on body surface. PMID:22709648

  8. Synergy of Raddeanin A and cisplatin induced therapeutic effect enhancement in human hepatocellular carcinoma.

    PubMed

    Jian-Nan, Li; Ye, Yu; Yan-Fei, Zhang; Zhi-Meng, Li; Guang-Zhi, Cai; Ji-Yu, Gong

    2017-02-17

    Cisplatin is a main compound for human hepatocellular carcinoma (HCC) chemotherapies, but it has certain cytotoxicity during applications. To release that, combining with other drugs are being as a regular plan in clinic. In our present study, we are focusing on one of active monomers extracted from Anemone Raddeana Regel, Raddeanin A (RA), which is on behalf of the same character like cisplatin in the tumor remedies. In order to investigate whether combination usage of RA and cisplatin can be priority to the later drug's effect development and its toxicity reduction in HCC, both of two drugs were treated 24 h or 48 h in QGY-7703 cells for estimating their abilities in tumor cell proliferation inhibition. Results show RA makes synergistic functions with cisplatin after measuring and analyzing their combination index (CI) values. Meanwhile it can strengthen cisplatin's effect by arresting the tumor cells in G0/G1 cycle and further promoting their apoptosis. Interestingly, the molecule signals correlated to tumor cell apoptosis containing both of p53 and bax are simultaneously activated, but bcl-2 and survivin are all depressed in mRNA level. Meanwhile, combining usage with RA can even raise the intracellular productions of reactive oxygen species (ROS). All these consequences reflect RA plays an important role in enhancing the therapeutic effect of cisplatin in HCC. This finding may guide for the drug usage of cisplatin in clinic practice.

  9. Convection enhanced delivery of cisplatin-loaded brain penetrating nanoparticles cures malignant glioma in rats.

    PubMed

    Zhang, Clark; Nance, Elizabeth A; Mastorakos, Panagiotis; Chisholm, Jane; Berry, Sneha; Eberhart, Charles; Tyler, Betty; Brem, Henry; Suk, Jung Soo; Hanes, Justin

    2017-03-07

    Glioblastoma multiforme (GBM) is highly invasive and uniformly fatal, with median survival<20months after diagnosis even with the most aggressive treatment that includes surgery, radiation, and systemic chemotherapy. Cisplatin is a particularly potent chemotherapeutic agent, but its use to treat GBM is limited by severe systemic toxicity and inefficient penetration of brain tumor tissue even when it is placed directly in the brain within standard delivery systems. We describe the development of cisplatin-loaded nanoparticles that are small enough (70nm in diameter) to move within the porous extracellular matrix between cells and that possess a dense polyethylene glycol (PEG) corona that prevents them from being trapped by adhesion as they move through the brain tumor parenchyma. As a result, these "brain penetrating nanoparticles" penetrate much deeper into brain tumor tissue compared to nanoparticles without a dense PEG corona following local administration by either manual injection or convection enhanced delivery. The nanoparticles also provide controlled release of cisplatin in effective concentrations to kill the tumor cells that they reach without causing toxicity-related deaths that were observed when cisplatin was infused into the brain without a delivery system. Median survival time of rats bearing orthotopic glioma was significantly enhanced when cisplatin was delivered in brain penetrating nanoparticles (median survival not reached; 80% long-term survivors) compared to cisplatin in conventional un-PEGylated particles (median survival=40days), cisplatin alone (median survival=12days) or saline-treated controls (median survival=28days).

  10. MATE-1 modulation by kinin B1 receptor enhances cisplatin efflux from renal cells.

    PubMed

    Estrela, Gabriel R; Wasinski, Frederick; Felizardo, Raphael J F; Souza, Laura L; Câmara, Niels O S; Bader, Michael; Araujo, Ronaldo C

    2017-04-01

    Cisplatin is a drug widely used in chemotherapy that frequently causes severe renal dysfunction. Organic transporters have an important role to control the absorption and excretion of cisplatin in renal cells. Deletion and blockage of kinin B1 receptor has already been show to protect against cisplatin-induced acute kidney injury. To test whether it exerts its protective function by modulating the organic transporters in kidney, we studied kinin B1 receptor knockout mice and treatment with a receptor antagonist at basal state and in presence of cisplatin. Cisplatin administration caused downregulation of renal organic transporters; in B1 receptor knockout mice, this downregulation of organic transporters in kidney was absent; and treatment by a B1 receptor antagonist attenuated the downregulation of the transporter MATE-1. Moreover, kinin B1 receptor deletion and blockage at basal state resulted in higher renal expression of MATE-1. Moreover we observed that kinin B1 receptor deletion and blockage result in less accumulation of platinum in renal tissue. Thus, we propose that B1 receptor deletion and blockage protect the kidney from cisplatin-induced acute kidney injury by upregulating the expression of MATE-1, thereby increasing the efflux of cisplatin from renal cells.

  11. Neoadjuvant chemotherapy in the management of muscle-invasive bladder cancer: bridging the gap between evidence and practice.

    PubMed

    Sfakianos, John P; Galsky, Matthew D

    2015-05-01

    Although cisplatin-based chemotherapy followed by radical cystectomy is the standard treatment of muscle-invasive bladder cancer, population-based studies reveal that only a small fraction of patients actually receive such treatment. A comprehensive understanding of the reasons for this gap between efficacy and effectiveness is necessary to increase the likelihood of cure of all patients with muscle-invasive bladder cancer. These reasons include systems-, provider-, and patient-level barriers that are not amenable to a single solution. Tackling each barrier will ultimately be necessary to bridge the disconnect between what is achievable and what is actually achieved.

  12. Nephrotic syndrome associated with metastatic thymoma treated with chemotherapy

    PubMed Central

    Yoo, Shin Hye; Kim, Hyean-Ji; Kim, Jeong-Han; Lee, Gyeong-Won; Lee, Jeong Hee; Kim, Se Hyun; Kim, Ji-Won; Kim, Jin Won; Lee, Jeong-Ok; Kim, Yu Jung; Lee, Keun-Wook; Kim, Jee Hyun; Bang, Soo-Mee; Lee, Jong Seok

    2017-01-01

    Abstract Rationale: Nephropathy with concurrent invasive thymoma is a type of paraneoplastic syndrome. Patient concerns and Diagnoses: We report a 32-year-old female with nephrotic syndrome that was first diagnosed along with invasive thymoma and treated by means of cisplatin-based chemotherapy for the thymoma. The patient initially presented with dyspnea and generalized edema. Chest radiography and computed tomography scans revealed right pleural effusion and a mass in the right middle lung field, which were confirmed by a percutaneous lung biopsy as metastatic invasive thymoma. Severe hypoalbuminemia, heavy proteinuria, hyponatremia, and hypercholesterolemia were features of the nephrotic syndrome. A kidney needle biopsy suggested focal segmental glomerulosclerosis. Interventions and Outcomes: All of the symptoms of nephrotic syndrome were resolved simultaneously during the first 2 cycles of chemotherapy. The patient was on regular follow-up with no specific treatment for nephrotic syndrome and underwent successful resection of the left pleura and anterior thymoma. The patient has shown no evidence of recurrence for 2 years. Lessons: We conclude that chemotherapy for invasive thymoma is an effective treatment for nephrotic syndrome accompanying the thymoma. PMID:28072685

  13. Gemcitabine and Cisplatin induced posterior reversible encephalopathy syndrome: A case report with review of literature

    PubMed Central

    Kabre, Rohit Santosh; Kamble, Krishna Marotirao

    2016-01-01

    Posterior reversible encephalopathy syndrome (PRES) is a recently described, scarcely documented clinical entity. PRES is caused by various factors, the most common being hypertension, followed by nonhypertensive causes such as renal diseases and immunosuppressive therapy. Recently, some cases have been reported about the association of increased use of cytotoxic and immunosuppressive agents in cancer patients, and relevant reports have increased with advances in radiological examinations. Here, we report a case of gallbladder cancer with liver metastasis undergoing gemcitabine- and cisplatin-based chemotherapy who presented with complaints of seizures, headache, and bilateral lower limb weakness. Thorough clinical examination, biochemical analysis, and radiological evaluation led to diagnosis of PRES. It is important to recognize this syndrome which will facilitate early diagnosis and prompt symptomatic management. Removal of causative agent is an important aspect of management. Studies are needed to identify factors of adverse prognostic significance and to develop neuroprotective strategies. PMID:27843969

  14. Promising survival for patients with glioblastoma multiforme treated with individualised chemotherapy based on in vitro drug sensitivity testing.

    PubMed

    Iwadate, Y; Fujimoto, S; Namba, H; Yamaura, A

    2003-11-17

    We retrospectively investigated the efficacy and feasibility of individualised chemotherapy based on in vitro drug sensitivity testing (DST) for patients with glioblastoma multiforme. A total of 40 consecutive patients with glioblastoma multiforme (GM) were enrolled into this study between January 1995 and December 2000. The flow cytometric (FCM) detection of apoptosis was used to determine the in vitro sensitivity of tumour cells obtained at surgery to 30 different kinds of anticancer agents. From the results of FCM assay, an in vitro best regimen was prospectively selected. All the patients concurrently received the individualised chemotherapy with the in vitro best regimen and 60 Gy of conventional radiation therapy. Of the 31 assessable patients, eight patients (26%) achieved partial response, and 20 patients (65%) had stable disease. The median survival time was 20.5 months. The individualised chemotherapy based on in vitro DST was associated with favourable survival time for the patients with GM compared with the reported results of conventional therapy regimens. The present result suggests that the currently available anticancer agents could be effective against GM when used in individualised chemotherapy.

  15. Cisplatin for small cell lung cancer: Associated publications in Science Citation Index Expanded.

    PubMed

    Ho, Yuh-Shan; Nakazawa, Kensuke; Sato, Shinya; Tamura, Tomohiro; Kurishima, Koichi; Satoh, Hiroaki

    2013-02-01

    This study was conducted to explore a bibliometric approach to quantitatively assess current research trends in cisplatin-containing chemotherapy for small cell lung cancer (SCLC), using related literature in the Science Citation Index Expanded database from 1992 to 2011. Articles were analyzed by the scientific output and research performances of countries and institutions. The distribution of key words in the article title and author-selected keywords were used to evaluate research trends. It was observed that the number of articles devoted to cisplatin-containing chemotherapy for SCLC did not increase with time. The USA and Japan were the top two countries with the highest number of articles devoted to cisplatin-containing chemotherapy for SCLC. In both countries, the number of articles did not increase with time, and a decreasing trend was identified in the USA over the last 10 years. This study demonstrates trends in cisplatin-containing chemotherapy for SCLC. The clinical application of novel drugs is required for successful SCLC treatment.

  16. Protective Role of Silymarin on Hepatic and Renal Toxicity Induced by MTX Based Chemotherapy in Children with Acute Lymphoblastic Leukemia

    PubMed Central

    Hagag, Adel A.; Elgamsy, Mohamed A.; El-Asy, Hassan M.; Mabrouk, Maaly M.

    2016-01-01

    Background ALL is the most common childhood malignancy. The children with ALL are treated with methotrexate (MTX) based chemotherapy protocols. MTX causes unpredictable serious hepatic and renal side effects. Silymarin has antioxidant and anti-inflammatory activities and stimulates tissue regeneration. This study aims to evaluate the protective effects of Silymarin on MTX-based chemotherapy-induced Hepatic and renal toxicity in children with ALL. Patients and Methods 80 children with newly diagnosed ALL were enrolled in the study. They were randomly divided into two groups. Group I included 40 children with ages ranging from 4–13 years and the mean age of 6.85± 2.89 years, who received Silymarin 420 mg/day in 3 divided doses for one week after each MTX dose. Group II included 40 children, with ages ranging from 4–12 years and the mean age of 7.30±2.6 years, who received placebo for one week after MTX therapy. For all patients liver functions including serum bilirubin, total proteins, albumin, globulin and albumin-globulin ratio, alkaline phosphatase, ALT and AST, prothrombin time and activity and renal functions including blood urea and serum creatinine, serum cystatin C and urinary N-acetyl-beta-D-glucosaminidase were done to assess hepatic and renal toxicity before and after chemotherapy. Results There were no significant differences between group I and II as regard liver and renal functions before chemotherapy. After chemotherapy, there were significantly higher values of ALT and AST and alkaline phosphatase, and significantly lower Prothrombin activity in group II compared with group I. No significant differences between group I and II were found in total bilirubin, serum protein, and albumin levels. There was significantly lower blood urea, serum creatinine, and cystatin C and urinary N-acetyl-beta-D-glucosaminidase in group I compared with group II. Conclusion Silymarin improved some hepatic and renal functions in children with ALL who received MTX-based

  17. Histone deacetylase mediated silencing of AMWAP expression contributes to cisplatin nephrotoxicity

    PubMed Central

    Ranganathan, Punithavathi; Hamad, Rania; Mohamed, Riyaz; Jayakumar, Calpurnia; Muthusamy, Thangaraju; Ramesh, Ganesan

    2015-01-01

    Cisplatin-induced acute kidney injury is a serious problem in cancer patients during treatment of solid tumors. Currently, there are no therapies available to treat or prevent cisplatin nephrotoxicity. Since histone deacetylase (HDAC) inhibition augments cisplatin anti-tumor activity, we tested whether HDAC inhibitors can prevent cisplatin-induced nephrotoxicity and determined the underlying mechanism. Cisplatin up-regulated the expression of several HDACs in the kidney. Inhibition of HDAC with clinically used trichostatin A suppressed cisplatin-induced kidney injury, inflammation and epithelial cell apoptosis. Moreover, trichostatin A upregulated the novel anti-inflammatory protein, activated microglia/macrophage WAP domain protein (AMWAP), in epithelial cells which was enhanced with cisplatin treatment. Interestingly, HDAC1 and -2 specific inhibitors are sufficient to potently up-regulate AMWAP in epithelial cells. Administration of recombinant AMWAP or its epithelial cell-specific overexpression reduced cisplatin-induced kidney dysfunction. Moreover, AMWAP treatment suppressed epithelial cell apoptosis, and siRNA-based knockdown of AMWAP expression abolished trichostatin A-mediated suppression of epithelial cell apoptosis in vitro. Thus, HDAC-mediated silencing of AMWAP may contribute to cisplatin nephrotoxicity. Hence, HDAC1 and -2 specific inhibitors or AMWAP could be useful therapeutic agents for the prevention of cisplatin nephrotoxicity. PMID:26509586

  18. Optimization of carboxylate-terminated poly(amidoamine) dendrimer-mediated cisplatin formulation.

    PubMed

    Kulhari, Hitesh; Pooja, Deep; Singh, Mayank K; Chauhan, Abhay S

    2015-02-01

    Abstract Cisplatin is mainly used in the treatment of ovarian, head and neck and testicular cancer. Poor solubility and non-specific interactions causes hurdles in the development of successful cisplatin formulation. There were few reports on poly(amidoamine) (PAMAM) dendrimer-cisplatin complexes for anticancer treatment. But the earlier research was mainly focused on therapeutic effect of PAMAM dendrimer-cisplatin complex, with less attention paid on the formulation development of these complexes. Objective of the present study is to optimize and validate the carboxylate-terminated, EDA core PAMAM dendrimer-based cisplatin formulation with respect to various variables such as dendrimer core, generation, drug entrapment, purification, yield, reproducibility, stability, storage and in-vitro release. Dendrimer-cisplatin complex was prepared by an efficient method which significantly increases the % platinum (Pt) content along with the product yield. Dendrimers showed reproducible (∼27%) platinum loading by weight. Variation in core and generations does not produce significant change in the % Pt content. Percentage Pt content of dendrimeric formulation increases with increase in drug/dendrimer mole ratio. Formulation with low drug/dendrimer mole ratio showed delayed release compared to the higher drug/dendrimer mole ratio; these dendrimer formulations are stable in room temperature. In vitro release profiles of the stored dendrimer-cisplatin samples showed comparatively slow release of cisplatin, which may be due to formation of strong bond between cisplatin and dendrimer. This study will contribute to create a fine print for the formulation development of PAMAM dendrimer-cisplatin complexes.

