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Sample records for cisplatin based chemotherapy

  1. Management of Chemotherapy Induced Nausea and Vomiting in Patients on Multiday Cisplatin Based Combination Chemotherapy.

    PubMed

    Ranganath, Praveen; Einhorn, Lawrence; Albany, Costantine

    2015-01-01

    Introduction of cisplatin based chemotherapy has revolutionized the treatment of germ cell tumors. A common side effect of multiday cisplatin chemotherapy is severe nausea and vomiting. Considerable progress has been made in the control of these side effects since the introduction of cisplatin based chemotherapy in the 1970s. Germ cell tumor which is a model for a curable neoplasm has also turned into an excellent testing ground to develop effective strategies to prevent chemotherapy induced nausea and vomiting (CINV) in multiday cisplatin based regimens. The use of combination of a 5-hydroxytryptamine (HT)3 receptor antagonist, a neurokinin-1 (NK1) antagonist, and dexamethasone has greatly improved our ability to prevent and control acute and delayed CINV. Mechanism and pattern of CINV with multiday chemotherapy may differ from those in single day chemotherapy and therefore efficacy of antiemetic drugs as observed in single day chemotherapy may not be applicable. There are only few randomized clinical trials with special emphasis on multiday chemotherapy. Further studies are essential to determine the efficacy, optimal dose, and duration of the newer agents and combinations in multiday cisplatin based chemotherapy. PMID:26425563

  2. Management of Chemotherapy Induced Nausea and Vomiting in Patients on Multiday Cisplatin Based Combination Chemotherapy

    PubMed Central

    Ranganath, Praveen; Einhorn, Lawrence; Albany, Costantine

    2015-01-01

    Introduction of cisplatin based chemotherapy has revolutionized the treatment of germ cell tumors. A common side effect of multiday cisplatin chemotherapy is severe nausea and vomiting. Considerable progress has been made in the control of these side effects since the introduction of cisplatin based chemotherapy in the 1970s. Germ cell tumor which is a model for a curable neoplasm has also turned into an excellent testing ground to develop effective strategies to prevent chemotherapy induced nausea and vomiting (CINV) in multiday cisplatin based regimens. The use of combination of a 5-hydroxytryptamine (HT)3 receptor antagonist, a neurokinin-1 (NK1) antagonist, and dexamethasone has greatly improved our ability to prevent and control acute and delayed CINV. Mechanism and pattern of CINV with multiday chemotherapy may differ from those in single day chemotherapy and therefore efficacy of antiemetic drugs as observed in single day chemotherapy may not be applicable. There are only few randomized clinical trials with special emphasis on multiday chemotherapy. Further studies are essential to determine the efficacy, optimal dose, and duration of the newer agents and combinations in multiday cisplatin based chemotherapy. PMID:26425563

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

    PubMed

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

    2016-07-01

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

  4. SERPINB1 expression is predictive for sensitivity and outcome of cisplatin-based chemotherapy in melanoma

    PubMed Central

    Willmes, Christoph; Kumar, Rajiv; Becker, Jürgen C.; Fried, Isabella; Rachakonda, P. Sivaramakrishna; Poppe, Lidia M.; Hesbacher, Sonja; Schadendorf, Dirk; Sucker, Antje

    2016-01-01

    Despite of highly effective new therapeutic strategies, chemotherapy still is an important treatment option in metastatic melanoma. Since predictors of chemotherapy response are rare, drugs and regimens are currently chosen arbitrarily. The present study was aimed at the identification of molecular markers predicting the outcome of chemotherapy in melanoma. Tumor biopsies from metastatic lesions were collected from 203 stage IV melanoma patients prior to chemotherapy onset and used for gene expression profiling (n = 6; marker identification set), quantitative real-time PCR (n = 127; validation set 1), and immunohistochemistry on tissue microarrays (n = 70; validation set 2). The results were correlated to the tumors' in-vitro chemosensitivity and to the patients' in-vivo chemotherapy outcome. SERPINB1 was found to correlate to the in-vitro sensitivity to cisplatin-containing chemotherapy regimens (p = 0.005). High SERPINB1 gene expression was associated with favorable tumor response (p = 0.012) and prolonged survival (p = 0.081) under cisplatin-based chemotherapy. High SERPINB1 protein expression in tumor tissue from cisplatin-treated patients was associated with a favorable survival (p = 0.011), and proved as an independent predictor of survival (p = 0.008) by multivariate analysis. We conclude, that SERPINB1 expression, although not functionally involved, is predictive for the outcome of cisplatin-based chemotherapy in melanoma, and thus may be useful to personalize melanoma chemotherapy. PMID:26799424

  5. Angioimmunoblastic lymphadenopathy with dysproteinemia. Complete remission with cisplatin-based chemotherapy.

    PubMed

    Uphouse, W J; Woods, J C

    1987-11-01

    Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is classified as a nonmalignant condition, yet the mortality associated with the disease rivals most malignancies. Although a leading standard text recommends prednisone as initial management, there has been increasing evidence that combination chemotherapy is the best initial treatment. The patient described here achieved a complete remission with cisplatin-based therapy but later died of pneumonia, perhaps because pathogens important in infections in AILD were not covered. Specific recommendations for management are discussed. PMID:2449941

  6. sFas levels increase in response to cisplatin-based chemotherapy in lung cancer patients.

    PubMed

    Ulukaya, Engin; Acilan, Ceyda; Yilmaz, Meryem; Yilmaztepe-Oral, Arzu; Ari, Ferda; Zik, Berrin; Ursavas, Ahmet; Tokullugil, Asuman H

    2010-10-01

    The Fas/Fas Ligand (FasL) system and survivin have counteracting roles in cell survival. Therefore, we explored the role of circulating soluble Fas (sFas) and the tissue levels of Fas and survivin with regard to response to chemotherapy in lung cancer patients. Serum samples from 52 lung cancer patients and 54 control subjects (19 benign lung disease and 35 healthy control subjects) were collected prior to and 24 and 48 h after chemotherapy. sFas was statistically significantly higher in the cancer group than that in the control groups (p < 0.001). Baseline (before chemotherapy) sFas values showed a statistically significant inverse correlation with overall survival (r = -0.599, p < 0.001). There was a significant increase in serum sFas levels 24 h after treatment (p < 0.05). Contrarily, tissue levels of Fas and survivin were not changed following the chemotherapy (p > 0,05). In conclusion, increased sFas may be an indicator of poor outcome in lung cancer patients. However, cisplatin-based chemotherapy may not be effective via neither the Fas/FasL system nor survivin pathway. Indeed, larger sample size is required for further evaluation.

  7. 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.

  8. 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.

  9. Expression of magnesium transporter genes in head and neck cancer patients underwent neoadjuvant cisplatin-based chemotherapy.

    PubMed

    Lin, Yu-Jung; Cheng, Fu-Chou; Chien, Li-Sheng; Lin, Jin-Ching; Jiang, Rong-San; Liu, Shih-An

    2015-10-01

    We aimed to investigate expression of magnesium transporter genes in patients with head and neck cancer who underwent cisplatin-based neoadjuvant chemotherapy and their association with serum magnesium level. Head and neck cancer patients scheduled to undergo neoadjuvant cisplatin-based chemotherapy were eligible for enrollment. Blood samples were obtained at three time points: prior to, during, and after completion of chemotherapy. Expression levels of magnesium transporter genes were determined by quantitative real-time PCR. A total of 23 patients were included in the final analysis. The average serum magnesium levels dropped 6.98 and 5.20% during and after completion of chemotherapy. There were neither significant associations between serum magnesium level and demographic variables nor tumor-related variables. SLC41A1 expression level was positively correlated with serum magnesium whereas TRPM6 expression level was negatively correlated with serum magnesium. Serum magnesium level decreased during cisplatin-based chemotherapy in head and neck cancer patients. Further studies are warranted to investigate optimal magnesium measurement and substitution protocol.

  10. 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.

  11. Sensorineural Hearing Loss after Combined Intensity Modulated Radiation Therapy and Cisplatin-Based Chemotherapy for Nasopharyngeal Carcinoma12

    PubMed Central

    Wang, Jin; Chen, Yuan-Yuan; Tai, An; Chen, Xue-Lin; Huang, Shao-Ming; Yang, Cungen; Bao, Yong; Li, Ning-Wei; Deng, Xiao-Wu; Zhao, Chong; Chen, Ming; Li, X. Allen

    2015-01-01

    PURPOSE: The incidence of sensorineural hearing loss (SNHL) after treatment with combination of intensity-modulated radiation therapy (IMRT) and cisplatin-based chemotherapy in nasopharyngeal carcinoma (NPC) patients was evaluated, and relationships of SNHL with host factors, treatment-related factors, and radiation dosimetric parameters were investigated. METHODS: Fifty-one NPC patients treated with IMRT from 2004 to 2009 were analyzed. All patients received neoadjuvant, concurrent, or adjuvant use of cisplatin. Pure tone audiometry was performed during the follow-up period with a median time of 60 months, ranging from 28 to 84 months. Correlation of SNHL at low frequencies (pure tone average, 0.5-2 kHz) with a series of factors was analyzed. RESULTS: Among 102 ears, 12.7% had low-frequency SNHL and 42.2% had high-frequency (4 kHz) SNHL. The incidence of low-frequency SNHL was greater in patients with age > 40, with T-stage 4, or who received cumulative cisplatin dose (CCD) > 200 mg/m2 (P = .034, .011, and .003, respectively) and in ears with secretory otitis media (SOM) (P = .002). Several dosimetric parameters were found to be correlated with SNHL. Univariate analysis showed that the minimum radiation dose to 0.1 ml highest dose volume (D0.1 ml) of the cochlea was the best radiation-related predictive parameter. Multivariate analysis indicated that CCD, SOM, and D0.1 ml of cochlea (P = .035, .012, and .022, respectively) were the factors associated with SNHL. CONCLUSION: For NPC patients treated with IMRT and chemotherapy, the incidence of treatment-related SNHL was associated with CCD, D0.1 ml of cochlea, and SOM. PMID:26692526

  12. The Cardiac Markers and Oxidative Stress Parameters in Advanced Non-Small Cell Lung Cancer Patients Receiving Cisplatin-Based Chemotherapy

    PubMed Central

    Biatas-Chromiec, Beata; Stelmaszczyk-Emmel, Anna; Radzikowska, Elzbieta; Wiatr, Elzbieta; Radwan-Rohrenschef, Piotr; Szturmowicz, Monika

    2011-01-01

    Introduction: Cardiotoxicity is a well known long-term consequence of lung cancer chemotherapy, however little is known about early subclinical changes in cardiac function. Aim: The goal of the study was to assess early cardiotoxic effects of cisplatin-containing chemotherapy in stage III and IV lung cancer patients, measuring serum levels of selected cardiac markers in relation to oxidant effects. Methods: We quantified the immediate impact of chemotherapy on cardiac troponin T (TnT), creatine kinase-myocardial band (CK-MB) and N- terminal pro-brain natriuretic peptide (NT-proBNP) in blood samples obtained from 12 non-small cell lung cancer (NSCLC) patients. All markers were measured using commercially available immunoassays. To investigate the oxidant effects of cisplatin-containing chemotherapy, we evaluated reduced glutathione (GSH), nitrite (NO2), derivatives of reactive oxygen metabolites (d-ROMs) and thiols (SH). Samples were collected prior to chemotherapy and 1 day after the first cycle of cisplatin administration. Results: Chemotherapy did not cause statistically significant elevations in serum CK-MB. Serum TnT levels were undetectable at both time points in 11 out of 12 patients with a threshold of 0.01 ng/ml. In the single patient with undetectable TnT at the baseline, after the first infusion TnT level reversibly rose to 0.03 ng/ml. The pre-treatment value of NT-proBNP was slightly elevated in 7 out of 12 lung cancer patients. In 1 case NT-proBNP level significantly increased after chemotherapy (from 221.8 to 1489.0 pg/ml p<0.001), in the remaining 11 patients it was stable Cisplatin-based combination chemotherapy induced significant nitrite production in 5 patients (p<0.05). The other measured oxidative stress parameters remained unchanged after the first infusion. Conclusion: This pilot study demonstrated occasional elevations of cardiac biomarkers during cisplatin administration. Administration of cisplatin-containing chemotherapy caused significant

  13. 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.

  14. 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

  15. 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

    2016-01-01

    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. PMID:27598218

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

    PubMed Central

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

    2016-01-01

    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. PMID:27598218

  17. 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

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

    PubMed

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

    1997-01-01

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

  19. [Hypomagnesemia in patients of gynecologic neoplasms following chemotherapy with cisplatin].

    PubMed

    Li, L; Huang, W; Zhu, B

    1995-06-01

    Serum magnesium in 79 patients of gynecologic neoplasms treated with cisplatin and their controls was measured. The results showed: (1) the average value of serum magnesium in patients following chemotherapy with cisplatin was significantly lower than in the controls; (2) the incidence of hypomagnesemia was positively correlated with the number of the courses and the total dosages of chemotherapy, being 52.9% after one to three courses of treatment and 92.0% after more than six courses of treatment; (3) the incidence of hypomagnesemia was directly related with the severity of gastrointestinal disorders; (4) serum magnesium following cisplatin chemotherapy was not correlated with serum blood urea nitrogen (BUN). Hypomagnesemia is clinically characterized by symptoms of the nervous system which are found in 14.0% of hypomagnesemic patients. PMID:7555373

  20. 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.

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

    PubMed Central

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

    2013-01-01

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

  2. HIPEC ROC I: a phase I study of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion followed by postoperative intravenous platinum-based chemotherapy in patients with platinum-sensitive recurrent epithelial ovarian cancer.

    PubMed

    Zivanovic, Oliver; Abramian, Alina; Kullmann, Maximilian; Fuhrmann, Christine; Coch, Christoph; Hoeller, Tobias; Ruehs, Hauke; Keyver-Paik, Mignon Denise; Rudlowski, Christian; Weber, Stefan; Kiefer, Nicholas; Poelcher, Martin L; Thiesler, Thore; Rostamzadeh, Babak; Mallmann, Michael; Schaefer, Nico; Permantier, Maryse; Latten, Sandra; Kalff, Joerg; Thomale, Juergen; Jaehde, Ulrich; Kuhn, Walther C

    2015-02-01

    This phase I study tested the safety, feasibility, pharmacokinetics and pharmacodynamics of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion (HIPEC) in patients with platinum-sensitive recurrent epithelial ovarian cancer (EOC) undergoing secondary cytoreductive surgery followed by postoperative platinum-based intravenous chemotherapy. Twelve patients with operable, recurrent platinum-sensitive EOC (recurrence ≥6 months after first-line therapy) were included according to the classical 3+3 dose-escalation design at three dose levels-60, 80 and 100 mg/m(2). After surgical cytoreduction, a single dose of cisplatin was administered via HIPEC for 90 min at 41-43°C. Postoperatively, all patients were treated with standard intravenous platinum-based combination chemotherapy. One of six patients experienced a dose-limiting toxicity (grade 3 renal toxicity) at a dose of 100 mg/m(2). The remaining five patients treated with 100 mg/m(2) tolerated their treatment well. The recommended phase II dose was established at 100 mg/m(2). The mean peritoneal-to-plasma AUC ratio was 19·5 at the highest dose level. Cisplatin-induced DNA adducts were confirmed in tumor samples. Common postoperative grade 1-3 toxicities included fatigue, postoperative pain, nausea, and surgical site infection. The ability to administer standard intravenous platinum-based chemotherapy after HIPEC was uncompromised. Cisplatin administered as HIPEC at a dose of 100 mg/m(2) has an acceptable safety profile in selected patients undergoing secondary cytoreductive surgery for platinum-sensitive recurrent EOC. Favorable pharmacokinetic and pharmacodynamic properties of HIPEC with cisplatin were confirmed at all dose levels, especially at 100 mg/m(2). The results are encouraging to determine the efficacy of HIPEC as a complementary treatment in patients with EOC. PMID:24895230

  3. Peripheral neuropathy induced by combination chemotherapy of docetaxel and cisplatin.

    PubMed Central

    Hilkens, P. H.; Pronk, L. C.; Verweij, J.; Vecht, C. J.; van Putten, W. L.; van den Bent, M. J.

    1997-01-01

    Docetaxel, a new semisynthetic taxoid that has demonstrated promising activity as an antineoplastic agent, was administered in combination with cisplatin to 63 patients in a dose-escalating study. As both drugs were known to be potentially neurotoxic, peripheral neurotoxicity was prospectively assessed in detail. Neuropathy was evaluated by clinical sum-score for signs and symptoms and by measurement of the vibration perception threshold (VPT). The severity of neuropathy was graded according to the National Cancer Institute's 'Common Toxicity Criteria'. The docetaxel-cisplatin combination chemotherapy induced a predominantly sensory neuropathy in 29 (53%) out of 55 evaluable patients. At cumulative doses of both cisplatin and docetaxel above 200 mg m(-2), 26 (74%) out of 35 patients developed a neuropathy which was mild in 15, moderate in ten and severe in one patient. Significant correlations were present between both the cumulative dose of docetaxel and cisplatin and the post-treatment sum-score of neuropathy (P < 0.01) as well as the post-treatment VPT (P < 0.01). The neurotoxic effects of this combination were more severe than either cisplatin or docetaxel as single agent at similar doses. PMID:9020489

  4. Platinum Concentration and Pathologic Response to Cisplatin-Based Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer

    PubMed Central

    Kilari, Deepak; Xiao, Guang-Qian; Abu-Farsakh, Sohaib H.; Baran, Andrea; Messing, Edward M.; Kim, Eric S.