  19. Chemotherapy and Targeted Therapies for Unresectable Malignant Mesothelioma

    PubMed Central

    Kelly, Ronan Joseph; Sharon, Elad; Hassan, Raffit

    2011-01-01

    The global burden of mesothelioma is expected to increase in the coming decades. As a result the development of more effective therapies with an emphasis on personalized treatments based on validated prognostic and predictive biomarkers is an essential requirement. Progress has been made in the last decade with the development of newer generation anti-folates leading to the current standard of care of pemetrexed and cisplatin in patients with unresectable disease. However, the median overall survival of patients with this combination treatment is only 12 months. There is no consensus regarding second line therapy for patients who have progressed or not responded to pemetrexed based therapies although gemcitabine in combination with a platinum compound or single agent vinorelbine is a reasonable option. The development of effective targeted agents that are active in mesothelioma has to date been disappointing. Strategies involving the addition of bevacizumab to pemetrexed and cisplatin in the frontline setting, the histone deacetylase inhibitor vorinostat as second line therapy and studies evaluating the utility of maintenance therapy in mesothelioma.are all ongoing and appear promising. In addition clinical trials investigating immunotherapy and gene therapy in combination with chemotherapy could potentially improve the prognosis of patients with mesothelioma. PMID:21620512

  20. Polymorphism in XRCC1 gene modulates survival and clinical outcomes of advanced North Indian lung cancer patients treated with platinum-based doublet chemotherapy.

    PubMed

    Singh, Amrita; Singh, Navneet; Behera, Digambar; Sharma, Siddharth

    2017-04-01

    Survival in lung cancer patients is genetically determined. Single nucleotide polymorphisms (SNPs) in DNA repair genes are observed to play a critical role in survival as DNA repair itself can behave as double-edged sword. We aim to explore the association of DNA repair gene XRCC1 in survival and clinical outcomes for North Indian population. Blood sample from patients diagnosed with lung cancer was taken. DNA isolation and genotyping were performed for the SNPs of XRCC1 gene. Further, patients were followed up through telephonic conversation after every 2 months for 3 years. Statistical analysis was carried out using Kaplan-Meier to determine the median survival time (MST) and Cox proportional regression model to determine the hazards ratio. Further, logistic regression was used to calculate to calculate the objective response. The mutant genotype for XRCC1 399 is observed to have a better survival (MST = 9.6). Histological stratification did not reveal any association for any SNP except for SCLC subtype in XRCC1 632 with an increased death rate (HR 3.08, p = 0.02). On stratification according to chemotherapy regimen administered; cisplatin/carboplatin + docetaxel was observed to increase survival for XRCC1 399 mutant genotype (AA) (HR 0.26, p = 0.05). Cisplatin/carboplatin + irinotecan increased survival in both heterozygotes (GA) and combined variants (GA + AA) (HR 0.22, p = 0.014; HR 0.23, p = 0.012). The polymorphic variants within the XRCC1 gene have found to play an important role in overall survival of lung cancer patients undergoing specific chemotherapy regimen.

  1. DNA polymeraseη protein expression predicts treatment response and survival of metastatic gastric adenocarcinoma patients treated with oxaliplatin-based chemotherapy

    PubMed Central

    2010-01-01

    Background DNA polymerase η (pol η) is capable of bypassing DNA adducts produced by cisplatin or oxaliplatin and is associated with cellular tolerance to platinum. Previous studies showed that defective pol η resulted in enhanced cisplatin or oxaliplatin sensitivity in some cell lines. The purpose of the present study was to investigate the role of pol η protein expression in metastatic gastric adenocarcinoma. Methods Four gastric adenocarcinoma cell lines were chosen to explore the relationship between pol η protein expression and oxaliplatin sensitivity by western blotting and MTT assay. Eighty metastatic gastric adenocarcinoma patients treated with FOLFOX or XELOX regimen as first-line chemotherapy were analyzed, corresponding pretreatment formalin-fixed paraffin-embedded tumor tissues were used to detect pol η protein expression by immunohistochemistry. Relationship between pol η protein expression and clinical features and outcome of these patients was analyzed. Results A positive linear relationship between pol η protein expression and 48 h IC50 values of oxaliplatin in four gastric cancer cell lines was observed. Positivity of pol η protein expression was strongly associated with poor treatment response, as well as shorter survival at both univariate (8 versus 14 months; P < 0.001) and multivariate (hazard ratio, 4.555; 95% confidence interval, 2.461-8.429; P < 0.001) analysis in eighty metastatic gastric adenocarcinoma patients. Conclusions Our study indicates that polη is a predictive factor of treatment response and survival of metastatic gastric adenocarcinoma patients treated with FOLFOX or XELOX as first-line chemotherapy. Therefore confirming the value of polη in studies with prospective design is mandatory. PMID:21110884

  2. Erlotinib and bevacizumab versus cisplatin, gemcitabine and bevacizumab in unselected nonsquamous nonsmall cell lung cancer.

    PubMed

    Thomas, Michael; Fischer, Jürgen; Andreas, Stefan; Kortsik, Cornelius; Grah, Christian; Serke, Monika; von Eiff, Michael; Witt, Christian; Kollmeier, Jens; Müller, Ernst; Schenk, Michael; Schröder, Michael; Villalobos, Matthias; Reinmuth, Niels; Penzel, Roland; Schnabel, Philipp; Acker, Thomas; Reuss, Alexander; Wolf, Martin

    2015-07-01

    Erlotinib with bevacizumab showed promising activity in recurrent nonsquamous (NS) nonsmall cell lung cancer (NSCLC). The INNOVATIONS study was designed to assess in first-line treatment of unselected cisplatin-eligible patients this combination compared to cisplatin, gemcitabine and bevacizumab. Stage IIIB/IV patients with NS-NSCLC were randomised on erlotinib (150 mg daily) and bevacizumab (15 mg·kg(-1) on day 1, every 3 weeks) (EB) until progression, or cisplatin (80 mg·m(-2) on day 1, every 3 weeks) and gemcitabine (1250 mg·m(-2) on days 1 and 8, every 3 weeks) up to six cycles and bevacizumab (15 mg·kg(-1) on day 1, every 3 weeks) (PGB) until progression. 224 patients were randomised (EB n=111, PGB n=113). The response rate (12% versus 36%; p<0.0001), progression-free survival (median 3.5 versus 6.9 months; hazard ratio (HR) 1.85, 95% CI 1.39-2.45; p<0.0001) and overall survival (median 12.6 versus 17.8 months; HR 1.41, 95% CI 1.01-1.97; p=0.04) clearly favoured PGB. In patients with epidermal growth factor receptor mutations (n=32), response rate, progression-free survival and overall survival were not superior with EB. Platinum-based combination chemotherapy remains the standard of care in first-line treatment of unselected NS-NSCLC. Molecular targeted approaches strongly mandate appropriate testing and patient selection.

  3. Which dogs with appendicular osteosarcoma benefit most from chemotherapy after surgery? Results from an individual patient data meta-analysis.

    PubMed

    Schmidt, A F; Groenwold, R H H; Amsellem, P; Bacon, N; Klungel, O H; Hoes, A W; de Boer, A; Kow, K; Maritato, K; Kirpensteijn, J; Nielen, M

    2016-03-01

    Osteosarcoma (OS) is a malignant tumor of mesenchymal origin that produces osteoid. Given that the prognosis can vary considerably between dogs, we aimed to explore whether treatment could be tailored towards patient subgroups, characterized by their predicted risk of mortality. For the current study, a subset of five nonrandomized studies (400 subjects of whom 88 were dead at 5 months follow-up) was used from a previously published 20 study individual patient data meta-analysis. Missing data was dependent on observed variables and was imputed to correct for this dependency. Based on a previously published multivariable prognostic model, the 5-month mortality risk was predicted. Subsequently, in surgically treated dogs, using a logistic regression model with a random intercept for a study indicator, we explored whether chemotherapy effectiveness depended on predicted 5-month mortality risk. After adjustment for potential confounders the main effect of any chemotherapy was 0.48 (odds ratio) (95%CI 0.30; 0.78). Testing for chemotherapy by predicted 5-month mortality risk interaction revealed that the effects of any chemotherapy decreased with increasing predicted risk; interaction OR 3.41 (1.07; 10.84). Results from individually comparing carboplatin, cisplatin, doxorubicin and doxorubicin combination therapy to no chemotherapy, were similar in magnitude and direction. These results indicate that the main treatment effects of chemotherapy do not necessarily apply to all patients.

  4. The synergistic effect of resveratrol in combination with cisplatin on apoptosis via modulating autophagy in A549 cells.

    PubMed

    Hu, Song; Li, Xiaolin; Xu, Rongrong; Ye, Lingyun; Kong, Hui; Zeng, Xiaoning; Wang, Hong; Xie, Weiping

    2016-06-01

    Several studies have shown that combination treatment with natural products and chemotherapy agents can improve the sensitivity and cytotoxicity of chemotherapy agents. Resveratrol, a natural product, has many biological effects including antitumor and antiviral activities, as well as vascular protective effect. The aim of this study is to investigate the synergistic anticancer effect of resveratrol in combination with cisplatin and the potential anticancer mechanisms involved in A549 cells. The results obtained from Cell Counting Kit-8 and isobolographic analysis demonstrated that combination of resveratrol and cisplatin resulted in synergistic cytotoxic effects in A549 cells. Results from Hoechst staining, flow cytometry and western blot analysis suggested that resveratrol enhanced cisplatin-mediated apoptosis. Meanwhile, the changes of LC3-II and P62 levels and formation of autophagosome suggested that resveratrol in combination with cisplatin triggered autophagy. More importantly, inhibiting autophagy by 3-methyladenine markedly attenuated the apoptosis caused by combination of resveratrol and cisplatin in A549 cells. Taken together, our study provides the first evidence that resveratrol combined with cisplatin synergistically induce apoptosis via modulating autophagic cell death in A549 cells. These findings also help us to understand the role of natural products in combination with chemotherapy agents in lung cancer.

  5. Synergistic Cytotoxicity of β-Elemene and Cisplatin in Gingival Squamous Cell Carcinoma by Inhibition of STAT3 Signaling Pathway

    PubMed Central

    Huang, Chengyi; Yu, Yufeng

    2017-01-01

    Background Cisplatin remains one of the most active agents and is the mainstay of combination chemotherapy regimens against gingival squamous cell carcinoma. However, the efficacy of cisplatin is limited by its high toxicity and the development of drug resistance. β-elemene, isolated from the Chinese herb Rhizoma zedoariahas, is highly effective against malignancies and has low toxicity, but the development of β-elemene sensitizing chemotherapy in targeting the STAT3 signaling pathway remains unexplored in gingival squamous cell carcinoma. The present study was conducted to assess the chemosensitizing effects of β-elemene for enhancing the cytotoxicity of cisplatin in gingival squamous cell carcinoma. Material/Methods The gingival squamous cell carcinoma YD-38 cell line was used. MTT assay, clonogenic assay, annexin V/PI apoptosis assay, Western blot analysis, and xenograft model treatment were carried out in vitro and in vivo. Results β-elemene significantly enhanced proliferative inhibition and cisplatin induced apoptosis in gingival squamous cell carcinoma. Cisplatin combined with β-elemene decreased the expressions of p-STAT3, p-JAK2, and Bcl-2, and increased the expressions of Bax and caspase-3 significantly compared to cisplatin only treatment, as well as in the xenograft model. Conclusions The results indicated that β-elemene promoted the anti-proliferative and apoptotic effect of cisplatin by inhibiting STAT3 and blocking the JAK2-STAT3 signaling pathway in GSCC in vitro and in vivo. PMID:28355175

  6. DNA damage response (DDR) pathway engagement in cisplatin radiosensitization of non-small cell lung cancer.

    PubMed

    Sears, Catherine R; Cooney, Sean A; Chin-Sinex, Helen; Mendonca, Marc S; Turchi, John J

    2016-04-01

    Non-small cell lung cancers (NSCLC) are commonly treated with a platinum-based chemotherapy such as cisplatin (CDDP) in combination with ionizing radiation (IR). Although clinical trials have demonstrated that the combination of CDDP and IR appear to be synergistic in terms of therapeutic efficacy, the mechanism of synergism remains largely uncharacterized. We investigated the role of the DNA damage response (DDR) in CDDP radiosensitization using two NSCLC cell lines. Using clonogenic survival assays, we determined that the cooperative cytotoxicity of CDDP and IR treatment is sequence dependent, requiring administration of CDDP prior to IR (CDDP-IR). We identified and interrogated the unique time and agent-dependent activation of the DDR in NSCLC cells treated with cisplatin-IR combination therapy. Compared to treatment with CDDP or IR alone, CDDP-IR combination treatment led to persistence of γH2Ax foci, a marker of DNA double-strand breaks (DSB), for up to 24h after treatment. Interestingly, pharmacologic inhibition of DDR sensor kinases revealed the persistence of γ-H2Ax foci in CDDP-IR treated cells is independent of kinase activation. Taken together, our data suggest that delayed repair of DSBs in NSCLC cells treated with CDDP-IR contributes to CDDP radiosensitization and that alterations of the DDR pathways by inhibition of specific DDR kinases can augment CDDP-IR cytotoxicity by a complementary mechanism.

  7. Regulation of cellular growth, apoptosis, and Akt activity in human U251 glioma cells by a combination of cisplatin with CRM197.

    PubMed

    Wang, Lifei; Wang, Ping; Liu, Yunhui; Xue, Yixue

    2012-01-01

    The aberrantly activated antiapoptotic phospatidyl-3-inositol-kinase (PI3K)/Akt signaling induced by cisplatin limits the effectiveness of chemotherapy; inhibition of this pathway may augment the sensitivity of tumor cells to cisplatin-induced toxicity and promote apoptosis. Cross-reacting material 197 (CRM197), the nontoxic mutant of diphtheria toxin, could act as an heparin-binding epidermal growth factor inhibitor and has been shown to have some anticancer effects, but the effect of CRM197 on glioma cells remains unclear. The aim of this study was to investigate the effects of a combination of cisplatin with CRM197 on the growth and apoptosis of human U251 glioma cells and the possible mechanism. In this study, we demonstrated that cisplatin or CRM197 induced a dose-dependent growth inhibition in U251 cells, but cisplatin at 5 µg/ml and CRM197 at 1 µg/ml did not affect the viability of human astrocytes. Cisplatin induced a time-dependent growth inhibition in U251 cells, whereas the growth-inhibitory effects induced by CRM197 alone or combined with cisplatin reached a peak at 24 h after treatment. Compared with the administration of cisplatin or CRM197 alone, CRM197 combined with cisplatin significantly enhanced U251 cell growth inhibition and apoptosis. Cisplatin induced sustained activation of Akt, whereas CRM197 markedly suppressed the Akt phosphorylation induced by cisplatin. The effects of growth inhibition and apoptosis were markedly enhanced after a combination of cisplatin with CRM197 plus the PI3K inhibitor LY294002 or wortmannin. Therefore, CRM197 combined with cisplatin could enhance growth inhibition and apoptosis of glioma cells by inhibiting the cisplatin-induced PI3K/Akt pathway.

  8. 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.

  9. Chemotherapy-Induced Peripheral Neurotoxicity and Ototoxicity: New Paradigms for Translational Genomics

    PubMed Central

    Fossa, Sophie D.; Sesso, Howard D.; Frisina, Robert D.; Herrmann, David N.; Beard, Clair J.; Feldman, Darren R.; Pagliaro, Lance C.; Miller, Robert C.; Vaughn, David J.; Einhorn, Lawrence H.; Cox, Nancy J.; Dolan, M. Eileen

    2014-01-01

    In view of advances in early detection and treatment, the 5-year relative survival rate for all cancer patients combined is now approximately 66%. As a result, there are more than 13.7 million cancer survivors in the United States, with this number increasing by 2% annually. For many patients, improvements in survival have been countered by therapy-associated adverse effects that may seriously impair long-term functional status, workplace productivity, and quality of life. Approximately 20% to 40% of cancer patients given neurotoxic chemotherapy develop chemotherapy-induced peripheral neurotoxicity (CIPN), which represents one of the most common and potentially permanent nonhematologic side effects of chemotherapy. Permanent bilateral hearing loss and/or tinnitus can result from several ototoxic therapies, including cisplatin- or carboplatin-based chemotherapy. CIPN and ototoxicity represent important challenges because of the lack of means for effective prevention, mitigation, or a priori identification of high-risk patients, and few studies have applied modern genomic approaches to understand underlying mechanisms/pathways. Translational genomics, including cell-based models, now offer opportunities to make inroads for the first time to develop preventive and interventional strategies for CIPN, ototoxicity, and other treatment-related complications. This commentary provides current perspective on a successful research strategy, with a focus on cisplatin, developed by an experienced, transdisciplinary group of researchers and clinicians, representing pharmacogenomics, statistical genetics, neurology, hearing science, medical oncology, epidemiology, and cancer survivorship. Principles outlined herein are applicable to the construction of research programs in translational genomics with strong clinical relevance and highlight unprecedented opportunities to understand, prevent, and treat long-term treatment-related morbidities. PMID:24623533

  10. Evaluation of platinum chemotherapy in combination with HER2-targeted α-particle radiation.

    PubMed

    Milenic, Diane E; Baidoo, Kwamena E; Shih, Joanna H; Wong, Karen J; Brechbiel, Martin W

    2013-01-01

    The studies described herein assess the potential of combining platinum-based chemotherapy with high-linear energy transfer (LET) α-particle-targeted radiation therapy using trastuzumab as the delivery vehicle. An initial study explored the combination of cisplatin with (213)Bi-trastuzumab in the LS-174T i.p. xenograft model. This initial study determined the administration sequence of cisplatin and (213)Bi-trastuzumab. Cisplatin coinjected with (213)Bi-trastuzumab increased the median survival (MS) to 90 days versus 65 days for (213)Bi-trastuzumab alone. Toxicity was observed with a weight loss of 17.6% in some of the combined treatment groups. Carboplatin proved to be better tolerated. Maximal therapeutic benefit, that is, a 5.1-fold increase in MS, was obtained in the group injected with (213)Bi-trastuzumab, followed by carboplatin 24 hours later. This was further improved by administration of multiple weekly doses of carboplatin. The MS achieved with administration of 3 doses of carboplatin was 180 days versus 60 days with (213)Bi-trastuzumab alone. The combination of carboplatin with (212)Pb radioimmunotherapy was also evaluated. The therapeutic efficacy of (212)Pb-trastuzumab (58-day MS) increased when the mice were pretreated with carboplatin 24 hours prior (157-day MS). These results again demonstrate the necessity of empirically determining the administration sequence when combining therapeutic modalities.