    2016-01-01

    Background Platinum (Pt)-based chemotherapy is the standard of care for muscle-invasive bladder cancer (MIBC). However, resistance is a major limitation. Reduced intratumoral drug accumulation is an important mechanism of platinum resistance. Our group previously demonstrated a significant correlation between tissue Pt concentration and tumor response to Pt-based neoadjuvant chemotherapy (NAC) in lung cancer. We hypothesized that increased Pt concentration in radical cystectomy (RC) specimens would correlate with improved pathologic response to Pt-based NAC in MIBC. Methods A cohort of 19 clinically annotated, archived, fresh frozen RC specimens from patients with MIBC treated with Pt-based NAC was identified [ypT0 (pathologic complete response, pCR), N = 4; ≤ypT1N0M0 (pathologic partial response, pPR), N = 6; ≥ypT2 (minimal pathologic response/progression), N = 9)]. RC specimens from 2 patients with MIBC who did not receive NAC and 1 treated with a non-Pt containing NAC regimen were used as negative controls. Total Pt concentration in normal adjacent urothelial tissue and bladder tumors from RC specimens was measured by flameless atomic absorption spectrophotometry. Results Total Pt concentration in normal urothelium differed by tumor pathologic response (P = 0.011). Specimens with pCR had the highest Pt concentrations compared to those with pPR (P = 0.0095) or no response/progression (P = 0.020). There was no significant difference in Pt levels in normal urothelium and tumor between pPR and no response/progression groups (P = 0.37; P = 0.25, respectively). Conclusions: Our finding of increased intracellular Pt in RC specimens with pCR following NAC for MIBC compared to those with residual disease suggests that enhanced Pt accumulation may be an important determinant of Pt sensitivity. Factors that modulate intracellular Pt concentration, such as expression of Pt transporters, warrant further investigation as predictive biomarkers of response to Pt-based NAC

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

    PubMed Central

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

    2016-01-01

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

  6. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer

    PubMed Central

    SIDERIS, SPYRIDON; AOUN, FOUAD; ZANATY, MARC; MARTINEZ, NIEVES CHANZA; LATIFYAN, SOFIA; AWADA, AHMAD; GIL, THIERRY

    2016-01-01

    The aim of the present study was to investigate the efficacy of paclitaxel following a first-line cisplatin regimen in patients with metastatic bladder cancer. The present study retrospectively evaluated the clinical effects and toxicities of second-line paclitaxel regimens following first-line cisplatin treatment in metastatic bladder cancer. A total of 42 patients with progressing metastatic urothelial bladder cancer following cisplatin-based chemotherapy were enrolled. The patients received weekly treatment with paclitaxel (80 mg/m2) with a median duration of 3 months. The overall response rate, disease control rate and median progression free survival were 9.5, 45.2 and 6.4 months, respectively. Weekly paclitaxel was well-tolerated with rare grade III or IV toxicities. Second-line weekly paclitaxel treatment following first-line cisplatin-based chemotherapy is an effective and well-tolerated regimen in urothelial metastatic bladder cancer. PMID:27284445

  7. Cisplatin containing chemotherapy influences HLA-DR expression on monocytes from cancer patients.

    PubMed

    Novellino, P S; Trejo, Y G; Beviacqua, M; Bordenave, R H; Rumi, L S

    1999-12-01

    The effect of cisplatin-containing chemotherapy regimen was evaluated on the expression of HLA-DR antigen in peripheral blood monocytes from patients with lung (LCP) and colorectal (CCP) cancer. Chemotherapeutic schedules employed in patients were etoposide and cisplatin for LCP and 5-fluorouracil and cisplatin for CCP. The results obtained showed a diminished percentage of monocytes expressing HLA-DR antigen in LCP (52.4 +/- 2.6, p < 0.004) and CCP (50.1 +/- 2.1, p < 0.001) respectively versus healthy donors (71.0 +/- 1.1%), and that their values increased during chemotherapy, raising them up to control level after the second cycle of treatment, independently of the course of the cancer growth. We conclude that both modalities of treatment allowed an increase of monocytes expressing HLA-DR antigen, suggesting that this effect may be due to cisplatin action. PMID:10746974

  8. Randomized Phase II/III Trial Assessing Gemcitabine/Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients With Advanced Urothelial Cancer Who Are Unfit for Cisplatin-Based Chemotherapy: EORTC Study 30986

    PubMed Central

    De Santis, Maria; Bellmunt, Joaquim; Mead, Graham; Kerst, J. Martijn; Leahy, Michael; Maroto, Pablo; Gil, Thierry; Marreaud, Sandrine; Daugaard, Gedske; Skoneczna, Iwona; Collette, Sandra; Lorent, Julie; de Wit, Ronald; Sylvester, Richard

    2012-01-01

    Purpose This is the first randomized phase II/III trial comparing two carboplatin-based chemotherapy regimens in patients with urothelial cancer who are ineligible (“unfit”) for cisplatin chemotherapy. Patients and Methods The primary objective of the phase III part of this study was to compare the overall survival (OS) of chemotherapy-naive patients with measurable disease and an impaired renal function (glomerular filtration rate < 60 but > 30 mL/min) and/or performance score of 2 who were randomly assigned to receive either gemcitabine/carboplatin (GC) or methotrexate/carboplatin/vinblastine (M-CAVI). To detect an increase of 50% in median survival with GC compared with M-CAVI (13.5 v 9 months) based on a two-sided log-rank test at error rates α = .05 and β = .20, 225 patients were required. Secondary end points were overall response rate (ORR), progression-free survival (PFS), toxicity, and quality of life. Results In all, 238 patients were randomly assigned by 29 institutions over a period of 7 years. The median follow-up was 4.5 years. Best ORRs were 41.2% (36.1% confirmed response) for patients receiving GC versus 30.3% (21.0% confirmed response) for patients receiving M-CAVI (P = .08). Median OS was 9.3 months in the GC arm and 8.1 months in the M-CAVI arm (P = .64). There was no difference in PFS (P = .78) between the two arms. Severe acute toxicity (death, grade 4 thrombocytopenia with bleeding, grade 3 or 4 renal toxicity, neutropenic fever, or mucositis) was observed in 9.3% of patients receiving GC and 21.2% of patients receiving M-CAVI. Conclusion There were no significant differences in efficacy between the two treatment groups. The incidence of severe acute toxicities was higher for those receiving M-CAVI. PMID:22162575

  9. Pemetrexed/cisplatin as first-line chemotherapy for advanced lung cancer with brain metastases

    PubMed Central

    He, Guangzhao; Xiao, Xiaoguang; Zou, Man; Zhang, Chengliang; Xia, Shu

    2016-01-01

    Abstract Background: Brain metastases (BMs) are a common and serious complication of non-small cell lung cancer (NSCLC). Whole-brain radiotherapy (WBRT), surgery, and molecular targeted therapy are usually used to treat NSCLC with BM. Chemotherapeutic options for BM are limited by tumor resistance, ineffective agents, and the blood–brain barrier. Pemetrexed/cisplatin is the preferred chemotherapy in nonsquamous NSCLC, but the efficacy of this treatment for nonsquamous NSCLC with BM is uncertain. Methods: We present a case of nonsquamous NSCLC with asymptomatic BM presenting with irritating cough and right shoulder back pain (unknown sensitizing epidermal growth factor receptor mutations or anaplastic lymphoma kinase). Results: He benefited from administration of first-line chemotherapy of pemetrexed/cisplatin. Partial remission was achieved in the primary lesion of the lungs and BM lesion. He was further given 3 cycles of pemetrexed monotherapy and WBRT. Complete remission was further achieved in BM lesion. Conclusion: The findings of clinical trials and theoretical studies about the current pemetrexed/cisplatin in the treatment of nonsquamous NSCLC with BM are also summarized to provide a reference for the application of pemetrexed/cisplatin in nonsquamous NSCLC with BM. Whether or not pemetrexed/cisplatin is definitely effective in nonsquamous NSCLC with BM must be proven by subsequent phase III clinical trials. PMID:27512852

  10. [A case of metastatic esophageal cancer responding remarkably to combination chemotherapy of TS-1 and cisplatin].

    PubMed

    Iwase, Hiroaki; Okeya, Masayuki; Shimada, Masaaki; Tsuzuki, Tomoyuki; Nakarai, Keiko; Kaida, Shogo; Doi, Reiko

    2004-05-01

    A 51-year-old male patient with esophageal cancer and cervical, thoracic and celiac artery lymph node metastases was treated by combination chemotherapy of TS-1 and cisplatin. TS-1 (80 mg/m2/day) was administered for 14 days followed by 14 days rest as 1 course. Cisplatin (70 mg/m2/day) was administered in 24-hour continuous intravenous infusion at day 8 after the start of TS-1. Before treatment, the tumor marker, CEA showed 27,060 ng/ml. After 5 courses of chemotherapy, endoscopy revealed that the primary tumor had disappeared and no cancer cells were detected by endoscopic biopsy. Chest and abdominal CT scan also showed almost total disappearance of the lymph nodes metastases. CEA decreased to 710 ng/ml. No high-grade toxicities (WHO grade 3 or 4) were seen during the chemotherapy. He is now very well. This TS-1/cisplatin chemotherapy regimen might be a useful treatment for metastatic esophageal cancer.

  11. 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.