  11. In vitro evaluation of folic acid-conjugated redox-responsive mesoporous silica nanoparticles for the delivery of cisplatin

    PubMed Central

    Alvarez-Berríos, Merlis P; Vivero-Escoto, Juan L

    2016-01-01

    The use of cisplatin(IV) prodrugs for the delivery of cisplatin have gained significant attention, because of their low toxicity and reactivity. Recent studies have shown that targeted cisplatin(IV)-prodrug nanoparticle-based delivery systems can improve the internalization of the cisplatin(IV) prodrug. We hypothesized that folic acid-conjugated mesoporous silica nanoparticles (MSNs) containing cisplatin(IV) prodrug could target cancer cells that overexpress the folate receptor and deliver the active cisplatin drug upon intracellular reduction. To prove this hypothesis, internalization and localization studies in HeLa cancer cells were performed using flow cytometry and confocal microscopy. The ability of MSNs to escape from the endolysosomal compartments, the formation of DNA adducts, and the cytotoxic effects of the MSNs were also evaluated. Our results confirmed that this MSN-based delivery platform was capable of delivering cisplatin into the cytosol of HeLa cells, inducing DNA adducts and subsequent cell death. PMID:27920531

  12. In vitro evaluation of folic acid-conjugated redox-responsive mesoporous silica nanoparticles for the delivery of cisplatin.

    PubMed

    Alvarez-Berríos, Merlis P; Vivero-Escoto, Juan L

    The use of cisplatin(IV) prodrugs for the delivery of cisplatin have gained significant attention, because of their low toxicity and reactivity. Recent studies have shown that targeted cisplatin(IV)-prodrug nanoparticle-based delivery systems can improve the internalization of the cisplatin(IV) prodrug. We hypothesized that folic acid-conjugated mesoporous silica nanoparticles (MSNs) containing cisplatin(IV) prodrug could target cancer cells that overexpress the folate receptor and deliver the active cisplatin drug upon intracellular reduction. To prove this hypothesis, internalization and localization studies in HeLa cancer cells were performed using flow cytometry and confocal microscopy. The ability of MSNs to escape from the endolysosomal compartments, the formation of DNA adducts, and the cytotoxic effects of the MSNs were also evaluated. Our results confirmed that this MSN-based delivery platform was capable of delivering cisplatin into the cytosol of HeLa cells, inducing DNA adducts and subsequent cell death.

  13. Bu-Zhong-Yi-Qi Decoction, the Water Extract of Chinese Traditional Herbal Medicine, Enhances Cisplatin Cytotoxicity in A549/DDP Cells through Induction of Apoptosis and Autophagy

    PubMed Central

    Xiong, Ying

    2017-01-01

    Cisplatin is one of the most active cytotoxic agents for non-small cell lung cancer (NSCLC) treatment. However, the development of cisplatin resistance is common. Bu-Zhong-Yi-Qi decoction (BZYQD), a Chinese traditional herbal medicine, is widely used for the enhancement of antitumor effect in other medications. In this study, we evaluated the effect and drug-resistance reversal mechanism of BZYQD combined with cisplatin on cisplatin-resistant A549/DDP cells. Our results showed that BZYQD exhibited direct cytotoxic and chemosensitizing effects. Cotreatment with BZYQD and cisplatin induced intrinsic apoptotic pathways which were measured by condensed nuclear chromatin, Annexin V/PI apoptosis assay, and apoptosis related proteins expression. In addition, cotreatment with BZYQD and cisplatin also activated autophagy, as indicated by an increase in LC3 puncta, classical autophagosomes and/or autolysosomes, and an accumulation of LC3-II and ATG7 protein. Finally, cotreatment with BZYQD and cisplatin resulted in the generation of ROS and scavenging ROS by NAC almost completely suppressing cell death. These results suggest that cotreatment with BZYQD and cisplatin might reverse cisplatin resistance by inducing ROS accumulation, which activates apoptosis and autophagy by oxidative stress. The combination of BZYQD and cisplatin may represent a novel approach in treatment for NSCLC and thus offer a new target for chemotherapy. PMID:28154825

  14. Bu-Zhong-Yi-Qi Decoction, the Water Extract of Chinese Traditional Herbal Medicine, Enhances Cisplatin Cytotoxicity in A549/DDP Cells through Induction of Apoptosis and Autophagy.

    PubMed

    Yu, Ning; Xiong, Ying; Wang, Chun

    2017-01-01

    Cisplatin is one of the most active cytotoxic agents for non-small cell lung cancer (NSCLC) treatment. However, the development of cisplatin resistance is common. Bu-Zhong-Yi-Qi decoction (BZYQD), a Chinese traditional herbal medicine, is widely used for the enhancement of antitumor effect in other medications. In this study, we evaluated the effect and drug-resistance reversal mechanism of BZYQD combined with cisplatin on cisplatin-resistant A549/DDP cells. Our results showed that BZYQD exhibited direct cytotoxic and chemosensitizing effects. Cotreatment with BZYQD and cisplatin induced intrinsic apoptotic pathways which were measured by condensed nuclear chromatin, Annexin V/PI apoptosis assay, and apoptosis related proteins expression. In addition, cotreatment with BZYQD and cisplatin also activated autophagy, as indicated by an increase in LC3 puncta, classical autophagosomes and/or autolysosomes, and an accumulation of LC3-II and ATG7 protein. Finally, cotreatment with BZYQD and cisplatin resulted in the generation of ROS and scavenging ROS by NAC almost completely suppressing cell death. These results suggest that cotreatment with BZYQD and cisplatin might reverse cisplatin resistance by inducing ROS accumulation, which activates apoptosis and autophagy by oxidative stress. The combination of BZYQD and cisplatin may represent a novel approach in treatment for NSCLC and thus offer a new target for chemotherapy.

  15. Origin of using cisplatin over transplatin for cancer treatment: An ab initio study

    NASA Astrophysics Data System (ADS)

    Li, Sa; Jena, Puru; Department of Physics, Virginia Commonwealth University Team

    2011-03-01

    Eventhough cisplatin has been used as a chemotherapy anti-cancer drug for over 40 years the thermodynamics and kinetics of the reactions are still largely unknown. Cisplatin molecules are known to be attacked by water molecules before they react with DNA. As a result, two Cl atoms are eliminated. The active piece in the cell, therefore, is not cisplatin but (NH3)2 Pt 2+ . To explain why only cisplatin but not transplatin functions as anticancer drug, we used first principles method to study the dechlorination process in cis- and transplatin. Although transplatin molecule is more stable than cisplatin by 0.52 eV, we found cisplatin to be more favorable for reaction due to the following reasons: 1) the energy cost to remove a Cl atom is less from cisplatin than transplatin. 2) cis-form (NH3)2 Pt 2+ derived from cisplatin with N-Pt-N angle of 97r is lower in energy than trans-form derived from transplatin with N-Pt-N angle of 180r. The rotation barrier for N-Pt-N changing from 180r to 97r is about 1.0 eV. 3) When cis-form of (NH3)2 Pt 2+ reacts with two Guanines in DNA, the two N atoms in Guanines can readily bind to the Pt atom in cisplatin. The transplatin due to steric reasons does not provide that opportunity. This work is supported by grants from the Department of Energy.

  16. miR-100 resensitizes resistant epithelial ovarian cancer to cisplatin.

    PubMed

    Guo, Peng; Xiong, Xiangpeng; Zhang, Sainan; Peng, Dongxian

    2016-12-01

    Epithelial ovarian cancer (EOC) is one of the malignant tumors that seriously affects women's health and chemotherapy resistance is an important reason for the poor prognosis. The present study was conducted to investigate whether microRNA-100 (miR-100) can be used to modulate the tolerance to cisplatin in EOC. Expression of miR-100 was compared between ovarian cancer cells tolerant and not tolerant to cisplatin. Mimic and antisense were used to study the roles and related mechanisms of miR-100 in cisplatin sensitivity in EOC. The alternation in the cisplatin sensitivity was investigated using grafted tumors derived from SKOV3/DDP cells with upregulated or downregulated miR-100 expression. miR-100 was lower in cisplatin resistant cell line SKOV3/DDP than in cisplatin sensitive cell line SKOV3. miR-100 might increase cisplatin sensitivity by inhibiting cell proliferation and conversion from G1 to S phase and increasing apoptosis. We showed that mTOR and PLK1 are targets of miR-100 and the cells were resensitized probably due to targeted downregulation of mTOR and PLK1 by miR-100. In vivo study with nude mice showed that tumors derived from miR-100 mimic-transfected cells were more sensitive to cisplatin and had reduced expression of mTOR and PLK1. miR-100 resensitizes resistant epithelial ovarian cancer to cisplatin probably by inhibiting cell proliferation, inducing apoptosis and arresting cell cycle and by targeted downregulation of mTOR and PLK1 expression.

  17. Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs)

    SciTech Connect

    Li, Qing; Guo, Dong; Dong, Zhongqi; Zhang, Wei; Zhang, Lei; Huang, Shiew-Mei; Polli, James E.; Shu, Yan

    2013-11-15

    cisplatin. • The antiemetic ondansetron is frequently co-administrated with cisplatin. • Ondansetron was here demonstrated as a potent inhibitor of MATE transporters. • Ondansetron enhanced cisplatin nephrotoxicity likely via Mate1 inhibition in mice. • Ondansetron may increase patient risk of nephrotoxicity in cisplatin chemotherapy.

  18. Pathological response after neoadjuvant bevacizumab- or cetuximab-based chemotherapy in resected colorectal cancer liver metastases.

    PubMed

    Pietrantonio, Filippo; Mazzaferro, Vincenzo; Miceli, Rosalba; Cotsoglou, Christian; Melotti, Flavia; Fanetti, Giuseppe; Perrone, Federica; Biondani, Pamela; Muscarà, Cecilia; Di Bartolomeo, Maria; Coppa, Jorgelina; Maggi, Claudia; Milione, Massimo; Tamborini, Elena; de Braud, Filippo

    2015-07-01

    Neoadjuvant chemotherapy (NACT) prior to liver resection is advantageous for patients with colorectal cancer liver metastases (CLM). Bevacizumab- or cetuximab-based NACT may affect patient outcome and curative resection rate, but comparative studies on differential tumour regression grade (TRG) associated with distinct antibodies-associated regimens are lacking. Ninety-three consecutive patients received NACT plus bevacizumab (n = 46) or cetuximab (n = 47) followed by CLM resection. Pathological response was determined in each resected metastasis as TRG rated from 1 (complete) to 5 (no response). Except for KRAS mutations prevailing in bevacizumab versus cetuximab (57 vs. 21 %, p = 0.001), patients characteristics were well balanced. Median follow-up was 31 months (IQR 17-48). Bevacizumab induced significantly better pathological response rates (TRG1-3: 78 vs. 34 %, p < 0.001) as well as complete responses (TRG1: 13 vs. 0 %, p = 0.012) with respect to cetuximab. Three-year progression-free survival (PFS) and overall survival (OS) were not significantly different in the two cohorts. At multivariable analysis, significant association with pathological response was found for number of resected metastases (p = 0.015) and bevacizumab allocation (p < 0.001), while KRAS mutation showed only a trend. Significant association with poorer PFS and OS was found for low grades of pathological response (p = 0.009 and p < 0.001, respectively), R2 resection or presence of extrahepatic disease (both p < 0.001) and presence of KRAS mutation (p = 0.007 and p < 0.001, respectively). Bevacizumab-based regimens, although influenced by the number of metastases and KRAS status, improve significantly pathological response if compared to cetuximab-based NACT. Possible differential impact among regimens on patient outcome has still to be elucidated.

  19. Optimal Chemotherapy for Leukemia: A Model-Based Strategy for Individualized Treatment

    PubMed Central

    Jayachandran, Devaraj; Rundell, Ann E.; Hannemann, Robert E.; Vik, Terry A.; Ramkrishna, Doraiswami

    2014-01-01

    Acute Lymphoblastic Leukemia, commonly known as ALL, is a predominant form of cancer during childhood. With the advent of modern healthcare support, the 5-year survival rate has been impressive in the recent past. However, long-term ALL survivors embattle several treatment-related medical and socio-economic complications due to excessive and inordinate chemotherapy doses received during treatment. In this work, we present a model-based approach to personalize 6-Mercaptopurine (6-MP) treatment for childhood ALL with a provision for incorporating the pharmacogenomic variations among patients. Semi-mechanistic mathematical models were developed and validated for i) 6-MP metabolism, ii) red blood cell mean corpuscular volume (MCV) dynamics, a surrogate marker for treatment efficacy, and iii) leukopenia, a major side-effect. With the constraint of getting limited data from clinics, a global sensitivity analysis based model reduction technique was employed to reduce the parameter space arising from semi-mechanistic models. The reduced, sensitive parameters were used to individualize the average patient model to a specific patient so as to minimize the model uncertainty. Models fit the data well and mimic diverse behavior observed among patients with minimum parameters. The model was validated with real patient data obtained from literature and Riley Hospital for Children in Indianapolis. Patient models were used to optimize the dose for an individual patient through nonlinear model predictive control. The implementation of our approach in clinical practice is realizable with routinely measured complete blood counts (CBC) and a few additional metabolite measurements. The proposed approach promises to achieve model-based individualized treatment to a specific patient, as opposed to a standard-dose-for-all, and to prescribe an optimal dose for a desired outcome with minimum side-effects. PMID:25310465

  20. Computational modeling of apoptotic signaling pathways induced by cisplatin

    PubMed Central

    2012-01-01

    Background Apoptosis is an essential property of all higher organisms that involves extremely complex signaling pathways. Mathematical modeling provides a rigorous integrative approach for analyzing and understanding such intricate biological systems. Results Here, we constructed a large-scale, literature-based model of apoptosis pathways responding to an external stimulus, cisplatin. Our model includes the key elements of three apoptotic pathways induced by cisplatin: death receptor-mediated, mitochondrial, and endoplasmic reticulum-stress pathways. We showed that cisplatin-induced apoptosis had dose- and time-dependent characteristics, and the level of apoptosis was saturated at higher concentrations of cisplatin. Simulated results demonstrated that the effect of the mitochondrial pathway on apoptosis was the strongest of the three pathways. The cross-talk effect among pathways accounted for approximately 25% of the total apoptosis level. Conclusions Using this model, we revealed a novel mechanism by which cisplatin induces dose-dependent cell death. Our finding that the level of apoptosis was affected by not only cisplatin concentration, but also by cross talk among pathways provides in silico evidence for a functional impact of system-level characteristics of signaling pathways on apoptosis. PMID:22967854

  1. Chemotherapy for Gallbladder Cancer

    MedlinePlus

    ... often used for gallbladder cancer include: Gemcitabine (Gemzar ® ) Cisplatin (Platinol ® ) 5-fluorouracil (5-FU) Capecitabine (Xeloda ® ) Oxaliplatin ( ... them more effective. For example, combining gemcitabine and cisplatin may help people live longer than getting just ...

  2. A Physiologically Based Pharmacokinetic Model of Isoniazid and Its Application in Individualizing Tuberculosis Chemotherapy

    PubMed Central

    Thiel, Christoph; Aschmann, Hélène E.; Baier, Vanessa; Blank, Lars M.