  12. 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

  13. Overcoming tumor resistance to cisplatin through micelle-mediated combination chemotherapy.

    PubMed

    Zhou, Dongfang; Cong, Yuwei; Qi, Yanxin; He, Shasha; Xiong, Hejian; Wu, Yanjuan; Xie, Zhigang; Chen, Xuesi; Jing, Xiabin; Huang, Yubin

    2015-01-01

    The main obstacles to cancer therapy are the inability to target cancer cells and the acquired drug resistance after a period of chemotherapy. Reduced drug uptake and DNA repair are the two main mechanisms involved in cisplatin resistance. In the present investigation, canthaplatin, a Pt(iv) pro-drug of cisplatin and a protein phosphatase 2A (PP2A) inhibitor (4-(3-carboxy-7-oxa-bicyclo[2.2.1]heptane-2-carbonyl)piperazine-1-carboxylic acid tert-butyl ester), was designed and delivered using PEG-b-PLGA micelles for combination chemotherapy. Polymer/canthaplatin micelles facilitated the delivery of the drug into cancer cells through endocytosis and diminished DNA repair by PP2A inhibition, resulting in enhanced anti-tumor efficiency and excellent reversal ability of tumor resistance to cisplatin both in vitro and in vivo. Additionally, the polymer/canthaplatin micelles could prolong drug residence in the blood and decrease the side effects when compared to cisplatin.

  14. Preoperative docetaxel/cisplatin/5-fluorouracil chemotherapy in patients with locally advanced gastro-esophageal adenocarcinoma.

    PubMed

    Bayraktar, Ulas Darda; Bayraktar, Soley; Hosein, Peter; Chen, Emerson; Koniaris, Leonidas G; Rocha-Lima, Caio Max S; Montero, Alberto J

    2012-09-01

    Perioperative chemotherapy plus surgery improves survival compared to surgery alone in GE junctional (GEJ) and gastric adenocarcinomas. The docetaxel/cisplatin/5-fluorouracil (DCF) combination is superior to CF in patients with metastatic gastric cancer. We retrospectively evaluated the safety and efficacy of preoperative DCF chemotherapy in patients with locally advanced gastric and GEJ cancer. Twenty-one gastric and 10 gastroesophageal junctional (GEJ) cancer patients received 2-3 cycles of preoperative docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) on day 1, 5-FU 750 mg/m(2) (continuous infusion) on days 1-5 every 3 weeks. Clinical response was evaluated by comparing pre- and postchemotherapy CT scans. Overall survival (OS) and progression-free survival (PFS) were calculated from the initiation of chemotherapy. None of the patients achieved complete clinical remission while 11 (35%) patients achieved partial clinical remission. Ten patients with GEJ cancer (100%) and 13 with gastric cancer (62%) underwent curative surgery (P = 0.023). Seventeen (55%) patients experienced grade 3-4 chemotherapy-related adverse events. The most common adverse events were anemia, nausea/vomiting, diarrhea, and febrile neutropenia. At a median follow-up of 17.0 months, median OS and PFS were 26.1 months (95% CI: 22.7-29.5) and 18.8 months (95% CI: 9.9-27.7), respectively. The DCF regimen is active in patients with gastric and GEJ adenocarcinoma in the preoperative setting.

  15. Synergism between propolis and hyperthermal intraperitoneal chemotherapy with cisplatin on ehrlich ascites tumor in mice.

    PubMed

    Oršolić, Nada; Car, Nikola; Lisičić, Duje; Benković, Vesna; Knežević, Anica Horvat; Dikić, Domagoj; Petrik, József

    2013-12-01

    We investigated antitumor, genotoxic, chemopreventive, and immunostimulative effects of local chemoimmunotherapy and hyperthermal intraperitoneal chemotherapy (HIPEC) in a mouse-bearing Ehrlich ascites tumor (EAT). Mice were treated with water-soluble derivative of propolis (WSDP) at a dose of 50 mg kg(-1) , 7 and 3 days before implantation of EAT cells, whereas cisplatin (5 or 10 mg kg(-1) ) was injected 3 days after implantation of EAT cells at 37°C and 43°C. The following variables were analyzed: the total number of cells, differential count of the cells present in the peritoneal cavity, functional activity of macrophages, comet assay, and micronucleus assay. The combination of WSDP + CIS 5 mg kg(-1) at 37°C resulted in tumor growth inhibition and increased the survival of mice by additional 115.25%. WSDP with HIPEC increased the survival of mice by additional 160.3% as compared with HIPEC. WSDP reduced cisplatin toxic and genotoxic effect to normal cells without affecting cisplatin cytotoxicity on EAT cells. In addition, WSDP with HIPEC increased the cytotoxic actions of macrophages to tumor cells. Water-soluble derivative of propolis increases macrophage activity and sensitivity of tumor cells to HIPEC and reduces cisplatin toxicity to normal cells.

  16. Evaluation of cisplatin plasma levels in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

    PubMed

    Fleres, Francesco; Saladino, Edoardo; Catanoso, Rosaria; Arcoraci, Vincenzo; Mandolfino, Tommaso; Cucinotta, Eugenio; Macrì, Antonio

    2016-02-01

    Introduction Peritoneal surface malignancies have long been regarded as incurable, however, they can be treated with cytoreductive surgery in addition to hyperthermic intraperitoneal chemotherapy. This approach is associated with an increase in morbidity and mortality, unless hyperhydration is provided in a timely manner. Methods Cisplatin (CDDP) is the most widely used chemotherapeutic agent. Plasma levels of cisplatin (CDDP), a widely used chemotherapeutic agent, were measured before, during, and after the procedure. This was done in order to identify the window of highest risk as a function of drug concentrations, assuming a dose-dependent effect. Results Plasma levels of CDDP peak during perfusion. The concentration remains high until the 4th post-operative day and returns to pre-operative levels by the 7th post-operative day. Conclusions Our findings suggest that ensuring hyperhydration as well as infusing albumin and fresh frozen plasma may be of particular value for at least the first 4 days after the procedure. PMID:27385136

  17. 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. PMID:27138804

  18. 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.

  19. Randomized Phase II/III Trial Assessing Gemcitabine/ Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients With Advanced Urothelial Cancer “Unfit” for Cisplatin-Based Chemotherapy: Phase II—Results of EORTC Study 30986

    PubMed Central

    De Santis, Maria; Bellmunt, Joaquim; Mead, Graham; Kerst, J. Martijn; Leahy, Michael; Maroto, Pablo; Skoneczna, Iwona; Marreaud, Sandrine; de Wit, Ronald; Sylvester, Richard

    2009-01-01

    Purpose There is no standard treatment for patients with advanced urothelial cancer who are ineligible (“unfit”) for cisplatin-based chemotherapy (CHT). To compare the activity and safety of two CHT combinations in this patient group, a randomized phase II/III trial was conducted by the EORTC (European Organisation for Research and Treatment of Cancer). We report here the phase II results of the study. Patients and Methods CHT-naïve patients with measurable disease and impaired renal function (30 mL/min < glomerular filtration rate [GFR] < 60 mL/min) and/or performance status (PS) 2 were randomly assigned to receive either GC (gemcitabine 1,000 mg/m2 on days 1 and 8 and carboplatin area under the serum concentration-time curve [AUC] 4.5) for 21 days or M-CAVI (methotrexate 30 mg/m2 on days 1, 15, and 22; carboplatin AUC 4.5 on day 1; and vinblastine 3 mg/m2 on days 1, 15, and 22) for 28 days. End points of response and severe acute toxicity (SAT) were evaluated with respect to treatment group, renal function, PS, and Bajorin risk groups. Results Three of 178 patients who were ineligible or did not start treatment were excluded. SAT was reported in 13.6% of patients on GC and in 23% on M-CAVI. Overall response rates were 42% (37 of 88) for GC and 30% (26 of 87) for M-CAVI. Patients with PS 2 and GFR less than 60 mL/min and patients in Bajorin risk group 2 showed a response rate of only 26% and 20% and an SAT rate of 26% and 25%, respectively. Conclusion Both combinations are active in this group of unfit patients. However, patients with PS 2 and GFR less than 60 mL/min do not benefit from combination CHT. Alternative treatment modalities should be sought in this subgroup of poor-risk patients. PMID:19786668

  20. Role of the human high-affinity copper transporter in copper homeostasis regulation and cisplatin sensitivity in cancer chemotherapy.

    PubMed

    Kuo, Macus Tien; Fu, Siqing; Savaraj, Niramol; Chen, Helen H W

    2012-09-15

    The high-affinity copper transporter (Ctr1; SCLC31A1) plays an important role in regulating copper homeostasis because copper is an essential micronutrient and copper deficiency is detrimental to many important cellular functions, but excess copper is toxic. Recent research has revealed that human copper homeostasis is tightly controlled by interregulatory circuitry involving copper, Sp1, and human (hCtr1). This circuitry uses Sp1 transcription factor as a copper sensor in modulating hCtr1 expression, which in turn controls cellular copper and Sp1 levels in a 3-way mutual regulatory loop. Posttranslational regulation of hCtr1 expression by copper stresses has also been described in the literature. Because hCtr1 can also transport platinum drugs, this finding underscores the important role of hCtr1 in platinum-drug sensitivity in cancer chemotherapy. Consistent with this notion is the finding that elevated hCtr1 expression was associated with favorable treatment outcomes in cisplatin-based cancer chemotherapy. Moreover, cultured cell studies showed that elevated hCtr1 expression can be induced by depleting cellular copper levels, resulting in enhanced cisplatin uptake and its cell-killing activity. A phase I clinical trial using a combination of trientine (a copper chelator) and carboplatin has been carried out with encouraging results. This review discusses new insights into the role of hCtr1 in regulating copper homeostasis and explains how modulating cellular copper availability could influence treatment efficacy in platinum-based cancer chemotherapy through hCtr1 regulation.