    2016-01-01

    Due to its high early bactericidal activity, isoniazid (INH) plays an essential role in tuberculosis treatment. Genetic polymorphisms of N-acetyltransferase type 2 (NAT2) cause a trimodal distribution of INH pharmacokinetics in slow, intermediate, and fast acetylators. The success of INH-based chemotherapy is associated with acetylator and patient health status. Still, a standard dose recommended by the FDA is administered regardless of acetylator type or immune status, even though adverse effects occur in 5 to 33% of all patients. Slow acetylators have a higher risk of development of drug-induced toxicity, while fast acetylators and immune-deficient patients face lower treatment success rates. To mechanistically assess the trade-off between toxicity and efficacy, we developed a physiologically based pharmacokinetic (PBPK) model describing the NAT2-dependent pharmacokinetics of INH and its metabolites. We combined the PBPK model with a pharmacodynamic (PD) model of antimycobacterial drug effects in the lungs. The resulting PBPK/PD model allowed the simultaneous simulation of treatment efficacies at the site of infection and exposure to toxic metabolites in off-target organs. Subsequently, we evaluated various INH dosing regimens in NAT2-specific immunocompetent and immune-deficient virtual populations. Our results suggest the need for acetylator-specific dose adjustments for optimal treatment outcomes. A reduced dose for slow acetylators substantially lowers the exposure to toxic metabolites and thereby the risk of adverse events, while it maintains sufficient treatment efficacies. Vice versa, intermediate and fast acetylators benefit from increased INH doses and a switch to a twice-daily administration schedule. Our analysis outlines how PBPK/PD modeling may be used to design and individualize treatment regimens. PMID:27480867

  3. Melatonin prevents cisplatin-induced primordial follicle loss via suppression of PTEN/AKT/FOXO3a pathway activation in the mouse ovary.

    PubMed

    Jang, Hoon; Lee, Ok-Hee; Lee, Youngeun; Yoon, Hyemin; Chang, Eun Mi; Park, Miseon; Lee, Jeong-Woong; Hong, Kwonho; Kim, Jung Oh; Kim, Nam Keun; Ko, Jung Jae; Lee, Dong Ryul; Yoon, Tae Ki; Lee, Woo Sik; Choi, Youngsok

    2016-04-01

    Premature ovarian failure (POF) is a major side effect of chemotherapy in young cancer patients. To develop pharmaceutical agents for preserving fertility, it is necessary to understand the mechanisms responsible for chemotherapy-induced follicle loss. Here, we show that treatment with cisplatin, a widely used anticancer drug, depleted the dormant follicle pool in mouse ovaries by excessive activation of the primordial follicles, without inducing follicular apoptosis. Moreover, we show that co-treatment with the antioxidant melatonin prevented cisplatin-induced disruption of the follicle reserve. We quantified the various stages of growing follicles, including primordial, primary, secondary, and antral, to demonstrate that cisplatin treatment alone significantly decreased, whereas melatonin co-treatment preserved, the number of primordial follicles in the ovary. Importantly, analysis of the PTEN/AKT/FOXO3a pathway demonstrated that melatonin significantly decreased the cisplatin-mediated inhibitory phosphorylation of PTEN, a key negative regulator of dormant follicle activation. Moreover, melatonin prevented the cisplatin-induced activating phosphorylation of AKT, GSK3β, and FOXO3a, all of which trigger follicle activation. Additionally, we show that melatonin inhibited the cisplatin-induced inhibitory phosphorylation and nuclear export of FOXO3a, which is required in the nucleus to maintain dormancy of the primordial follicles. These findings demonstrate that melatonin attenuates cisplatin-induced follicle loss by preventing the phosphorylation of PTEN/AKT/FOXO3a pathway members; thus, melatonin is a potential therapeutic agent for ovarian protection and fertility preservation during chemotherapy in female cancer patients.

  4. Caspase 8 polymorphisms contribute to the prognosis of advanced lung adenocarcinoma patients after platinum-based chemotherapy.

    PubMed

    Liu, Di; Xu, Wen; Ding, Xi; Yang, Yang; Lu, Yanlin; Fei, Ke; Su, Bo

    2017-02-16

    Lung cancer is the leading cause of cancer deaths in China, and about 60% of the cases are diagnosed with histological adenocarcinoma. The caspase 8 (CASP8) gene is a critical initiator of the extrinsic apoptosis pathway. To explore the relationship between tagSNPs or haplotypes of CASP8 and the efficacy of platinum-based chemotherapy in advanced lung adenocarcinoma patients of China, we recruited 555 advanced adenocarcinoma patients. We extracted the genomic DNA from patients' peripheral blood samples and sequenced tagSNPs of CASP8. We calculated the individual haplotype of CASP8 frequencies using the PHASE 2.0 program. The association between CASP8 tagSNPs and overall survival (OS) was calculated by univariate and multivariate Cox regression analysis. A univariate logistic regression analysis was done to analyze the CASP8 tagSNPs and the toxicity of platinum-based chemotherapy. The same statistical methods were used for exploring haplotypes of CASP8. Rs3769821 and rs1045494 of CASP8 were independent prognosis factors for overall survival (OS) using multivariate Cox's regression models. For the haplotype of the seven tagSNPs, haplotype AGGAAAGA was correlated with the efficacy of platinum-based chemotherapy. The polymorphisms of CASP8, rs7608692, and haplotype AGAACAG correlated with neutropenia toxicity. The haplotype GGGGAAA was associated with thrombocytopenia toxicity. We conclude that the polymorphisms of CASP8 contribute to the prognosis of advanced lung adenocarcinoma and influence the quality of life and survival.

  5. [Magnesium premedication prevents Cisplatin-induced nephrotoxicity in patients with esophageal and hypopharyngeal cancer].

    PubMed

    Hirai, Shiho; Kaida, Sachiko; Ito, Tadaaki; Hasebe, Shinobu; Ueno, Masaki; Udagawa, Harushi; Hayashi, Masahiro

    2013-06-01

    Hypomagnesemia is one of the well-known side effects in patients receiving cisplatin-containing chemotherapy. However, the relevance between hypomagnesemia and cisplatin-induced nephrotoxicity remain to be completely elucidated. Although patients with esophageal and hypopharyngeal cancer are susceptible to dehydration, there is no evidence yet that magnesium supplementation for these patients will prevent nephrotoxicity during cisplatin-containing chemotherapy. The aim of this study was to examine the effect of magnesium supplementation on the prevention of cisplatin-induced nephrotoxicity for patients with esophageal and hypopharyngeal cancer. Twenty-three patients with esophageal or hypopharyngeal cancer were studied over 2 weeks. Ten of them received magnesium supplementation and 13 did not. Magnesium sulphate(20 mEq) was administered before 5-fluorouracil(800mg/m2/24 h/day 1-5)and cisplatin(80mg/m2/day 1)(FP)treatment. The maximum serum creatinine concentration of magnesium-supplemented group demonstrated a significantly lower concentration compared to the non-magnesium-supplemented group(p=0. 018). As a result, magnesium supplementation successfully reduced the incidence rate of nephrotoxicity(p=0. 038). These results showed that magnesium supplementation before FP treatment may be quite beneficial for preventing nephrotoxicity in patients with esophageal and hypopharyngeal cancer, and it is therefore recommended that magnesium be routinely supplemented during FP treatment for esophageal or hypopharyngeal cancer.

  6. miR-145 sensitizes gallbladder cancer to cisplatin by regulating multidrug resistance associated protein 1.

    PubMed

    Zhan, Ming; Zhao, Xiaonan; Wang, Hui; Chen, Wei; Xu, Sunwang; Wang, Wei; Shen, Hui; Huang, Shuai; Wang, Jian

    2016-08-01

    Gallbladder cancer (GBC) is the most common malignancy in biliary tract with poor prognosis. Due to its high chemoresistance, systemic chemotherapies have had limited success in treating GBC patients. MicroRNAs (miRNAs) are emerging novel regulators of chemoresistance, which modulate the expression of drug resistance-related genes. In this study, we investigated the association between miR-145 expression and cisplatin sensitivity by both in vivo and in vitro analysis. Quantitative PCR (q-PCR) analysis indicated an increased miR-145 expression in GBC tissues. In addition, studies on GBC cell lines suggested an increased cisplatin efficacy with miR-145 overexpression, whereas decreasing miR-145 expression reduced cisplatin sensitivity. Further, we found that miR-145 accelerated MRP1 mRNA degradation by directly targeting its 3'-UTR and therefore caused increased cisplatin toxicity in GBC cells. Moreover, lower miR-145 and higher MRP1 expression levels predicted poor prognosis in GBC patients who received chemotherapy. Collectively, our findings established a rationale for using miR-145 expression as a biomarker to identify cisplatin-resistant GBC patients and propose that treatment strategies increasing the expression of miR-145 could be a new therapeutic approach for GBC patients.

  7. A practical approach to improve safety and management in chemotherapy units based on the PROCHE - programme for optimisation of the chemotherapy network monitoring program.

    PubMed

    Scotté, Florian; Oudard, Stéphane; Aboudagga, Hail; Elaidi, Reza; Bonan, Brigitte

    2013-02-01

    The PROCHE (PRogramme d'Optimisation du circuit CHimiothErapie [Programme for optimisation of the chemotherapy network]) initiative is an innovative oncology-monitoring program designed to reduce patient waiting time and chemotherapy wastage, ultimately improving patient care. Laboratory test results and side effects data were collected for patients in the PROCHE monitoring program group 2d prior to scheduled chemotherapy visits, allowing oncologists to confirm or delay each patient's chemotherapy. Data from 1037 patients entered in the PROCHE program were compared with 513 control patients, who had been treated according to previous typical hospital procedures. Results demonstrated significant reductions in mean hospital stay i.e. decreased it by 66 min and drug wastage decreased from 6% to 2% (95% CI (confidence interval) 0.21-0.59, P<0.0001), and a significant increase in bed occupancy rates with the PROCHE initiative (all P<0.0001 vs. controls). The incidence of pain and severity of fatigue were also reduced. In conclusion, the PROCHE initiative resulted in improved patient quality of care and reduced chemotherapy toxicities, and improved hospital and pharmacy productivity. These encouraging preliminary results warrant further study.

  8. Prognostic Value of Neutrophil-Related Factors in Locally Advanced Cervical Squamous Cell Carcinoma Patients Treated with Cisplatin-Based Concurrent Chemoradiotherapy.

    PubMed

    Wang, Yan-Yang; Bai, Zhou-Lan; He, Jian-Li; Yang, Yan; Zhao, Ren; Hai, Ping; Zhe, Hong

    2016-01-01

    The aim of this study was to explore the relationship between neutrophil-related factors, including neutrophil-lymphocyte ratio (NLR) and the responses of neutrophil to granulocyte colony-stimulating factors (RNG), and the prognosis of patients with locally advanced cervical squamous cell carcinoma (LACSCC) undergoing cisplatin-based concurrent chemoradiotherapy (CCCRT). A total of sixty LACSCC patients were enrolled in this study. We analyzed the association of NLR or RNG with clinicopathologic characteristics of these patients. The prognostic factors were evaluated by univariate and multivariate survival analysis. The optimal cut-off value of the NLR was determined to be 2.0 for the overall survival (OS). A higher level of the NLR was associated with younger age (P = 0.017) and higher baseline platelet count (P = 0.040). NLR was identified to be the only independent prognostic factor for OS by multivariate analysis (P = 0.037). The median RNG was 3.01, with a range of 1.19-16.84. RNG level was significantly associated with lymph node metastasis of these patients (P = 0.023). And higher RNG was identified as being a closely independent poor prognostic factor for OS (P = 0.055). This study showed that NLR and RNG may be used as potential biomarkers for survival prediction in patients with LACSCC receiving CCCRT.

  9. Chemotherapy in advanced ovarian cancer: an overview of randomised clinical trials. Advanced Ovarian Cancer Trialists Group.

    PubMed Central

    1991-01-01

    OBJECTIVES--To consider the role of platinum and the relative merits of single agent and combination chemotherapy in the treatment of advanced ovarian cancer. DESIGN--Formal quantitative overview using updated individual patient data from all available randomised trials (published and unpublished). SUBJECTS--8139 patients (6408 deaths) included in 45 different trials. RESULTS--No firm conclusions could be reached. Nevertheless, the results suggest that in terms of survival immediate platinum based treatment was better than non-platinum regimens (overall relative risk 0.93; 95% confidence interval 0.83 to 1.05); platinum in combination was better than single agent platinum when used in the same dose (overall relative risk 0.85; 0.72 to 1.00); and cisplatin and carboplatin were equally effective (overall relative risk 1.05; 0.94 to 1.18). CONCLUSIONS--In the past, randomised clinical trials of chemotherapy in advanced ovarian cancer have been much too small to detect the degree of benefit which this overview suggests is realistic for currently available chemotherapeutic regimens. Hence a new trial comparing cisplatin, doxorubicin, and cyclophosphamide (CAP) with carboplatin has been launched and plans to accrue 2000 patients. PMID:1834291

  10. A case of intimal sarcoma of the pulmonary artery successfully treated with chemotherapy.

    PubMed

    Xu, Yanjie; Wang, Kai; Geng, Yiting; Shao, Yongfeng; Yin, Yongmei

    2012-10-01

    Intimal sarcoma of pulmonary artery (PAIS) is a rare disease with no characteristic symptoms. No standard therapeutic guidelines have been established so far. A 55-year-old woman who underwent pulmonary endarterectomy in 2005 with a pathological and immunohistochemical result of PAIS was re-admitted to our hospital on August 24, 2009, presenting with cough and dyspnea. The thoracic computed tomography (CT) scan revealed a 12.5 cm × 9 cm well-defined mass in the right lobe, considered a local neoplasm recurrence after a 44 month symptom-free period. As surgical resection was not proposed, she received combined chemotherapy consisting of doxorubicin, cisplatin, and ifosfamide for two cycles. Because of intolerable side effects, she received vinorelbine and cisplatin for the next four cycles. CT scans after six cycles showed remarkable regression of the tumor. After that, she began to take oral cyclophosphamide (50 mg t.i.d) everyday as a maintenance therapy. As of the time of writing, 19 months after the onset of the recurrence, she remains stable. Several antineoplastic drugs have been reported to be used in PAIS, with poor effects in most cases. To our knowledge, this is the first case of PAIS that has been successfully treated by a vinorelbine-based regimen used as second-line chemotherapy. Vinorelbine is a promising drug that may be relatively well tolerated in heavily pretreated patients with PAIS.

  11. Metformin sensitizes the response of oral squamous cell carcinoma to cisplatin treatment through inhibition of NF-κB/HIF-1α signal axis.

    PubMed

    Qi, Xiaofeng; Xu, Wengguang; Xie, Junqi; Wang, Yufeng; Han, Shengwei; Wei, Zheng; Ni, Yanhong; Dong, Yingchun; Han, Wei

    2016-10-20

    Resistance towards chemotherapy is a common complication in treatment of oral cancers, which leads to treatment failure and poor outcome. In recent years, a growing body of evidence has shown that tumour hypoxia significantly contributes to chemoresistance. Metformin, a widely used oral hypoglycaemic drug, can reportedly potentiate the efficacy of chemotherapeutic drugs in various cancers; however, the underlying mechanisms are intricate and have not been fully understood. In this study, we explored the role of metformin in chemosensitivity of oral squamous cell carcinoma cells (OSCC) to cisplatin both in vitro and in vivo, and attempted to elucidate its possible underlying mechanisms. Encouragingly, we found that metformin synergistically enhanced cisplatin cytotoxicity and reversed the chemoresistance to certain extent. This mechanism could likely be related with inhibition of the NF-κB/HIF-1α signal axis and lead to the downregulation of hypoxia-regulated genes products. Therefore, metformin could serve as a chemosensitiser for cisplatin-based regimens for OSCC, thereby providing a theoretical basis for future use in the treatment of oral cancers.

  12. Metformin sensitizes the response of oral squamous cell carcinoma to cisplatin treatment through inhibition of NF-κB/HIF-1α signal axis

    PubMed Central

    Qi, Xiaofeng; Xu, Wengguang; Xie, Junqi; Wang, Yufeng; Han, Shengwei; Wei, Zheng; Ni, Yanhong; Dong, Yingchun; Han, Wei

    2016-01-01

    Resistance towards chemotherapy is a common complication in treatment of oral cancers, which leads to treatment failure and poor outcome. In recent years, a growing body of evidence has shown that tumour hypoxia significantly contributes to chemoresistance. Metformin, a widely used oral hypoglycaemic drug, can reportedly potentiate the efficacy of chemotherapeutic drugs in various cancers; however, the underlying mechanisms are intricate and have not been fully understood. In this study, we explored the role of metformin in chemosensitivity of oral squamous cell carcinoma cells (OSCC) to cisplatin both in vitro and in vivo, and attempted to elucidate its possible underlying mechanisms. Encouragingly, we found that metformin synergistically enhanced cisplatin cytotoxicity and reversed the chemoresistance to certain extent. This mechanism could likely be related with inhibition of the NF-κB/HIF-1α signal axis and lead to the downregulation of hypoxia-regulated genes products. Therefore, metformin could serve as a chemosensitiser for cisplatin-based regimens for OSCC, thereby providing a theoretical basis for future use in the treatment of oral cancers. PMID:27762347

  13. Endogenously produced nitric oxide mitigates sensitivity of melanoma cells to cisplatin.

    PubMed

    Godoy, Luiz C; Anderson, Chase T M; Chowdhury, Rajdeep; Trudel, Laura J; Wogan, Gerald N

    2012-12-11

    Melanoma patients experience inferior survival after biochemotherapy when their tumors contain numerous cells expressing the inducible isoform of NO synthase (iNOS) and elevated levels of nitrotyrosine, a product derived from NO. Although several lines of evidence suggest that NO promotes tumor growth and increases resistance to chemotherapy, it is unclear how it shapes these outcomes. Here we demonstrate that modulation of NO-mediated S-nitrosation of cellular proteins is strongly associated with the pattern of response to the anticancer agent cisplatin in human melanoma cells in vitro. Cells were shown to express iNOS constitutively, and to generate sustained nanomolar levels of NO intracellularly. Inhibition of NO synthesis or scavenging of NO enhanced cisplatin-induced apoptotic cell death. Additionally, pharmacologic agents disrupting S-nitrosation markedly increased cisplatin toxicity, whereas treatments favoring stabilization of S-nitrosothiols (SNOs) decreased its cytotoxic potency. Activity of the proapoptotic enzyme caspase-3 was higher in cells treated with a combination of cisplatin and chemicals that decreased NO/SNOs, whereas lower activity resulted from cisplatin combined with stabilization of SNOs. Constitutive protein S-nitrosation in cells was detected by analysis with biotin switch and reduction/chemiluminescence techniques. Moreover, intracellular NO concentration increased significantly in cells that survived cisplatin treatment, resulting in augmented S-nitrosation of caspase-3 and prolyl-hydroxylase-2, the enzyme responsible for targeting the prosurvival transcription factor hypoxia-inducible factor-1α for proteasomal degradation. Because activities of these enzymes are inhibited by S-nitrosation, our data thus indicate that modulation of intrinsic intracellular NO levels substantially affects cisplatin toxicity in melanoma cells. The underlying mechanisms may thus represent potential targets for adjuvant strategies to improve the efficacy

  14. Contribution of genetic factors to platinum-based chemotherapy sensitivity and prognosis of non-small cell lung cancer.

    PubMed

    Pérez-Ramírez, Cristina; Cañadas-Garre, Marisa; Molina, Miguel Ángel; Robles, Ana I; Faus-Dáder, María José; Calleja-Hernández, Miguel Ángel

    Although platinum-based chemotherapy remains the standard treatment for advanced NSCLC patients, clinical outcomes are poor and most patients develop high-grade toxicities. Genetic factors, such as single nucleotide polymorphisms (SNPs) involved in platinum pharmacodynamics, metabolism and mechanism of action, may account for inter-individual differences shown in effectiveness and toxicity. Polymorphisms in genes involved in DNA repair and others such as PI3K/PTEN/AKT and TGF-β pathways have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with platinum-based chemotherapy. Other cellular processes, like DNA methylation and proliferation have been connected with clinical outcome for platinum-based chemotherapy regimens through folate metabolism and cytokine signaling. The influence of gene polymorphisms in the NER pathway on clinical outcome has been extensively investigated in advanced NSCLC patients treated with platinum-based chemotherapy but contradictory results have been reported. The most recent and thorough meta-analyses have failed to show an association between ERCC1 C118T/C8092A and ERCC5 rs1047768 polymorphisms and response to platinum based chemotherapy. However, other polymorphisms in ERCC2 (Lys751Gln and Asp312Asn) and ERCC5 (rs2094258 and rs2296147) and have been related with overall survival (OS) and progression-free survival (PFS), respectively. The Arg194Trp and Gln399Arg polymorphisms in XRCC1, have also been extensively investigated. Their effects seem to be dependent on ethnicity, and recent meta-analyses have confirmed an association with response in Asian but not in Caucasian patients. The influence on overall response rate (ORR) of the rs861539 polymorphism in XRCC3, part of (DSB) repair pathway, has also been confirmed in a meta-analysis. Finally, SNPs in genes coding proteins of the p53, PI3K, TGF-β, membrane transporters, gluthatione metabolism enzymes and cytokine pathways have

  15. Antiemetic and Myeloprotective Effects of Rhus verniciflua Stoke in a Cisplatin-Induced Rat Model

    PubMed Central

    Kim, Hyo-Seon; Kim, Hyeong-Geug; Im, Hwi-Jin; Lee, Jin-Seok; Lee, Sung-Bae; Kim, Won-Yong; Lee, Hye-Won; Lee, Sam-Keun; Byun, Chang Kyu

    2017-01-01

    Rhus verniciflua Stoke has been commonly used in traditional medicine to treat gastrointestinal (GI) dysfunction diseases. In order to investigate pharmacological properties of Rhus verniciflua Stoke water extract (RVX) on cisplatin-induced amnesia, RVX (0, 25, 50, or 100 mg/kg) was orally administrated for five consecutive days after a single intraperitoneal injection of cisplatin (6 mg/kg) to SD rat. Cisplatin injection significantly increased the kaolin intake (emesis) but reduced the normal diet intake (anorexia) whereas the RVX treatment significantly improved these abnormal diet behaviors at both the acute and delayed phase. The serotonin concentration and the related gene expressions (5-HT3 receptors and SERT) in small intestine tissue were abnormally altered by cisplatin injection, which were significantly attenuated by the RVX treatment. Histological findings of gastrointestinal tracts, as well as the proteins level of proinflammatory cytokines (TNF-α, IL-6, and IL-1β), revealed the beneficial effect of RVX on cisplatin-induced gastrointestinal inflammation. In addition, RVX significantly improved cisplatin-induced myelosuppression, as evidenced by the observation of leukopenia and by histological examinations in bone marrow. Our findings collectively indicated Rhus verniciflua Stoke improved the resistance of rats to chemotherapy-related adverse effects in the gastrointestinal track and bone marrow. PMID:28270854

  16. Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer.

    PubMed

    Roh, Jong-Lyel; Kim, Eun Hye; Jang, Hye Jin; Park, Jin Young; Shin, Daiha

    2016-10-10

    Inhibition of key molecules related to ferroptosis, cystine/glutamate antiporter and glutathione peroxidase, may induce eradication of chemotherapy/radiotherapy-resistant cancer cells. The present study investigated whether ferroptosis could overcome head and neck cancer (HNC) resistance to cisplatin treatment. Three cisplatin-resistant HNC cell lines (AMC-HN3R, -HN4R, and -HN9R) and their parental lines were used. The effects of cystine and glutamate alteration and pharmacological and genetic inhibition of cystine/glutamate antiporter were assessed by measuring viability, death, reactive oxygen species production, protein expression, and preclinical mouse tumor xenograft models. Conditioned media with no cystine or glutamine excess induced ferroptosis of both cisplatin-sensitive and -resistant HNC cells without any apparent changes to necrosis and apoptosis markers. The cystine/glutamate antiporter inhibitors erastin and sulfasalazine inhibited HNC cell growth and accumulated lipid reactive oxygen species, thereby inducing ferroptosis. Genetic silencing of cystine/glutamate antiporter with siRNA or shRNA treatment also induced effective ferroptotic cell death of resistant HNC cells and enhanced the cisplatin cytotoxicity of resistant HNC cells. Pharmacological and genetic inhibition of cystine/glutamate antiporter significantly sensitized resistant HNC cells to cisplatin in vitro and in vivo. Pharmacological and genetic inhibition of cystine/glutamate antiporter overcomes the cisplatin resistance of HNC cells by inducing ferroptosis.

  17. Protective effects of icariin on cisplatin-induced acute renal injury in mice

    PubMed Central

    Ma, Pei; Zhang, Sen; Su, Xinlin; Qiu, Guixing; Wu, Zhihong

    2015-01-01

    Cisplatin chemotherapy often causes acute kidney injury in cancer patients. Icariin is a bioactive flavonoid, which has renal protection and anti-inflammation effects. This study investigated the mechanism underlying the attenuation of cisplatin-induced renal injury by icariin. BALB/c mice were treated with cisplatin (15 mg/kg) with or without treatment with icariin (30 or 60 mg/kg for 5 days). Renal function, histological changes, degree of oxidative stress and tubular apoptosis were examined. The effects of icariin on cisplatin-induced expression of renal TNF-α, NF-κB, cleaved caspase-3 and Bcl-2 family proteins were evaluated. Treatment of mice with cisplatin resulted in renal damage, showing an increase in blood urea nitrogen and creatinine levels, tubular damage, oxidative stress and apoptosis. These renal changes could be significantly improved by icariin treatment, especially in high dose of icariin group. Examination of molecules involving inflammation and apoptosis of the kidney revealed that treatment of icariin reduced expression of TNF-α, NF-κB, cleaved caspase-3, and Bax, increased the expression of BCL-2. These results indicate that icariin ameliorates the cisplatin-mediated nephrotoxicity via improving renal oxidant status, consequent NF-κB activation and inflammation cascade and apoptosis, and the following disturbed expression of apoptosis related proteins. PMID:26692955

  18. Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Cisplatin-Induced Neuropathy in Mice.

    PubMed

    Harris, Hannah M; Sufka, Kenneth J; Gul, Waseem; ElSohly, Mahmoud A

    2016-08-01

    Sativex, a cannabinoid extract with a 1 : 1 ratio of tetrahydocannabinol and cannabidiol, has been shown to alleviate neuropathic pain associated with chemotherapy. This research examined whether tetrahydocannabinol or cannabidiol alone could attenuate or prevent cisplatin-induced tactile allodynia. In experiment 1, mice (C57BL/6) received eight administrations of 2.3 mg/kg cisplatin or saline solution IP every other day to induce tactile allodynia. Mice were then administered vehicle, 100 mg/kg gabapentin, 2 mg/kg tetrahydocannabinol, or 2 mg/kg cannabidiol IP and tested 60 min later on an electronic Von Frey. In experiment 2, prevention studies, cannabidiol (0.0, 0.5, 1.0, and 2.0 mg/kg) or tetrahydocannabinol (0.0, 0.5, 1.0, and 2.0 mg/kg) was given IP 30 min prior to cisplatin administration (2.3 or 1.0 mg/kg) utilizing a six-dose alternate day protocol. In both studies, tactile responses to the hind paws were quantified in g of force using an electronic Von Frey prior to and after the cisplatin administration protocol. Cisplatin produced a reduction in g of force indicative of neuropathy that was attenuated by gabapentin, tetrahydocannabinol, and cannabidiol but not prevented by either cannabinoid. These data demonstrate that each of the major constituents of Sativex alone can achieve analgesic effects against cisplatin neuropathy.

  19. Risk Factors of Ototoxicity After Cisplatin-Based Chemo-Irradiation in Patients With Locally Advanced Head-and-Neck Cancer: A Multivariate Analysis

    SciTech Connect

    Zuur, Charlotte L. . E-mail: cl.zuur@vumc.nl; Simis, Yvonne J.; Lansdaal, Pauline E.; Hart, Augustinus A.; Rasch, Coen R.; Schornagel, Jan H.; Dreschler, Wouter A.; Balm, Alfons J.

    2007-08-01

    Purpose: Cisplatin chemo-irradiation is increasingly used in locally advanced squamous cell carcinoma of the head and neck. The objective of this study is to determine risk factors of ototoxicity due to intra-arterial high-dose cisplatin chemoradiation. Methods and Materials: A prospective analysis of hearing thresholds at low and (ultra) high frequencies obtained before, during, and after treatment in 146 patients. Treatment consisted of intra-arterial infusion of high-dose cisplatin (150 mg/m{sup 2}, four courses) with sodium thiosulfate rescue and concurrent radiation therapy (70 Gy). Patient and chemoradiation variables were studied in a multivariate analysis. Results: After treatment, 23% of the ears were under consideration for hearing aids because of therapy. Twenty-two percent of the patients developed an increase in air-bone gap >10 dB during or after therapy. In the multivariate explanatory analysis, cumulative dose of cisplatin and radiation therapy, and young age displayed a causal relationship with increased sensorineural hearing loss during and after therapy (p < 0.001). In the multivariate prediction analysis, pretreatment hearing level of the concerning ear was identified as an independent predictive factor for hearing capability after therapy (p < 0.0001). Conclusions: Both cisplatin and radiation therapy were proven to induce sensorineural hearing loss, in this study with short-term follow-up. Of all patient and treatment variables studied, the patients pretreatment hearing level appeared to be the main predictive factor for hearing capability after high-dose intra-arterial cisplatin chemoradiation.

  20. Potential therapeutic strategies for non - muscle invasive bladder cancer based on association of intravesical immunotherapy with P-MAPA and systemic administration of cisplatin and doxorubicin

    PubMed Central

    Dias, Queila Cristina; Nunes, Iseu da Silva; Garcia, Patrick Vianna; Fávaro, Wagner José

    2016-01-01

    ABSTRACT The present study describes the histopathological and molecular effects of P-MAPA (Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride) intravesical immunotherapy combined with systemic doxorubicin or cisplatin for treatment of non-muscle invasive bladder cancer (NMIBC) in an appropriate animal model. Our results showed an undifferentiated tumor, characterizing a tumor invading mucosa or submucosa of the bladder wall (pT1) and papillary carcinoma in situ (pTa) in the Cancer group. The histopathological changes were similar between the combined treatment with intravesical P-MAPA plus systemic Cisplatin and P-MAPA immunotherapy alone, showing decrease of urothelial neoplastic lesions progression and histopathological recovery in 80% of the animals. The animals treated systemically with cisplatin or doxorubicin singly, showed 100% of malignant lesions in the urinary bladder. Furthemore, the combined treatment with P-MAPA and Doxorubicin showed no decrease of urothelial neoplastic lesions progression and histopathological recovery. Furthermore, Akt, PI3K, NF-kB and VEGF protein levels were significantly lower in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments than other groups. In contrast, PTEN protein levels were significantly higher in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments. Thus, it could be concluded that combination of intravesical P-MAPA immunotherapy and systemic cisplatin in the NMIBC animal model was effective, well tolerated and showed no apparent signs of antagonism between the drugs. In addition, intravesical P-MAPA immunotherapy may be considered as a valuable option for treatment of BCG unresponsive patients that unmet the criteria for early cystectomy. PMID:24893914

  1. Potential therapeutic strategies for non - muscle invasive bladder cancer based on association of intravesical immunotherapy with p - mapa and systemic administration of cisplatin and doxorubicin.

    PubMed

    Dias, Queila Cristina; Nunes, Iseu da Silva; Garcia, Patrick Vianna; Favaro, Wagner Jose

    2016-01-01

    The present study describes the histopathological and molecular effects of P-MAPA (Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride) intravesical immunotherapy combined with systemic doxorubicin or cisplatin for treatment of non-muscle invasive bladder cancer (NMIBC) in an appropriate animal model. Our results showed an undifferentiated tumor, characterizing a tumor invading mucosa or submucosa of the bladder wall (pT1) and papillary carcinoma in situ (pTa) in the Cancer group. The histopathological changes were similar between the combined treatment with intravesical P-MAPA plus systemic Cisplatin and P-MAPA immunotherapy alone, showing decrease of urothelial neoplastic lesions progression and histopathological recovery in 80% of the animals. The animals treated systemically with cisplatin or doxorubicin singly, showed 100% of malignant lesions in the urinary bladder. Furthemore, the combined treatment with P-MAPA and Doxorubicin showed no decrease of urothelial neoplastic lesions progression and histopathological recovery. Furthermore, Akt, PI3K, NF-kB and VEGF protein levels were significantly lower in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments than other groups. In contrast, PTEN protein levels were significantly higher in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments. Thus, it could be concluded that combination of intravesical P-MAPA immunotherapy and systemic cisplatin in the NMIBC animal model was effective, well tolerated and showed no apparent signs of antagonism between the drugs. In addition, intravesical P-MAPA immunotherapy may be considered as a valuable option for treatment of BCG unresponsive patients that unmet the criteria for early cystectomy.