  1. [Transarterial infusion chemotherapy using fine-powder cisplatin in patients with advanced hepatocellular carcinoma].

    PubMed

    Hatanaka, Takeshi; Kakizaki, Satoru; Ueno, Takashi; Takeuchi, Suguru; Takizawa, Daichi; Katakai, Kenji

    2014-02-01

    We investigated the therapeutic effects and safety of fine powder cisplatin for patients with advanced hepatocellular carcinoma( HCC). From January 2006 to March 2012, 123 patients with advanced HCC were treated by transarterial infusion chemotherapy(TAI)with fine-powder cisplatin(IA-call®, Nippon Kayaku Co. Ltd., Tokyo, Japan). The drug was infused into the liver through the feeding artery at a dose of 65 mg/m2. The treatment was repeated every 4 to 8 weeks until evidence of either tumor progression or unacceptable toxicity appeared. Treatment responses were classified as complete response(CR), partial response(PR), stable disease(SD), and progressive disease(PD)in 3.2%, 12.0%, 32.2%, and 52.4% of patients, respectively. The median survival durations were as follows: overall, 12.2 months; CR/PR patients, 23.8 months; and SD/PD patients, 10.6 months. The cumulative survival rates of CR/PR patients were significantly higher than those of SD/PD patients (p<0.05). Multivariate analyses revealed that treatment response, etiology, Child-Pugh grading, and level of protein induced by the vitamin K antagonist- II (PIVKA- II )were predictive factors of survival duration. Problematic adverse events were not observed in any of the patients. Our results suggest that TAI using fine-powder cisplatin can be safely administered for advanced HCC and can improve the prognosis of patients with advanced disease. PMID:24743198

  2. [Hepatic Resection of Multiple Liver Metastases from Gastric Cancer after Molecular Targeted Chemotherapy(S-1 plus Cisplatin plus Trastuzumab)].

    PubMed

    Kim, Yongkook; Hosoda, Yohei; Nishino, Masaya; Okano, Miho; Kawada, Junji; Yamasaki, Masaru; Nagai, Ken-ichi; Yasui, Masayosi; Okuyama, Masaki; Tsujinaka, Toshimasa

    2015-11-01

    A 62-year-old man was diagnosed with gastric cancer and underwent distal gastrectomy, and D1+b lymph node dissection. He was diagnosed postoperatively with T1b (sm2) N0M0, StageⅠA gastric adenocarcinoma and did not receive any adjuvant chemotherapy after surgery. One year and 6 months after gastrectomy, blood analysis indicated high levels of carcinoembryonic antigen (CEA 262.1 ng/mL) while abdominal computed tomography (CT) revealed multiple liver tumors (S7: 15 mm, S7/8: 20 mm). The patient was diagnosed with metachronous multiple liver metastases from gastric cancer. Chemotherapy, combined with molecular targeted therapy (S-1 plus cisplatin [CDDP] plus trastuzumab), was administered because of overexpression of the human epidermal growth factor receptor 2 (HER2) protein in the primary tumor as assessed by immunohistochemistry, the CEA levels decreased immediately after 2 cycles of the chemotherapy, and the liver metastases shrank markedly with no evidence of new lesions on abdominal CT. However, after treatment, Grade 3 neutropenia and diarrhea were observed. Chemotherapy was suspended and hepatic resection was performed. After hepatic resection, the liver tumors were histologically evaluated as Grade 2 metastatic gastric adenocarcinoma, and the HER2 expression of remnant carcinoma cells was established. The patient has been in good health and remained free of recurrences in the 2 years and 3 months after the liver resection. Surgery with preoperative chemotherapy (S-1 plus CDDP plus trastuzumab) can be an effective treatment for liver metastasis from HER2-positive gastric cancer. PMID:26805121

  3. 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.

  4. Prospective Pilot Study of Consolidation Chemotherapy With Docetaxel and Cisplatin After Concurrent Chemoradiotherapy for Advanced Head and Neck Cancer

    SciTech Connect

    Lee, Kyun Chan; Lee, Seok Ho; Lee, Yuna; Park, Se Hoon Park, Jinny; Cho, Eun Kyung; Shin, Dong Bok; Lee, Jae Hoon; Kim, Dong Young; Kim, Seon Tae

    2008-05-01

    Purpose: With the improvement concurrent chemoradiotherapy (CCRT) in the management of patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC), distant failures have become a more relevant problem in terms of survival. The primary objective of this Phase II study is to assess the feasibility of docetaxel and cisplatin consolidation after primary CCRT for patients with HNSCC. Methods and Materials: Patients with locoregionally advanced HNSCC received chemotherapy with three cycles of cisplatin, 100 mg/m{sup 2}, on Days 1, 22, and 43. Concurrent radiotherapy to the primary tumor and neck was given in a daily dose of 2 Gy to a total dose of 70-70.2 Gy over 7 weeks. After completion of CCRT, patients without evidence of disease progression received an additional four cycles of consolidation chemotherapy with docetaxel, 75 mg/m{sup 2}, and cisplatin, 75 mg/m{sup 2}, every 3 weeks. Results: Of 33 patients, 27 (81%) completed CCRT. After CCRT, three complete and 19 partial responses were recorded, giving an overall response rate of 67%. Of 19 patients who went to the consolidation phase, only 4 (21%) received all four cycles of docetaxel and cisplatin. Causes of failure of consolidation chemotherapy were toxicity in 11 patients, including three treatment-related deaths, and progression in 4 patients. Three patients died of sepsis during the consolidation phase. Median survival was 11 months for all patients and 8 months for those treated with consolidation chemotherapy. Conclusion: The poor compliance and high incidence of severe toxicities prompted no further evaluation of this consolidation chemotherapy after CCRT.

  5. [Clinical evaluation of M-VAC (methotrexate, vinblastine, adriamycin and cisplatin) chemotherapy for advanced urothelial cancer].

    PubMed

    Mikami, K; Nakagawa, S; Takada, H; Ebisui, K; Sugimoto, K; Watanabe, H; Maegawa, M; Nakao, M

    1994-04-01

    M-VAC (methotrexate, vinblastine, adriamycin and cisplatin) chemotherapy was performed on 27 patients with advanced urothelial cancer. The patients included 20 with bladder cancer, 4 with upper urinary tract cancer and 3 with both lesions. Complete response (CR) was observed in 2 (7.4 +/- 9.9%) patients and partial response (PR) in 10 (37.0 +/- 18.2%) patients after the treatment, i.e., the overall objective response rate was 44.4 +/- 18.7%. The rate of relapse or recurrence in the patients with CR and PR was 100% and 90.0%, respectively. The mean duration of the response was 18.5 +/- 13.4 months and 10.7 +/- 10.9 months for CR and PR, respectively. The overall survival rate after one year was 30.2%. Bone marrow suppression was the most serious side effect. The white blood cell count became below 1,000/microliters in 10 patients (36.7%). Among them, 4 patients suffered from sepsis. In conclusion, M-VAC chemotherapy was effective for induction therapy against advanced urothelial cancer, although the effective duration was short. Further maintenance therapy should be established.

  6. Stevens-Johnson Syndrome Patient Received Combination Chemotherapy Gemcitabine, Cisplatin, and 5-FU for Biliary Tract Cancer

    PubMed Central

    Aznab, Mozaffar; Khazaei, Mansour

    2016-01-01

    Stevens-Johnson syndrome has been an acute, usually self-limiting disease of the skin and mucous membranes. This case report has presented an evidence of the development Stevens - Johnson syndrome associated with combination chemotherapy administration of 5FU, gemcitabin and cisplatin in a patient with biliary tract cancer. Our case was a 54-year-old woman patient, a case of biliary tract cancer who has developed more severe symptoms of Stevens-Johnson syndrome. Diagnosis has confirmed by skin biopsy of an affected area .The patient has improved with supportive care, and during 25 day occurred recovery. Although Stevens-Johnson syndrome has been a rare toxicity, physicians should pay a special attention to the monitoring of biliary tract cancer patients on combination chemotherapy with 5FU, cisplatin and gemcitabin.

  7. Combination of Cisplatin, Ifosfamide, and Adriamycin as Neoadjuvant Chemotherapy for Extremity Soft Tissue Sarcoma: A Report of Twenty-Eight Patients.