  2. Cardioprotective Effect of Dexrazoxane in Patients with HER2-Positive Breast Cancer Who Receive Anthracycline Based Adjuvant Chemotherapy Followed by Trastuzumab

    PubMed Central

    Kim, In-Ho; Lee, Ji Eun; Youn, Ho-Joong; Song, Byung Joo

    2017-01-01

    Purpose We intended to determine whether dexrazoxane (DZR) is cardioprotective during administration of adjuvant anthracycline-based chemotherapy followed by a 1-year trastuzumab treatment. Methods The medical records of 228 patients who underwent surgical resection and received adjuvant chemotherapy with trastuzumab for human epidermal growth factor receptor type 2 (HER2)-positive breast cancer between January 2010 and December 2014 were reviewed. Approximately 25% of patients received DZR prior to each administration of doxorubicin during doxorubicin with cyclophosphamide (AC) chemotherapy. DZR was not administered during the 1-year trastuzumab maintenance period. Rates of cardiac events (reduction in left ventricular ejection fraction [LVEF] by 10% or more; reduction in absolute LVEF to <45%) and cardiac event-free duration (CFD) were examined. The trastuzumab interruption rate was also assessed. Results Twelve percent of patients experienced a cardiac event. Repeated-measures analysis of variance for ejection fraction revealed a significant main effect of time, and a significant group (DZR)×time interaction. The group treated with adjuvant chemotherapy and DZR experienced significantly lower frequencies of cardiac events than the adjuvant chemotherapy only group. In multivariate analysis, DZR administration was associated with significantly fewer cardiac events. Moreover, DZR administration was an independent good prognostic factor for CFD. Only one patient (2.3%) experienced early interruption of trastuzumab in the adjuvant chemotherapy with DZR group due to cardiac toxicity, whereas 10 patients (7.6%) experienced a trastuzumab stop event in the adjuvant chemotherapy only group. Conclusion DZR is cardioprotective in HER2-positive breast cancer patients who received adjuvant chemotherapy with trastuzumab. A large cohort randomized trial is needed to determine if DZR has an effect on trastuzumab interruption and completion of 12-month trastuzumab. Because

  3. Metronomic chemotherapy.

    PubMed

    Mutsaers, Anthony J

    2009-08-01

    Chemotherapy drugs are usually administered at doses that are high enough to result in an obligatory break period to allow for the observation of potential side effects and institution of supportive care, if required. In recent years, efforts to administer chemotherapy on a more continuous basis, with a much shorter break period, or none at all, have received increased interest, and the practice has come to be known as metronomic chemotherapy. The basis for success with this currently investigational approach may be rooted in continuous drug exposure to susceptible cancer cells, inhibition of tumor blood vessel growth-a process known as tumor angiogenesis, and/or alterations in tumor immunology. Increased benefit also appears to occur when metronomic chemotherapy is used in combination with newer, targeted antiangiogenic agents, and therefore represents a promising approach to combination therapy, particularly as targeted oncology drugs make their way into veterinary oncology applications. There is still much to be learned in this field, especially with regard to optimization of the proper drugs, dose, schedule, and tumor applications. However, the low cost, ease of administration, and acceptable toxicity profiles potentially associated with this therapeutic strategy make metronomic chemotherapy protocols attractive and suitable to veterinary applications. Preliminary clinical trial results have now been reported in both human and veterinary medicine, including adjuvant treatment of canine splenic hemangiosarcoma and incompletely resected soft tissue sarcoma, and, further, more powerful studies are currently ongoing.

  4. Effect of chemotherapy on health-related quality of life among early-stage ovarian cancer survivors: a study from the population-based PROFILES registry

    PubMed Central

    Bhugwandass, C.S.; Pijnenborg, J.M.A.; Pijlman, B.; Ezendam, N.P.M.

    2016-01-01

    Background There is wide variation in the application of adjuvant chemotherapy in early-stage epithelial ovarian cancer. Our aim was to assess differences in health-related quality of life (hrqol) between patients with early-stage ovarian cancer who did or did not receive chemotherapy as adjuvant treatment. Methods All patients diagnosed with early-stage ovarian cancer between 2000 and 2010 within the population-based Eindhoven Cancer Registry (n = 191) were enrolled in this study. Patients were requested to complete questionnaires, including the cancer-specific (qlq-C30) and ovarian cancer-specific (qlq-OV28) quality of life measures from the European Organisation for Research and Treatment of Cancer. Primary outcome measures were the generic-and cancer-specific domain scores for hrqol in ovarian cancer survivors. Results Of the 107 patients (56%) who returned the questionnaires, 57 (53.3%) had received adjuvant chemotherapy and 50 (46.7%) had been treated with surgery alone. Significant differences in hrqol between those groups were found in the symptom scales for peripheral neuropathy, attitude toward sickness, and financial situation, with worse scores in the chemotherapy group. Conclusions Results of our study show that patients who receive adjuvant chemotherapy have a significantly worse score for 3 aspects of hrqol. Efforts should be made to reduce use of adjuvant chemotherapy in early-stage ovarian cancer. Moreover, preventive strategies to improve long-term quality of life for those who need adjuvant chemotherapy should be explored. PMID:28050144

  5. Cisplatin selects for stem-like cells in osteosarcoma by activating Notch signaling.

    PubMed

    Yu, Ling; Fan, Zhengfu; Fang, Shuo; Yang, Jian; Gao, Tian; Simões, Bruno M; Eyre, Rachel; Guo, Weichun; Clarke, Robert B

    2016-05-31

    Notch signaling regulates normal stem cells and is also thought to regulate cancer stem cells (CSCs). Recent data indicate that Notch signaling plays a role in the development and progression of osteosarcoma, however the regulation of Notch in chemo-resistant stem-like cells has not yet been fully elucidated. In this study we generated cisplatin-resistant osteosarcoma cells by treating them with sub-lethal dose of cisplatin, sufficient to induce DNA damage responses. Cisplatin-resistant osteosarcoma cells exhibited lower proliferation, enhanced spheroid formation and more mesenchymal characteristics than cisplatin-sensitive cells, were enriched for Stro-1+/CD117+ cells and showed increased expression of stem cell-related genes. A similar effect was observed in vivo, and in addition in vivo tumorigenicity was enhanced during serial transplantation. Using several publicly available datasets, we identified that Notch expression was closely associated with osteosarcoma stem cells and chemotherapy resistance. We confirmed that cisplatin-induced enrichment of osteosarcoma stem cells was mediated through Notch signaling in vitro, and immunohistochemistry showed that cleaved Notch1 (NICD1) positive cells were significantly increased in a relapsed xenograft which had received cisplatin treatment. Furthermore, pretreatment with a γ-secretase inhibitor (GSI) to prevent Notch signalling inhibited cisplatin-enriched osteosarcoma stem cell activity in vitro, including Stro-1+/CD117+ double positive cells and spheroid formation capacity. The Notch inhibitor DAPT also prevented tumor recurrence in resistant xenograft tumors. Overall, our results show that cisplatin induces the enrichment of osteosarcoma stem-like cells through Notch signaling, and targeted inactivation of Notch may be useful for the elimination of CSCs and overcoming drug resistance.

  6. YM155 reverses cisplatin resistance in head and neck cancer by decreasing cytoplasmic survivin levels

    PubMed Central

    Kumar, Bhavna; Yadav, Arti; Lang, James C.; Cipolla, Michael; Schmitt, Alessandra C.; Arradaza, Nicole; Teknos, Theodoros N.; Kumar, Pawan

    2013-01-01

    Cisplatin is one of the commonly used chemotherapeutic drugs for the treatment of head and neck squamous cell carcinoma (HNSCC). However, acquisition of cisplatin resistance is common in patients with HNSCC and it often leads to local and distant failure. In this study, we demonstrate that survivin expression is significantly upregulated in HNSCC primary tumors and cell lines. In addition, survivin levels were significantly higher in HPV negative patients that normally respond poorly to cisplatin treatment. Survivin expression was further increased in cisplatin resistant cells (CAL27-CisR) as compared to its parent cells (CAL27). Therefore, we hypothesize that targeting of survivin in HNSCC could reverse the resistant phenotype in tumor cells thereby enhancing the therapeutic efficacy of cisplatin. We used both in vitro and in vivo models to test the efficacy of YM155, a small molecule survivin inhibitor, either as a single agent or in combination with cisplatin. YM155 significantly decreased survivin levels and cell proliferation in a dose-dependent manner. In addition, YM155 pretreatment significantly reversed cisplatin resistance in cancer cells. Interestingly, YM155 treatment altered the dynamic localization of survivin in cells by inducing a rapid reduction in cytoplasmic survivin, which plays a critical role in its anti-apoptotic function. In a SCID mouse xenograft model, YM155 significantly enhanced the anti-tumor and anti-angiogenic effects of cisplatin with no added systemic toxicity. Taken together, our results suggest a potentially novel strategy to use YM155 to overcome the resistance in tumor cells thereby enhancing the effectiveness of the chemotherapy in HNSCC. PMID:22723337

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

    PubMed

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

    2015-07-01

    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.

  8. REV3L modulates cisplatin sensitivity of non-small cell lung cancer H1299 cells.

    PubMed

    Wang, Wenjie; Sheng, Wenjiong; Yu, Chenxiao; Cao, Jianping; Zhou, Jundong; Wu, Jinchang; Zhang, Huojun; Zhang, Shuyu

    2015-09-01

    Lung cancer remains the leading cause of cancer-related mortality worldwide and non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all cases of lung cancer. Cisplatin plays a significant role in the management of human lung cancer. Translesion DNA synthesis (TLS) is involved in DNA damage repair. DNA polymerase ζ (Pol ζ) is able to mediate the DNA replication bypass of DNA damage, which is suggested to be involved in chemoresistance. REV3L is the catalytic subunit of Pol ζ. Due to its critical role in translesion DNA synthesis, whether REV3L modulates cisplatin response in NSCLC cells remains unknown. In this study, REV3L overexpression and silencing H1299 cell lines were established. The reports showed that cisplatin induced the expression of REV3L by recruiting Sp1 to its promoter. Similar results were obtained when the ability of the cells to express luciferase from a platinated plasmid was measured. Co-transfection of the reporter with the REV3L overexpression vector or REV3L plus REV7L significantly enhanced the reporter activity. Nuclear condensation and fragmentation of shRNA-REV3L H1299 cells were more pronounced than shRNA-NC H1299 cells after cisplatin exposure, indicating that REV3L overexpression abolished cisplatin-induced DNA damage. Moreover, a forced expression of REV3L conferred the resistance of H1299 cells to cisplatin, whereas the knockdown of REV3L sensitized cisplatin efficacy in H1299 cells. Taken together, we demonstrated that inhibition of REV3L sensitized lung cancer H1299 cells to cisplatin treatment. Thus, REV3L may be a novel target for the chemotherapy of NSCLC.

  9. Mitochondrial fission determines cisplatin sensitivity in tongue squamous cell carcinoma through the BRCA1-miR-593-5p-MFF axis.

    PubMed

    Fan, Song; Liu, Bodu; Sun, Lijuan; Lv, Xiao-bin; Lin, Zhaoyu; Chen, Weixiong; Chen, Weiliang; Tang, Qionglan; Wang, Youyuan; Su, Yuxiong; Jin, Shaowen; Zhang, Daming; Zhong, Jianglong; Li, Yilin; Wen, Bin; Zhang, Zhang; Yang, Pu; Zhou, Bin; Liang, Qixiang; Yu, Xing; Zhu, Yinghua; Hu, Pengnan; Chu, Junjun; Huang, Wei; Feng, Yuhuan; Peng, Hongzhuang; Huang, Qihong; Song, Erwei; Li, Jinsong

    2015-06-20

    Cisplatin has been widely employed as a cornerstone chemotherapy treatment for a wide spectrum of solid neoplasms; increasing tumor responsiveness to cisplatin has been a topic of interest for the past 30 years. Strong evidence has indicated that mitochondrial fission participates in the regulation of apoptosis in many diseases; however, whether mitochondrial fission regulates cisplatin sensitivity remains poorly understood. Here, we show that MFF mediated mitochondrial fission and apoptosis in tongue squamous cell carcinoma (TSCC) cells after cisplatin treatment and that miR-593-5p was downregulated in this process. miR-593-5p attenuated mitochondrial fission and cisplatin sensitivity by targeting the 3' untranslated region sequence of MFF and inhibiting its translation. In exploring the underlying mechanism of miR-593-5p downregulation, we observed that BRCA1 transactivated miR-593-5p expression and attenuated cisplatin sensitivity in vitro. The BRCA1-miR-593-5p-MFF axis also affected cisplatin sensitivity in vivo. Importantly, in a retrospective analysis of multiple centers, we further found that the BRCA1-miR-593-5p-MFF axis was significantly associated with cisplatin sensitivity and the survival of patients with TSCC. Together, our data reveal a model for mitochondrial fission regulation at the transcriptional and post-transcriptional levels; we also reveal a new pathway for BRCA1 in determining cisplatin sensitivity through the mitochondrial fission program.

  10. Custom-designed Laser-based Heating Apparatus for Triggered Release of Cisplatin from Thermosensitive Liposomes with Magnetic Resonance Image Guidance.

    PubMed

    Dou, Yannan N; Weersink, Robert A; Foltz, Warren D; Zheng, Jinzi; Chaudary, Naz; Jaffray, David A; Allen, Christine

    2015-12-13

    Liposomes have been employed as drug delivery systems to target solid tumors through exploitation of the enhanced permeability and retention (EPR) effect resulting in significant reductions in systemic toxicity. Nonetheless, insufficient release of encapsulated drug from liposomes has limited their clinical efficacy. Temperature-sensitive liposomes have been engineered to provide site-specific release of drug in order to overcome the problem of limited tumor drug bioavailability. Our lab has designed and developed a heat-activated thermosensitive liposome formulation of cisplatin (CDDP), known as HTLC, to provide triggered release of CDDP at solid tumors. Heat-activated delivery in vivo was achieved in murine models using a custom-built laser-based heating apparatus that provides a conformal heating pattern at the tumor site as confirmed by MR thermometry (MRT). A fiber optic temperature monitoring device was used to measure the temperature in real-time during the entire heating period with online adjustment of heat delivery by alternating the laser power. Drug delivery was optimized under magnetic resonance (MR) image guidance by co-encapsulation of an MR contrast agent (i.e., gadoteridol) along with CDDP into the thermosensitive liposomes as a means to validate the heating protocol and to assess tumor accumulation. The heating protocol consisted of a preheating period of 5 min prior to administration of HTLC and 20 min heating post-injection. This heating protocol resulted in effective release of the encapsulated agents with the highest MR signal change observed in the heated tumor in comparison to the unheated tumor and muscle. This study demonstrated the successful application of the laser-based heating apparatus for preclinical thermosensitive liposome development and the importance of MR-guided validation of the heating protocol for optimization of drug delivery.

  11. Metronomic chemotherapy

    PubMed Central

    Maiti, Rituparna

    2014-01-01

    Toxic effects and chemoresistance are major hurdles in chemotherapy and to avoid these problems caused by traditional chemotherapeutic regimens, a new modality of drug administration called “metronomic chemotherapy” has emerged. Such regimen involves the frequent administration of conventional chemotherapeutic agents at very low doses to target activated endothelial cells in tumors, the advantages of which include minimal adverse effects and a rare chance of developing acquired drug resistance. Previously it was thought that they act by targeting angiogenesis, but recently additional mechanisms have been discovered which has established metronomic chemotherapy as a type of multi-targeted therapy. The knowledge gained from the preclinical studies of metronomic chemotherapy, along with clinical experience, will help to design better therapeutic protocols against cancer. Detailed pharmacogenomic and pharmacoproteomic studies on tumor endothelial cells and large multi-centered clinical trials, integrating bio-marker analyzes, are needed to investigate and validate the best treatment combinations for each tumor type and patient population. PMID:25210398

  12. Intracavitary chemotherapy

    SciTech Connect

    Markman, M.

    1985-01-01

    Pharmacokinetic modeling has suggested, and clinical investigations have confirmed, that intracavitary drug administration can result in a much greater drug exposure for the cavity into which the agent is instilled compared to the plasma. Both the safety and the efficacy of several agents administered individually or in combination have now been demonstrated. Several malignancies, in particular ovarian carcinoma and malignant mesothelioma, which remain confined to body cavities for much of their natural history, might be most rationally treated by the intracavitary treatment approach. Early clinical trials have demonstrated significant activity of intracavitary chemotherapy in both of these malignancies. Optimal drugs and dosages as well as appropriate scheduling for the various tumors involving body cavities remain to be defined. Whether or not combination intracavitary chemotherapy will significantly improve survival of patients with malignant disease confined to body cavities must await carefully controlled clinical trials comparing this treatment approach to standard systemically administered chemotherapy. 144 references.

  13. Upregulation of miR-21 in cisplatin resistant ovarian cancer via JNK-1/c-Jun pathway.

    PubMed

    Echevarría-Vargas, Ileabett M; Valiyeva, Fatma; Vivas-Mejía, Pablo E

    2014-01-01

    Cisplatin has been the most accepted drug for the treatment of ovarian cancer for almost 40 years. Although the majority of patients with ovarian cancer respond to front-line platinum combination chemotherapy, many patients will develop cisplatin-resistance disease, which is extremely rapid and fatal. Although various mechanisms of cisplatin resistance have been postulated, the key molecules involved in such resistance have not been identified. MiRNAs are endogenously expressed small non-coding RNAs, which are evolutionarily conserved and function as post-transcriptional regulators of gene expression. Dysregulation of miRNAs have been associated with cancer initiation, progression and drug resistance. The oncogenic miRNA-21, one of the best-studied miRNAs, is upregulated in almost all human cancers. However, the regulation of miR-21 in cisplatin resistant ovarian cancer cells has not been assessed. In this study, we measured the miR-21 expression by real-time PCR and found upregulation of miR-21 in cisplatin resistant compared with cisplatin sensitive ovarian cancer cells. Chromatin immunoprecipitation studies demonstrated the association of the c-Jun transcription factor to the pri-mir-21 DNA promoter regions. Blocking the JNK-1, the major activator of c-Jun phosphorylation, reduced the expression of pre-mir-21 and increased the expression of its well-known target gene, PDCD4. Overexpression of miR-21 in cisplatin sensitive cells decreased PDCD4 levels and increased cell proliferation. Finally, targeting miR-21 reduced cell growth, proliferation and invasion of cisplatin resistant ovarian cancer cells. These results suggest that the JNK-1/c-Jun/miR-21 pathway contributes to the cisplatin resistance of ovarian cancer cells and demonstrated that miR-21 is a plausible target to overcome cisplatin resistance.

  14. Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial

    PubMed Central

    Stathopoulos, G. P.; Antoniou, D.; Dimitroulis, J.; Michalopoulou, P.; Bastas, A.; Marosis, K.; Provata, A.; Yiamboudakis, P.; Veldekis, D.; Lolis, N.; Georgatou, N.; Toubis, M.; Pappas, Ch.; Tsoukalas, G.

    2010-01-01

    Background: Liposomal cisplatin is a new formulation developed to reduce the systemic toxicity of cisplatin while simultaneously improving the targeting of the drug to the primary tumor and to metastases by increasing circulation time in the body fluids and tissues. The primary objectives were to determine nephrotoxicity, gastrointestinal side-effects, peripheral neuropathy and hematological toxicity and secondary objectives were to determine the response rate, time to tumor progression (TTP) and survival. Patients and methods: Two hundred and thirty-six chemotherapy-naive patients with inoperable non-small-cell lung cancer were randomly allocated to receive either 200 mg/m2 of liposomal cisplatin and 135 mg/m2 paclitaxel (arm A) or 75 mg/m2 cisplatin and 135 mg/m2 paclitaxel (arm B), once every 2 weeks on an outpatient basis. Two hundred and twenty-nine patients were assessable for toxicity, response rate and survival. Nine treatment cycles were planned. Results: Arm A patients showed statistically significant lower nephrotoxicity, grade 3 and 4 leucopenia, grade 2 and 3 neuropathy, nausea, vomiting and fatigue. There was no significant difference in median and overall survival and TTP between the two arms; median survival was 9 and 10 months in arms A and B, respectively, and TTP was 6.5 and 6 months in arms A and B, respectively. Conclusions: Liposomal cisplatin in combination with paclitaxel has been shown to be much less toxic than the original cisplatin combined with paclitaxel. Nephrotoxicity in particular was negligible after liposomal cisplatin administration. TTP and survival were similar in both treatment arms. PMID:20439345

  15. Death by bleomycin pulmonary toxicity in ovarian dysgerminoma with pathologic complete response to chemotherapy. A case report.

    PubMed

    Calzas Rodríguez, Julia; Carmen Juarez Morales, María Del; Casero, Miguel Angel Racionero

    2016-01-01

    With cisplatin-based chemotherapy, most patients with ovarian dysgerminoma will survive long-term. Bleomycin is an important part of ovarian germ cell tumors (OGCT) treatment, and its dose-limiting toxicity is the development of pulmonary toxicity and it is increased in patients older than 40 years. We report the case of an elderly patient with an unresectable ovarian dysgerminoma who received neoadjuvant chemotherapy and who developed fatal bleomycin pulmonary toxicity (BPT) after surgery. A monitoring of pulmonary function is not routinely recommended for detecting BPT, although together with carefully assessment for symptoms or signs suggestive of pulmonary toxicity is the best way to reduce the risk of BPT. The frequency of pulmonary events in older patients makes us to think about the possibility of either reduce the dose of bleomycin or removing it from the BEP in ovarian GCT.

  16. Cytoreductive surgery and intraperitoneal chemotherapy: an evidence-based review—past, present and future

    PubMed Central

    Dehal, Ahmed; Smith, J. Joshua

    2016-01-01

    Peritoneal carcinomatosis (PC) has historically been considered a terminal condition with merely palliative treatment achieving a survival rate measured in months. Cytoreductive surgery (CyRS) and intraperitoneal chemotherapy (IPC) have emerged as potentially effective regional treatments with the potential for long-term survival in well-selected patients. The fundamentals of CyRS and IPC are patient selection and complete cytoreduction. Since there is now sufficient evidence for the superiority of CyRS and IPC to systemic chemotherapy alone in a highly select group of patients, surgeons and oncologists should be aware of this modality as a potential benefit for patients with PC. The aim of this report is to highlight cancer-specific evidence in the context of ongoing studies regarding the outcome of this treatment. PMID:26941992

  17. MiR-488 inhibits proliferation and cisplatin sensibility in non-small-cell lung cancer (NSCLC) cells by activating the eIF3a-mediated NER signaling pathway

    PubMed Central

    Fang, Chao; Chen, Yi-Xin; Wu, Na-Yiyuan; Yin, Ji-Ye; Li, Xiang-Ping; Huang, Hsuan-Shun; Zhang, Wei; Zhou, Hong-Hao; Liu, Zhao-Qian

    2017-01-01

    Our previous studied indicated that eukaryotic translation initiation factor 3a (eIF3a) increases the sensitive of platinum-based chemotherapy in lung cancer. MiRNAs play an important role in lung carcinogenesis and drug response. In this study, we aimed to identify potential endogenous miRNAs that inhibit eIF3a expression and determine their influence of this inhibition on cisplatin resistance. Using bioinformatics analysis prediction and confirmation with dual-luciferase reporter assays, we found that miRNA-488 inhibited eIF3a expression by directly binding to the 3’UTR of eIF3a. In addition, the overexpression of miRNA-488 inhibited cell migration and invasion in A549 cells, and also inhibited cell proliferation, cell cycle progression by elevated P27 expression. Compared to the parental cell line, A549/cisplatin (DDP) resistant cells exhibited a higher level of miRNA-488. Moreover, we found that miRNA-488 was associated with cisplatin resistance in three NSCLC cells (A549, H1299 and SK-MES-1). The mechanism of miRNA-488 induced cisplatin resistance was that miRNA-488 activated nucleotide excision repair (NER) by increasing the expression of Replication Protein A (RPA) 14 and Xeroderma pigmentosum group C (XPC). In conclusion, our results demonstrated that miRNA-488 is a tumor suppressor miRNA that acts by targeting eIF3a. Moreover, miRNA-488 also participates in eIF3a mediated cisplatin resistance in NSCLC cells. PMID:28074905

  18. Applying quantitative adiposity feature analysis models to predict benefit of bevacizumab-based chemotherapy in ovarian cancer patients

    NASA Astrophysics Data System (ADS)

    Wang, Yunzhi; Qiu, Yuchen; Thai, Theresa; More, Kathleen; Ding, Kai; Liu, Hong; Zheng, Bin

    2016-03-01

    How to rationally identify epithelial ovarian cancer (EOC) patients who will benefit from bevacizumab or other antiangiogenic therapies is a critical issue in EOC treatments. The motivation of this study is to quantitatively measure adiposity features from CT images and investigate the feasibility of predicting potential benefit of EOC patients with or without receiving bevacizumab-based chemotherapy treatment using multivariate statistical models built based on quantitative adiposity image features. A dataset involving CT images from 59 advanced EOC patients were included. Among them, 32 patients received maintenance bevacizumab after primary chemotherapy and the remaining 27 patients did not. We developed a computer-aided detection (CAD) scheme to automatically segment subcutaneous fat areas (VFA) and visceral fat areas (SFA) and then extracted 7 adiposity-related quantitative features. Three multivariate data analysis models (linear regression, logistic regression and Cox proportional hazards regression) were performed respectively to investigate the potential association between the model-generated prediction results and the patients' progression-free survival (PFS) and overall survival (OS). The results show that using all 3 statistical models, a statistically significant association was detected between the model-generated results and both of the two clinical outcomes in the group of patients receiving maintenance bevacizumab (p<0.01), while there were no significant association for both PFS and OS in the group of patients without receiving maintenance bevacizumab. Therefore, this study demonstrated the feasibility of using quantitative adiposity-related CT image features based statistical prediction models to generate a new clinical marker and predict the clinical outcome of EOC patients receiving maintenance bevacizumab-based chemotherapy.

  19. Differences in vanadocene dichloride and cisplatin effect on MOLT-4 leukemia and human peripheral blood mononuclear cells.

    PubMed

    Havelek, Radim; Siman, Pavel; Cmielova, Jana; Stoklasova, Alena; Vavrova, Jirina; Vinklarek, Jaromir; Knizek, Jiri; Rezacova, Martina

    2012-07-01

    Modern chemotherapy is interested in developing new agents with high efficiency of treatment in low-dose medication strategies, lower side toxicity and stronger specificity to the tumor cells. Vanadocene dichloride (VDC) belongs to the group of the most promising metallocene antitumor agents; however, its mechanism of action and cytotoxicity profile are not fully understood. In this paper we assess cytotoxic effects of VDC in comparison to cisplatin using opposite prototype of cells; human peripheral blood mononuclear (PBMCs) cells and human acute lymphoblastic leukemia cell line (MOLT-4). Our findings showed cytotoxic effect of VDC on leukemia cells, but unfortunately on human peripheral blood mononuclear cells as well. VDC induces apoptosis in leukemia cells; the induction is, however, lower than that of cisplatin, and in contrary to cisplatin, VDC does not induce p53 up-regulation. Cytotoxic effect of VDC on leukemia cells is less pronounced than that of cisplatin and more pronounced in PBMCs than in MOLT-4 cells.

  20. Treatment with para-chlorophenylalanine antagonises the emetic response and the serotonin-releasing actions of cisplatin in cancer patients.

    PubMed Central

    Alfieri, A. B.; Cubeddu, L. X.

    1995-01-01

    To test the role of serotonin in chemotherapy-induced nausea and emesis, ten cancer patients were pretreated with the serotonin synthesis inhibitor para-chlorophenylalanine (PCPA). PCPA (2 g 8 hourly for 2 or 3 days prior to cisplatin) reduced the spontaneous urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), inhibited the increase in urinary 5-HIAA induced by cisplatin and markedly attenuated the acute period of nausea and vomiting associated with the cytotoxic drug. These results indicate that gastrointestinal serotonin mediates cisplatin-induced emesis and that the amount of serotonin released by cisplatin is a major factor in determining the severity of the acute period of emesis experienced by the patient. PMID:7533519

  1. Downregulation of ATG14 by EGR1-MIR152 sensitizes ovarian cancer cells to cisplatin-induced apoptosis by inhibiting cyto-protective autophagy.

    PubMed

    He, Jun; Yu, Jing-Jie; Xu, Qing; Wang, Lin; Zheng, Jenny Z; Liu, Ling-Zhi; Jiang, Bing-Hua

    2015-01-01

    Cisplatin is commonly used in ovarian cancer treatment by inducing apoptosis in cancer cells as a result of lethal DNA damage. However, the intrinsic and acquired resistance to cisplatin in cancer cells remains a big challenge for improving overall survival. The cyto-protective functions of autophagy in cancer cells have been suggested as a potential mechanism for chemoresistance. Here, we reported MIR152 as a new autophagy-regulating miRNA that plays a role in cisplatin-resistance. We showed that MIR152 expression was dramatically downregulated in the cisplatin-resistant cell lines A2780/CP70, SKOV3/DDP compared with their respective parental cells, and in ovarian cancer tissues associated with cisplatin-resistance. Overexpression of MIR152 sensitized cisplatin-resistant ovarian cancer cells by reducing cisplatin-induced autophagy, enhancing cisplatin-induced apoptosis and inhibition of cell proliferation. A mouse subcutaneous xenograft tumor model using A2780/CP70 cells with overexpressing MIR152 was established and displayed decreased tumor growth in response to cisplatin. We also identified that ATG14 is a functional target of MIR152 in regulating autophagy inhibition. Furthermore, we found that EGR1 (early growth response 1) regulated the MIR152 gene at the transcriptional level. Ectopic expression of EGR1 enhanced efficacy of chemotherapy in A2780/CP70 cells. More importantly, these findings were relevant to clinical cases. Both EGR1 and MIR152 expression levels were significantly lower in ovarian cancer tissues with high levels of ERCC1 (excision repair cross-complementation group 1), a marker for cisplatin-resistance. Collectively, these data provide insights into novel mechanisms for acquired cisplatin-resistance. Activation of EGR1 and MIR152 may be a useful therapeutic strategy to overcome cisplatin-resistance by preventing cyto-protective autophagy in ovarian cancer.

  2. MiR-129 regulates cisplatin-resistance in human gastric cancer cells by targeting P-gp.

    PubMed

    Lu, Chaojing; Shan, Zhengxiang; Li, Chunguang; Yang, Lixin

    2017-02-01

    Development of multiple drug resistance (MDR) to chemotherapy is the major reason for the failure of gastric cancer (GC) treatment. P-glycoprotein (P-gp), which is encoded by MDR gene 1, as one of the mechanisms responsible for MDR. Mounting evidence has demonstrated that the drug-induced dysregulation of microRNAs (miRNAs) function may mediate MDR in cancer cells. However, the underling mechanisms of miRNA-mediated MDR in GC remain unclear. Here, we found that miR-129 was downregulated in cisplatin-resistant GC tissues/cells. Our results also showed that overexpression of miR-129 decreased cisplatin-resistance in cisplatin-resistant GC cells, and miR-129 knockdown reduced chemosensitivity to cisplatin in cisplatin-sensitive GC cells. Furthermore, miR-129 activated the intrinsic apoptotic pathway via upregulating caspase-9 and caspase-3. Most importantly, we further confirmed that P-gp is the functional target of miR-129 by regulating cisplatin-resistance in GC cells. These results suggested that miR-129 reversed cisplatin-resistance through inhibiting the P-gp expression in GC cells.

  3. Pharmacological Protection From Radiation {+-} Cisplatin-Induced Oral Mucositis

    SciTech Connect

    Cotrim, Ana P.; Yoshikawa, Masanobu; Sunshine, Abraham N.; Zheng Changyu; Sowers, Anastasia L.; Thetford, Angela D.; Cook, John A.; Mitchell, James B.; Baum, Bruce J.

    2012-07-15

    Purpose: To evaluate if two pharmacological agents, Tempol and D-methionine (D-met), are able to prevent oral mucositis in mice after exposure to ionizing radiation {+-} cisplatin. Methods and Materials: Female C3H mice, {approx}8 weeks old, were irradiated with five fractionated doses {+-} cisplatin to induce oral mucositis (lingual ulcers). Just before irradiation and chemotherapy, mice were treated, either alone or in combination, with different doses of Tempol (by intraperitoneal [ip] injection or topically, as an oral gel) and D-met (by gavage). Thereafter, mice were sacrificed and tongues were harvested and stained with a solution of Toluidine Blue. Ulcer size and tongue epithelial thickness were measured. Results: Significant lingual ulcers resulted from 5 Multiplication-Sign 8 Gy radiation fractions, which were enhanced with cisplatin treatment. D-met provided stereospecific partial protection from lingual ulceration after radiation. Tempol, via both routes of administration, provided nearly complete protection from lingual ulceration. D-met plus a suboptimal ip dose of Tempol also provided complete protection. Conclusions: Two fairly simple pharmacological treatments were able to markedly reduce chemoradiation-induced oral mucositis in mice. This proof of concept study suggests that Tempol, alone or in combination with D-met, may be a useful and convenient way to prevent the severe oral mucositis that results from head-and-neck cancer therapy.