    PubMed

    Wang, Bing; Yu, Xiuchun; Xu, Songfeng; Xu, Ming

    2016-01-01

    To investigate the clinical efficacy of neoadjuvant chemotherapy in the treatment of extremity soft tissue sarcomas (STSs). We retrospectively analyzed 28 patients with extremity STS that received 2 cycles of preoperative and 6 cycles of postoperative neoadjuvant chemotherapy between May 2009 and June 2012. Chemotherapy comprised intravenous cisplatin (DDP) (120  mg/m(2), for 1 day), followed 1 week later with 5 days 2  g/m(2) ifosfamide (IFO) and 3 days 30  mg/m(2) adriamycin (ADM). CT scans of the lungs and X-ray films of the lesion sites were reviewed. Eighteen patients were treated for primary tumor and 10 for tumor recurrence. Overall tumor diameter ranged from 8 to 30  cm based on body surface measurement. A total of 224 cycles of chemotherapy were carried out and patients were followed up for 12 to 59 months. Twenty-five patients underwent wide resection surgery (89.2%), and 3 underwent amputation (10.7%). Disease-free survival was realized in 20 patients and 3 patients survived with tumors. Two-year disease-free survival rate was 71.4%, and overall 2-year survival rate was 82.1%. Postoperative metastases were observed in 5 patients, and all died of lung metastases. Postoperative recurrence was observed in 4 patients (including 1 patient occurred metastases later). Tumor size was reduced by 30% ± 11.3% on average after the preoperative chemotherapy, and was reduced by 43% ± 7.8% in 22 patients with tumors >15  cm in the diameter. Twelve patients achieved partial remission, 14 stable disease and 2 experienced progressive disease. Objective response rate was 42.9%. Disease control rate was 92.9%. Chemotherapy was well tolerated in all the patients. Main adverse reactions were transient and resolved after chemotherapy. Neoadjuvant chemotherapy is effective in the treatment of extremity STS. PMID:26825914

  8. Renal Medullary Carcinoma: Case Report of an Aggressive Malignancy with Near-Complete Response to Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin Chemotherapy

    PubMed Central

    Amjad, Ali Imran; Ali, Hira; Appleman, Leonard J.; Parwani, Anil; Dhir, Rajiv; Roy, Somak; Parikh, Rahul A.

    2014-01-01

    Renal medullary carcinoma (RMC) is a rare but aggressive malignancy affecting young individuals with sickle cell trait. Renal medullary carcinoma commonly presents with advanced or metastatic disease and is associated with a rapidly progressive clinical course and an extremely short overall survival measured in weeks to few months. Due to the rarity of RMC, there is no proven effective therapy and patients are often treated with platinum-based chemotherapy. We report near-complete radiological and pathological response in a patient treated with dose-dense MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) chemotherapy. The patient underwent consolidation nephrectomy and retroperitoneal lymph node dissection and had a 16-month progression-free survival, one of the longest reported in patients with RMC. PMID:25215253

  9. [Clinical results of combination chemotherapy with cisplatin, vinblastine and bleomycin (pvb) for advanced testicular cancer: evaluation of risk criteria].

    PubMed

    Mikami, K; Nakagawa, S; Sugimoto, K; Nomoto, T; Urano, S; Watanabe, H; Iwamoto, N; Yamazaki, S; Hiratake, Y; Maegawa, M

    1997-08-01

    Between 1982 and 1991, 24 patients with advanced testicular germ cell tumor were treated by combination chemotherapy with cisplatin, vinblastine and bleomycin (PVB). Based on short-term efficacy of the PVB regimen and long-term prognosis in our patients, we evaluated 4 risk criteria proposed by Indiana University, National Cancer Institute (NCI), Memorial Sloan-Kettering Cancer Center (MSKCC) and European Organization for Research and Treatment of Cancer (EORTC). Clinical staging were IIA in 8 patients, IIB in 8, IIIA in 1, IIIB in 5 and IIIC in 2. Metastases included retroperitoneal lymph node in 20 cases (> 5 cm in 10), lung in 6, bone and liver in each 1. Complete response (CR) was obtained in 12 (50%) patients and partial response (PR) in 9 (38%). According to the stage and metastatic site, CR was achieved in 75%, 38% and 38%of the stage IIA, IIB and III tumors, respectively, and in 60% and 50% of retroperitoneal and pulmonary metastases, respectively. However, neither CR nor PR was recognized for live and bone metastases. Prognosis was assessed with a mean followup period of 88.5 months. Although all 12 patients with CR were alive, 4 of the 9 with PR and all patients on whom the drug was ineffective died of cancer. Accuracy in predicting prognosis was 82%, 75%, 74%, and 63% using the MSKCC, Indiana, NCI and EORTC risk criteria, respectively.

  10. [A case report-highly advanced gastric cancer leading to perforation during neoadjuvant chemotherapy with docetaxel, cisplatin and S-1].

    PubMed

    Mihara, Koki; Egawa, Tomohisa; Kemmochi, Takeshi; Irino, Tomoyuki; Okamura, Akihiko; Inaba, Yusaku; Eto, Eiichi; Segami, Kenki; Ito, Yasuhiro; Hayashi, Shinobu; Nagashima, Atsushi

    2011-11-01

    A 70-year-old man was found to have advanced gastric cancer with a deep ulcer and multiple lymph-node metastases. Although the tumor was resectable, we predicted that the patient would have a poor outcome. We therefore administered neoadjuvant chemotherapy with docetaxel, cisplatin, and S-1 to improve the prognosis before curative resection. On day 15 of chemotherapy, sudden abdominal pain occurred, and we performed an emergency surgery for a diagnosis of panperitonitis due to gastric cancer perforation. The defect in the gastric wall was about 2 cm in diameter and was located in the anterior wall of the antrum, consistent with the center of the tumor. The operative findings suggested that the perforation was caused by chemotherapy-induced necrosis of gastric cancer cells. We saved the patient's life, but intensive care with high-dose catecholamine therapy was needed for several days after the surgery. Gastric cancer perforation induced by neoadjuvant chemotherapy appeared to be more severe than perforation caused by other factors. The adverse effects of chemotherapy apparently increased the severity. Our findings suggest that the risk of gastric cancer perforation should be borne in mind when we administer neoadjuvant chemotherapy to patients who have advanced gastric cancer with a deep ulcer.

  11. Phenytoin toxicity in a patient receiving concomitant use of phenytoin and S-1 plus cisplatin chemotherapy for advanced gastric cancer.

    PubMed

    Mimatsu, Kenji; Oida, Takatsugu; Kawasaki, Atsushi; Kida, Kazutoshi; Fukino, Nobutada; Kuboi, Youichi; Kano, Hisao; Amano, Sadao

    2011-06-01

    A 61-year-old man had been receiving phenytoin(225mg/day)and valproate(600mg/day)for several years as the treatment for seizures. He was diagnosed with advanced gastric cancer,and S-1 plus cisplatin treatment was administered as neoadjuvant chemotherapy because bulky lymph node metastases were found at the time of the initial diagnosis. He complained of weakness of the lower extremities,light -headedness,and trembling of the upper extremities 2 months after the start of concomitant treatment with S-1 plus cisplatin. The serum phenytoin concentration increased to 21. 2mg/mL. Head computed tomography and magnetic resonance imaging did not reveal any intracranial lesion such as brain metastasis. Therefore, we diagnosed phenytoin toxicity due to concomitant use of S-1 and phenytoin,and the dose of phenytoin was then decreased to 150 mg. Although the weakness of the lower extremities improved,light -headedness remained. Phenytoin and valproate treatments were stopped,and he was able to walk 7 days after the termination of therapy. It is important to predict the timing of phenytoin toxicity due to S-1,and therapeutic drug monitoring should be performed in patients receiving S-1 plus cisplatin and phenytoin. PMID:21677496

  12. 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.

  13. Impact of the radiotherapy combined with cisplatin plus paclitaxel chemotherapy on the immunologic functions in the patients with esophageal cancer.

    PubMed

    Liu, Ru; Zhang, Jianlong; He, Chunyu; Jiang, Qiong; Liu, Jinsong; Fan, Ruitai

    2016-07-01

    To study the impact of radiotherapy combined with cisplatin plus paclitaxel chemotherapy on the immunologic functions in the patients with esophageal cancer, from July 2012 to September 2014, 82 patients of esophageal cancer which were receiving treatment in our hospital chose out for this research. Among them, 42 patients received radiotherapy only, as the control group; while the other 40 patients with concurrent cisplatin plus paclitaxel chemo radiotherapy was taken as the observation group. Then the immunologic functions, toxic and side effects were compared between the two groups as well as the survival rates after 3-year-followup-visit, Th level of the total T cells, Th cells and the ratio of Th cells to Ts cells after receiving treatment all increased significantly compared with prior treatment. And the difference was statistically significant (P<0.05). After the treatment, the level of T cells, Th cells and the ratio of Th cells to Ts cells of the observation group were all significantly lower than the control group, and the difference was statistically significant (P<0.05). While the difference of the ratio of Ts cells to natural killer cells (NK cells) between the two groups were not significant. The toxic and side effects were mainly myelosuppression, decrease leukocyte, esophagit, nausea and vomiting, and it was not statistically significant in the difference between the two groups (P >0.05), the survival rates from the first year to the third year in the observation group were respectively significantly higher than the control group, and the difference was statistically significant (P<0.05). Radiotherapy combined with cisplatin plus paclitaxel chemotherapy could properly increase the immunologic functions in patients with esophageal cancer, benefiting for the survival rate with a good security. Therefore, it was worth promoting. PMID:27592476

  14. 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.

  15. Persistence of cisplatin-induced mutagenicity in hematopoietic stem cells: implications for secondary cancer risk following chemotherapy.

    PubMed

    Dertinger, Stephen D; Avlasevich, Svetlana L; Torous, Dorothea K; Bemis, Jeffrey C; Phonethepswath, Souk; Labash, Carson; Carlson, Kristine; Mereness, Jared; Cottom, John; Palis, James; MacGregor, James T

    2014-08-01

    Cisplatin is a cytostatic agent used in the treatment of many types of cancer, but its use is associated with increased incidences of secondary leukemia. We evaluated cisplatin's in vivo genotoxic potential by analyzing peripheral blood for Pig-a mutant phenotype erythrocytes and for chromosomal damage in the form of micronuclei. Mutant phenotype reticuloyte and erythrocyte frequencies, based on anti-CD59 antibody labeling and flow cytometric analysis, were determined in male Sprague Dawley rats treated for 28 consecutive days (days 1-28) with up to 0.4 mg cisplatin/kg/day, and sampled on days -4, 15, 29, and 56. Vehicle and highest dose groups were evaluated at additional time points post-treatment up to 6 months. Day 4 and 29 blood samples were also analyzed for micronucleated reticulocyte frequency using flow cytometry and anti-CD71-based labeling. Mutant phenotype reticulocytes were significantly elevated at doses ≥0.1 mg/kg/day, and mutant phenotype erythrocytes were elevated at doses ≥0.05 mg/kg/day. In the 0.4 mg/kg/day group, these effects persisted for the 6 month observation period. Cisplatin also induced a modest but statistically significant increase in micronucleus frequency at the highest dose tested. The prolonged persistence in the production of mutant erythrocytes following cisplatin exposure suggests that this drug mutates hematopoietic stem cells and that this damage may ultimately contribute to the increased incidence of secondary leukemias seen in patients cured of primary malignancies with platinum-based regimens.

  16. Molecular portrait of cisplatin induced response in human testis cancer cell lines based on gene expression profiles

    PubMed Central

    Duale, Nur; Lindeman, Birgitte; Komada, Mitsuko; Olsen, Ann-Karin; Andreassen, Ashild; Soderlund, Erik J; Brunborg, Gunnar

    2007-01-01

    Background Testicular germ cell tumors (TGCTs) respond well to cisplatin-based chemotherapy and show a low incidence of acquired resistance compared to most somatic tumors. The reasons for these specific characteristics are not known in detail but seem to be multifactorial. We have studied gene expression profiles of testicular and colon cancer derived cell lines treated with cisplatin. The main goal of this study was to identify novel gene expression profiles with their functional categories and the biochemical pathways that are associated with TGCT cells' response to cisplatin. Results Genes that were differentially expressed between the TGCT cell lines vs the (somatic) HCT116 cell line, after cisplatin treatment, were identified using the significance analysis of microarrays (SAM) method. The response of TGCT cells was strikingly different from that of HCT116, and we identified 1794 genes that were differentially expressed. Functional classification of these genes showed that they participate in a variety of different and widely distributed functional categories and biochemical pathways. Database mining showed significant association of genes (n = 41) induced by cisplatin in our study, and genes previously reported to by expressed in differentiated TGCT cells. We identified 37 p53-responsive genes that were altered after cisplatin exposure. We also identified 40 target genes for two microRNAs, hsa-mir-372 and 373 that may interfere with p53 signaling in TGCTs. The tumor suppressor genes NEO1 and LATS2, and the estrogen receptor gene ESR1, all have binding sites for p53 and hsa-mir-372/373. NEO1 and LATS2 were down-regulated in TGCT cells following cisplatin exposure, while ESR1 was up-regulated in TGCT cells. Cisplatin-induced genes associated with terminal growth arrest through senescence were identified, indicating associations which were not previously described for TGCT cells. Conclusion By linking our gene expression data to publicly available databases and

  17. 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

  18. Role of the DNA base excision repair protein, APE1 in cisplatin, oxaliplatin, or carboplatin induced sensory neuropathy.

    PubMed

    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

  19. 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

  20. PD-L1 polymorphism can predict clinical outcomes of non-small cell lung cancer patients treated with first-line paclitaxel-cisplatin chemotherapy

    PubMed Central

    Lee, Shin Yup; Jung, Deuk Kju; Choi, Jin Eun; Jin, Cheng Cheng; Hong, Mi Jeong; Do, Sook Kyung; Kang, Hyo-Gyoung; Lee, Won Kee; Seok, Yangki; Lee, Eung Bae; Jeong, Ji Yun; Shin, Kyung Min; Yoo, Seung Soo; Lee, Jaehee; Cha, Seung Ick; Kim, Chang Ho; Park, Jae Yong

    2016-01-01

    This study was conducted to investigate whether polymorphisms of genes involved in immune checkpoints can predict the clinical outcomes of patients with advanced stage non-small cell lung cancer (NSCLC) after 1st line paclitaxel-cisplatin chemotherapy. A total of 379 NSCLC patients were enrolled. Twelve single nucleotide polymorphisms (SNPs) of PD-1, PD-L1, and CTLA-4 genes were selected and genotyped. The associations of SNPs with chemotherapy response and overall survival (OS) were analyzed. Among the 12 SNPs investigated, PD-L1 rs2297136T > C and rs4143815C > G were significantly associated with clinical outcomes after chemotherapy. The rs2297136T > C was significantly associated with both better chemotherapy response and better OS, and the rs4143815C > G had a significantly better response to chemotherapy. Consistent with the individual genotype analyses, rs2297136C-rs4143815G haplotype (ht4) carrying variant alleles at both loci was significantly associated with better chemotherapy response and OS compared with combined other haplotypes. Patients with at least one ht4 had significantly better chemotherapy response and OS compared to those without ht4. PD-L1 rs2297136T > C and rs4143815C > G polymorphisms may be useful for the prediction of clinical outcome of 1st line paclitaxel-cisplatin chemotherapy in NSCLC. Further studies are needed to confirm our findings and to understand the role of PD-L1 in the chemotherapy outcome of NSCLC patients. PMID:27181838

  1. Concomitant chemobrachyradiotherapy with ifosfamide and cisplatin followed by consolidation chemotherapy in the treatment of locally advanced adenocarcinoma or adenosquamous carcinoma of the cervix uteri.

    PubMed

    Vrdoljak, E; Boraska Jelavic, T; Saratlija-Novakovic, Z; Hamm, W

    2005-01-01

    The optimal treatment of women with locally advanced adenocarcinoma or adenosquamous carcinoma of the cervix uteri is still undefined. We report a series of four consecutive patients with locally advanced adeno- or adenosquamous carcinomas of the uterine cervix (FIGO Stages IB-IIIB) treated by concomitant chemobrachyradiotherapy with ifosfamide and cisplatin followed by one to four cycles of consolidation chemotherapy with the same drug combination. After completion of this treatment all patients showed complete clinical remission. Now, after a median follow-up of 40 (range: 13.5-61) months all patients still present with no evidence of disease. Despite the low number of patients in this series we may conclude that concomitant chemobrachyradiotherapy with ifosfamide and cisplatin followed by consolidation chemotherapy with the same drug combination is an efficacious treatment of patients with locally advanced adeno- or adenosquamous carcinomas of the cervix uteri.

  2. 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

  3. [Chemotherapy].

    PubMed

    Aiba, Keisuke

    2004-05-01

    Cancer chemotherapy in the treatment of colorectal cancer has been evolving so extensively than ever. 5-fluorouracil (5-FU) has been a pivotal and a single active agent in the treatment of colorectal cancer. Reproducing and consistent better response rate has been shown since the introduction of the concept of biochemical modulation of 5-FU by leucovorin, a reduced folate, to the clinic and a combination chemotherapy of 5-FU and leucovorin (FL) has enable us to obtain a response rate around 20-30% and a median survival time ranging from 10 to 12 months. IFL regimen combing CPT-11 with FL showed a better MST ranging from 14 to 15 months, but now serious toxicity precludes general use outside of clinical trials. In the Europe, de Gramont regimen, an unique dose and schedule of 5-FU using a combination of continuous intravenous infusion of 5-FU with leucovorin over two days and bolus infusion of 5-FU twice over the same period, has been developed and shown improved antitumor activity and toxic profiles. FOLFOX 4, a combination chemotherapy of de Gramont regimen and oxaliplatin which is a third generation of cisplatin and a uniqe toxic profile with neuropathy, has demonstrated improved MST over a year and acceptable toxic profiles. Now FOLFOX 4 is considered to be a standard chemotherapy for the patients with advanced colorectal cancer, since a large phase III randomized study has shown that FOLFOX 4 was the most active and less toxic treatment regimen among active regimens such as IFL and IROX (CPT-11 and oxaliplatin). More recently, a combination of IFL and bevacizumab which is one of the molecular target agents and a antibody agent against vascular endothelial growth factor (VEGF), has demonstrated better MST reaching 20 months. Future large scale trials will attempt to develop more active regimen incorporating so-called molecular target agents.