  4. Clinical overview on Lipoplatin: a successful liposomal formulation of cisplatin.

    PubMed

    Boulikas, Teni

    2009-08-01

    Nanoparticle formulations for packaging existing drugs have been used to treat cancer. Lipoplatin is a liposomal cisplatin encapsulated into liposome nanoparticles of an average diameter of 110 nm. Lipoplatin has substantially reduced the renal toxicity, peripheral neuropathy, ototoxicity, myelotoxicity as well as nausea/vomiting and asthenia of cisplatin in Phase I, II and III clinical studies with enhanced or similar efficacy to cisplatin. During clinical development, 10- to 200-fold higher accumulation of Lipoplatin in solid tumors compared to adjacent normal tissue was found in patients. Targeting of tumor vasculature by Lipoplatin in animals suggested its antiangiogenesis potential and Lipoplatin was proposed to act like a double-sword: as chemotherapy and an antiangiogenesis drug. Lipoplatin has finished successfully one Phase III non-inferiority clinical study as first-line against NSCLC in its combination with paclitaxel showing statistically significant reduction in nephrotoxicity; two more Phase III studies are in progress, one in NSCLC with gemcitabine also showing noninferiority with reduced toxicity and another in squamous cell carcinoma of the head and neck with 5-fluorouracil. A registrational Phase II/III study against pancreatic cancer is in progress under the orphan drug status granted to Lipoplatin by the European Medicines Agency. Phase II studies are continuing in advanced breast cancer with vinorelbine and gastrointestinal cancers with radiotherapy and 5-fluorouracil. The highlights of the clinical development of Lipoplatin are reviewed.

  5. Chemotherapy-based control of schistosomiasis haematobia. 3. Snail studies monitoring the effect of chemotherapy on transmission in the Msambweni area, Kenya.

    PubMed

    Sturrock, R F; Kinyanjui, H; Thíongo, F W; Tosha, S; Ouma, J H; King, C H; Koech, D; Siongok, T K; Mahmoud, A A

    1990-01-01

    Regular snail sampling was performed at 40 sites, representing the principal snail habitats, during a 4 year chemotherapy programme targetted at school-children in the Msambweni area of the coastal plain of Kenya. Populations of Bulinus africanus group snails, primarily from pools, showed seasonal variations, dropping when sites dried out and rising when they were refilled by the rains. Transmission, judged by the recovery of snails shedding typical fucocercous cercariae, continued throughout the treatment period at very low levels (less than 1% of the snails collected were infected) with peaks in October/November and in January/February after seasonal rains. Spatially, most infected snails were recovered from 2 large pools near the sea, close to the school that responded least well to the initial chemotherapy programme. Later, infected snails were found sporadically in inland pools, rice fields and temporary streams near another school where there was evidence of substantial reinfection as the study progressed. The snail findings are consistent with a reduction but not elimination of transmission associated with the chemotherapy programme.

  6. Antigenotoxic and anticytotoxic effect of camel milk in mice treated with cisplatin

    PubMed Central

    Salwa, M. Quita; Lina, A.F. Kurdi

    2010-01-01

    Camel milk (CM) has good nutritive value, in addition to its antigenotoxic and anticytotoxic effects. Therefore the aim of this investigation was to evaluate the capacity of CM to inhibit the micronucleated polychromatic erythrocytes (MnPCEs) in the bone marrow and improve the mitotic activity produced by cisplatin. Cisplatin is one of the most widely used antineoplastic drugs in the treatment of cancer. The 70 adult male Swiss albino mice were divided into seven groups:Gr. I: treated with distilled water and considered as a control group.Gr. II: treated with camel milk (33 ml/kg, b.w).Gr. III: treated previously with cisplatin (0.5 mg/kg, b.w).Gr. IV: treated with camel milk and followed after 2 h. with cisplatin (33 ml/kg → 0.5 mg/kg, b.w).Gr. V: treated with camel milk and cisplatin at the same time (33 ml/kg + 0.5 mg/kg, b.w).Gr. VI: treated with an acute single dose of cisplatin (2.5 mg/kg, b.w).Gr. VII: treated with camel milk prior and followed with an acute single dose of cisplatin (33 ml/kg → 2.5 mg /kg, b.w). The animals were sacrificed 24 h after cisplatin injection. The pretreatment with CM dose caused a significant decrease (P < 0.001) in the frequency of MnPCEs and increase (P < 0.001) in the mitotic index (MI) induced by cisplatin when compared with the groups treated with cisplatin alone. The possible explanation for the antigenotoxic and anticytotoxic effects observed in the pretreatment with CM is ascribed to its contents. In conclusion, from the findings we suggest that this milk has some antioxidant effect, and the antigenotoxic mechanism of this milk needs to be explored further before their use during cisplatin chemotherapy. PMID:23961073

  7. Effects of Cisplatin in Neuroblastoma Rat Cells: Damage to Cellular Organelles

    PubMed Central

    Santin, Giada; Scietti, Luigi; Veneroni, Paola; Barni, Sergio; Bernocchi, Graziella; Bottone, Maria Grazia

    2012-01-01

    Cisplatin (cisPt) is a chemotherapy agent used as a treatment for several types of cancer. The main cytotoxic effect of cisplatin is generally accepted to be DNA damage. Recently, the mechanism by which cisPt generates the cascade of events involved in the apoptotic process has been demonstrated. In particular it has been shown that some organelles are cisPt target and are involved in cell death. This paper aims to describe the morphological and functional changes of the Golgi apparatus and lysosomes during apoptosis induced in neuronal rat cells (B50) by cisplatin. The results obtained show that the cellular organelles are the target of cisPt, so their damage can induce cell death. PMID:22505928

  8. Bisphenol A and Estradiol are Equipotent in Antagonizing Cisplatin-Induced Cytotoxicity in Breast Cancer Cells

    PubMed Central

    LaPensee, Elizabeth W.; LaPensee, Christopher R.; Fox, Sejal; Schwemberger, Sandy; Afton, Scott; Ben-Jonathan, Nira

    2010-01-01

    Resistance to chemotherapy is a major problem facing breast cancer patients. Cisplatin, a highly effective DNA-damaging drug, has shown only little success in breast cancer treatment. We are reporting that low nanomolar doses of bisphenol A (BPA) or estradiol antagonize cisplatin cytotoxicity in breast cancer cells, with their effects not mediated via classical estrogen receptors. Although both compounds increase the expression of Bcl-2, a Bcl-2 inhibitor completely blocked the protective effects of BPA while only partially affecting those of estradiol. Blockade of BPA and E2 actions should sensitize ER-negative breast tumors to anti-cancer drugs and allow for the inclusion of cisplatin in treatment regimens. PMID:19796866

  9. Sensitizing mucoepidermoid carcinomas to chemotherapy by targeted disruption of cancer stem cells

    PubMed Central

    Martins, Manoela D.; Warner, Kristy A.; Silva, Alan R. S.; Vargas, Pablo A.; Nunes, Fabio D.; Squarize, Cristiane H.; Nör, Jacques E.; Castilho, Rogerio M.

    2016-01-01

    Mucoepidermoid carcinoma (MEC) is the most common malignancy of salivary glands. The response of MEC to chemotherapy is unpredictable, and recent advances in cancer biology suggest the involvement of cancer stem cells (CSCs) in tumor progression and chemoresistance and radioresistance phenotype. We found that histone acetyltransferase inhibitors (HDACi) were capable of disrupting CSCs in MEC. Furthermore, administration of HDACi prior to Cisplatin (two-hit approach) disrupts CSCs and sensitizes tumor cells to Cisplatin. Our findings corroborate to emerging evidence that CSCs play a key role in tumor resistance to chemotherapy, and highlights a pharmacological two-hit approach that disrupts tumor resistance to conventional therapy. PMID:27285758

  10. Oral Chemotherapy: What You Need to Know

    MedlinePlus

    ... How Is Chemotherapy Used to Treat Cancer? How Chemotherapy Drugs Work Getting Chemotherapy Questions to Ask About Chemotherapy Chemotherapy ... How Is Chemotherapy Used to Treat Cancer? How Chemotherapy Drugs Work Getting Chemotherapy Questions to Ask About Chemotherapy Chemotherapy ...

  11. Peptide receptor radionuclide therapy of Merkel cell carcinoma using (177)lutetium-labeled somatostatin analogs in combination with radiosensitizing chemotherapy: a potential novel treatment based on molecular pathology.

    PubMed

    Salavati, Ali; Prasad, Vikas; Schneider, Claus-Peter; Herbst, Rudolf; Baum, Richard Paul

    2012-05-01

    Few studies have been published on the safety and feasibility of synchronous use of peptide receptor radionuclide therapy (PRRNT), as source of internal radiation therapy, in combination with chemotherapy. In this study we reported a 53-year-old man with stage IV Merkel cell carcinoma (MCC), who underwent synchronous internal radiation therapy and chemotherapy. Based on presumable poor prognosis with chemotherapy only, functional similarities of MCC with other neuroendocrine tumors and available evidence of effectiveness and safety of synchronous use of external beam radiation therapy and chemotherapy in treatment of high-risk MCC patients, our interdisciplinary neuroendocrine tumor board recommended him to add PRRNT to his ongoing chemotherapy. He received 2 courses of (177)Lu-DOTATATE(1, 4, 7, 10-Tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid-1-D-Phe1-Tyr3-Thr8-octreotide) in combination with ongoing 8 cycles of liposomal doxorubicin based on standard protocols. Response to therapy was evaluated by (18)F-FDG and (68)gallium-somatostatin-receptor PET/CT. There was an impressive improvement of the clinical symptoms. However, follow-up PET/CT studies showed mixed pattern of response. Synchronous use of PRRNT and radiosensitizing chemotherapy seems safe and feasible in high risk MCC patients, however, further prospective studies and clinical trials are warranted to provide reliable evidence of possible pitfalls and effectiveness of PRRNT and (68)Ga-somatostatin-receptor PET/CT in the management of MCC.

  12. Optimizing Liposomal Cisplatin Efficacy through Membrane Composition Manipulations.

    PubMed

    Zisman, Natalia; Dos Santos, Nancy; Johnstone, Sharon; Tsang, Alan; Bermudes, David; Mayer, Lawrence; Tardi, Paul

    2011-01-01

    The first liposomal formulation of cisplatin to be evaluated clinically was SPI-077. Although the formulation demonstrated enhanced cisplatin tumor accumulation in preclinical models it did not enhance clinical efficacy, possibly due to limited cisplatin release from the formulation localized within the tumor. We have examined a series of liposomal formulations to address the in vivo relationship between cisplatin release rate and formulation efficacy in the P388 murine leukemia model. The base formulation of phosphatidylcholine: phosphatidylglycerol: cholesterol was altered in the C18 and C16 phospholipid content to influence membrane fluidity and thereby impacting drug circulation lifetime and drug retention. Phase transition temperatures (T(m)) ranged from 42-55°C. The high T(m) formulations demonstrated enhanced drug retention properties accompanied by low antitumor activity while the lowest T(m) formulations released the drug too rapidly in the plasma, limiting drug delivery to the tumor which also resulted in low antitumor activity. A formulation composed of DSPC : DPPC : DSPG : Chol; (35 : 35 : 20 : 10) with an intermediate drug release rate and a cisplatin plasma half-life of 8.3 hours showed the greatest antitumor activity. This manuscript highlights the critical role that drug release rates play in the design of an optimized drug delivery vehicle.

  13. Optimizing Liposomal Cisplatin Efficacy through Membrane Composition Manipulations

    PubMed Central

    Zisman, Natalia; Dos Santos, Nancy; Johnstone, Sharon; Tsang, Alan; Bermudes, David; Mayer, Lawrence; Tardi, Paul

    2011-01-01

    The first liposomal formulation of cisplatin to be evaluated clinically was SPI-077. Although the formulation demonstrated enhanced cisplatin tumor accumulation in preclinical models it did not enhance clinical efficacy, possibly due to limited cisplatin release from the formulation localized within the tumor. We have examined a series of liposomal formulations to address the in vivo relationship between cisplatin release rate and formulation efficacy in the P388 murine leukemia model. The base formulation of phosphatidylcholine: phosphatidylglycerol: cholesterol was altered in the C18 and C16 phospholipid content to influence membrane fluidity and thereby impacting drug circulation lifetime and drug retention. Phase transition temperatures (Tm) ranged from 42–55°C. The high Tm formulations demonstrated enhanced drug retention properties accompanied by low antitumor activity while the lowest Tm formulations released the drug too rapidly in the plasma, limiting drug delivery to the tumor which also resulted in low antitumor activity. A formulation composed of DSPC : DPPC : DSPG : Chol; (35 : 35 : 20 : 10) with an intermediate drug release rate and a cisplatin plasma half-life of 8.3 hours showed the greatest antitumor activity. This manuscript highlights the critical role that drug release rates play in the design of an optimized drug delivery vehicle. PMID:22312548

  14. Loss of DNA mismatch repair facilitates reactivation of a reporter plasmid damaged by cisplatin

    PubMed Central

    Cenni, B; Kim, H-K; Bubley, G J; Aebi, S; Fink, D; Teicher, B A; Howell, S B; Christen, R D

    1999-01-01

    In addition to recognizing and repairing mismatched bases in DNA, the mismatch repair (MMR) system also detects cisplatin DNA adducts and loss of MMR results in resistance to cisplatin. A comparison was made of the ability of MMR-proficient and -deficient cells to remove cisplatin adducts from their genome and to reactivate a transiently transfected plasmid that had previously been inactivated by cisplatin to express the firefly luciferase enzyme. MMR deficiency due to loss of hMLH1 function did not change the extent of platinum (Pt) accumulation or kinetics of removal from total cellular DNA. However, MMR-deficient cells, lacking either hMLH1 or hMSH2, generated twofold more luciferase activity from a cisplatin-damaged reporter plasmid than their MMR-proficient counterparts. Thus, detection of the cisplatin adducts by the MMR system reduced the efficiency of reactivation of the damaged luciferase gene compared to cells lacking this detector. The twofold reduction in reactivation efficiency was of the same order of magnitude as the difference in cisplatin sensitivity between the MMR-proficient and -deficient cells. We conclude that although MMR-proficient and -deficient cells remove Pt from their genome at equal rates, the loss of a functional MMR system facilitates the reactivation of a cisplatin-damaged reporter gene. © 1999 Cancer Research Campaign PMID:10360646

  15. Inhibition of Pyruvate Kinase M2 Markedly Reduces Chemoresistance of Advanced Bladder Cancer to Cisplatin

    PubMed Central

    Wang, Xing; Zhang, Fenglin; Wu, Xue-Ru

    2017-01-01

    Chemoresistance to cisplatin is a principal cause of treatment failure and mortality of advanced bladder cancer (BC). The underlying mechanisms remain unclear, which hinders the development of preventive strategies. Recent data indicate that pyruvate kinase M2 (PKM2), a glycolytic enzyme for Warburg effect, is strongly upregulated in BC. This study explores the role of PKM2 in chemoresistance and whether inhibiting PKM2 augments the chemosensitivity to cisplatin and reduces BC growth and progression. We found that Shikonin binds PKM2 and inhibits BC cell survival in a dose-dependent but pyruvate kinase activity-independent manner. Down-regulation of PKM2 by shRNA blunts cellular responses to shikonin but enhances the responses to cisplatin. Shikonin and cisplatin together exhibit significantly greater inhibition of proliferation and apoptosis than when used alone. Induced cisplatin-resistance is strongly associated with PKM2 overexpression, and cisplatin-resistant cells respond sensitively to shikonin. In syngeneic mice, shikonin and cisplatin together, but not as single-agents, markedly reduces BC growth and metastasis. Based on these data, we conclude that PKM2 overexpression is a key mechanism of chemoresistance of advanced BC to cisplatin. Inhibition of PKM2 via RNAi or chemical inhibitors may be a highly effective approach to overcome chemoresistance and improve the outcome of advanced BC. PMID:28378811

  16. Pilot Testing a Web-Based System for the Assessment and Management of Chemotherapy-Induced Peripheral Neuropathy.

    PubMed

    Knoerl, Robert; Dudley, William N; Smith, Gloria; Bridges, Celia; Kanzawa-Lee, Grace; Lavoie Smith, Ellen M

    2017-04-01

    Because numerous barriers hinder the assessment and management of chemotherapy-induced peripheral neuropathy in clinical practice, the Carevive Care Planning System, a novel Web-based platform, was developed to address these barriers. It provides patients an opportunity to report their symptoms before their clinic visit and generates customizable care plans composed of evidence-based management strategies. The purpose of this study was to evaluate patient and provider perspectives of feasibility, usability, acceptability, and satisfaction with the Carevive platform. We used a single-arm, pretest/posttest, prospective design and recruited 25 women with breast cancer who were receiving neurotoxic chemotherapy and six advanced practice providers from an academic hospital. At three consecutive clinical visits, patients reported their neuropathy symptoms on a tablet via the Carevive system. The Diffusion of Innovations Theory served as an overarching evaluation framework. The Carevive platform was feasible to u