  4. Cisplatin-induced antitumor immunomodulation: a review of preclinical and clinical evidence.

    PubMed

    de Biasi, Andreas R; Villena-Vargas, Jonathan; Adusumilli, Prasad S

    2014-11-01

    Contrary to the long held belief that chemotherapy is immunosuppressive, emerging evidence indicates that the anticancer activity of cisplatin is not limited to its ability to inhibit mitosis, but that cisplatin also has important immunomodulatory effects. We therefore methodically examined the relevant preclinical literature and identified four main mechanisms of cisplatin-induced antitumor immunomodulation: (i) MHC class I expression upregulation; (ii) recruitment and proliferation of effector cells; (iii) upregulation of the lytic activity of cytotoxic effectors; and (iv) downregulation of the immunosuppressive microenvironment. Cisplatin-based combination chemotherapy's antitumor immunomodulatory effects are also beginning to be harnessed in the clinic; we therefore additionally reviewed the applicable clinical literature and discussed how monitoring various components of the immune system (and their responses to cisplatin) can add new levels of sophistication to disease monitoring and prognostication. In summation, this growing body of literature on cisplatin-induced antitumor immunomodulation ultimately highlights the therapeutic potential of synergistic strategies that combine traditional chemotherapy with immunotherapy.

  5. [Urgent gastrectomy in a patient who developed perforated gastric cancer during preoperative chemotherapy with S-1 plus cisplatin].

    PubMed

    Okabe, Yasuyuki; Yajima, Kazuhito; Ishikawa, Takashi; Kosugi, Shin-ichi; Sakamoto, Kaoru; Sato, Yu; Kanda, Tatsuo; Wakai, Toshifumi

    2014-01-01

    A 66 -year-old man presenting with a chief complaint of upper abdominal pain was diagnosed as having an advanced adenocarcinoma, type 2, of the lower third of the stomach after endoscopy was performed. An abdominal computed tomography( CT)scan revealed 4 lymph node metastases at the infrapyloric nodes(station No. 6)and the nodes around the proximal splenic artery(station No. 11p)and the abdominal aorta(station No. 16a2). The clinical stage was determined to be T3(SS)N2M1(LYM), Stage IV. Gastrectomy with D2 plus para-aortic node dissection was scheduled after 2 courses of S-1 plus cisplatin(CDDP)with curative intent. On day 14 after starting S-1 therapy, the patient complained of severe abdominal pain and peritoneal irritation of acute onset. Because the abdominal CT scan showed a large amount of intra-abdominal free air, we performed an urgent laparotomy with a tentative diagnosis of perforation of the gastric cancer. On laparotomy, we found a perforated malignant ulcer, 5 cm in maximum diameter, in the lesser curvature of the stomach; therefore, distal gastrectomy with D1 plus lymphadenectomy and reconstruction using the Roux-en-Y method were performed. At the end of the surgery, a macroscopic residual tumor remained in the para-aortic lymph node. The postoperative course was uneventful, and the patient was discharged on day 23 after surgery. In the present case, despite the performance of urgent gastrectomy while the patient was receiving strong chemotherapy, perioperative management was successful, with no serious postoperative complication or adverse events as a result of the chemotherapy.

  6. 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.

  7. 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.

  8. Comparative effectiveness and safety between oxaliplatin-based and cisplatin-based therapy in advanced gastric cancer: A meta-analysis of randomized controlled trials

    PubMed Central

    Zhu, Yanjie; Huang, Jiale; Liu, Yanna; Zhao, Liying; Li, Zhijia; Liu, Hao; Wang, Qi-long; Qi, Xiaolong

    2016-01-01

    Background & Aims Platinum-based drugs are the most significant chemotherapy for advanced gastric cancer. The study aims to compare the efficacy and safety of oxaliplatin-based therapy versus cisplatin-based therapy in patients with advanced gastric cancer. Materials and Methods An adequate literature search in EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) was conducted. Phase II or III randomized controlled trials (RCTs) that compared effectiveness and safety between oxaliplatin-based and cisplatin-based therapy in patients with advanced gastric cancer were eligible. The primary endpoint was overall response rate (ORR), progression free survival (PFS) and overall survival (OS). The second endpoint was the adverse events. Results Five phase II or III RCTs involving a total of 2,046 patients were identified. The results showed that there were no significant difference in ORR (OR = 1.17, 95% CI = 0.98–1.40, p = 0.08, I2 = 0%), PFS (HR = 0.92, 95% CI = 0.84–1.01, p = 0.09, I2 = 0%) and OS (HR = 0.91, 95% CI = 0.82–1.01, p = 0.07, I2 = 0%) between oxaliplatin-based therapy and cisplatin-based therapy. In addition, oxaliplatin-based therapy had lower risk of neutropenia, anemia, nausea, alopecia, thromboembolism, stomatitis and creatinine increased at all grades, and neutropenia, anemia, leukopenia and alopecia at 3–4 grades than cisplatin-based therapy. However, oxaliplatin-based therapy was associated with increased risk of neurosensory toxicity and thrombocytopenia. Conclusions Our meta-analysis showed that there were no significant difference in ORR, PFS and OS between oxaliplatin-based therapy and cisplatin-based therapy. The oxaliplatin-based therapy could generally decrease the risk of adverse effects except neurosensory toxicity and thrombocytopenia. PMID:27166187

  9. A Head and Neck Cancer Tumor Response-Specific Gene Signature for Cisplatin, 5-Fluorouracil Induction Chemotherapy Fails with Added Taxanes

    PubMed Central

    Agier, Nicolas; Delacroix, Hervé; Marisa, Laetitia; Brasnu, Daniel; Aggerbeck, Lawrence P.; Badoual, Cécile; Barouki, Robert; Aggerbeck, Martine

    2012-01-01

    Background It is a major clinical challenge to predict which patients, with advanced stage head and neck squamous cell carcinoma, will not exhibit a reduction in tumor size following induction chemotherapy in order to avoid toxic effects of ineffective chemotherapy and delays for instituting other therapeutic options. Further, it is of interest to know to what extent a gene signature, which identifies patients with tumors that will not respond to a particular induction chemotherapy, is applicable when additional chemotherapeutic agents are added to the regimen. Methodology/Principal Findings To identify genes that predict tumor resistance to induction with cisplatin/5-fluorouracil (PF) or PF and a taxane, we analyzed patient tumor biopsies with whole genome microarrays and quantitative reverse transcriptase-PCR (TLDA) cards. A leave one out cross-validation procedure allowed evaluation of the prediction tool. A ten-gene microarray signature correctly classified 12/13 responders and 7/10 non-responders to PF (92% specificity, 82.6% accuracy). TLDA analysis (using the same classifier) of the patients correctly classified 12/12 responders and 8/10 non-responders (100% specificity, 90.9% accuracy). Further, TLDA analysis correctly predicted the response of 5 new patients and, overall, 12/12 responders and 13/15 non-responders (100% specificity, 92.6% accuracy). The protein products of the genes constituting the signature physically associate with 27 other proteins, involved in regulating gene expression, constituting an interaction network. In contrast, TLDA-based prediction (with the same gene signature) of responses to induction with PF and either of two taxanes was poor (0% specificity, 25% accuracy and 33.3% specificity, 25% accuracy). Conclusions/Significance Successful transfer of the microarray-based gene signature to an independent, PCR-based technology suggests that TLDA-based signatures could be a useful hospital-based technology for determining therapeutic

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

    PubMed Central

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

    2016-01-01

    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] PMID:26728272

  11. Effectiveness of neoadjuvant chemotherapy with cisplatin and irinotecan followed by surgery on small-cell carcinoma of the esophagus: A case report

    PubMed Central

    Akiyama, Yuji; Iwaya, Takeshi; Shioi, Yoshihiro; Endo, Fumitaka; Chiba, Takehiro; Otsuka, Koki; Nitta, Hiroyuki; Koeda, Keisuke; Mizuno, Masaru; Uesugi, Noriyuki; Kimura, Yusuke; Sasaki, Akira

    2015-01-01

    Introduction Small-cell carcinoma of the esophagus (SCCE) is a rare disease with aggressive progression and a poor prognosis. A standard treatment strategy for SCCE is yet to be established. Presentation of case A 40-year-old woman with dysphagia was admitted to our hospital. A clinical diagnosis of SCCE (T3N1N0 stage IIIA) was established. She was initially treated with chemotherapy using cisplatin (CDDP) and irinotecan (CPT-11). After two courses of treatment, the primary lesion in the esophagus was not detectable by esophageal endoscopy. Likewise, swelling of the right recurrent nerve lymph node present prior to treatment could not be detected. The chemotherapy resulted in a complete response. One month after the conclusion of chemotherapy, radical esophagectomy with three-field lymph node dissection was performed. Histopathological examination of the excised specimen revealed no residual tumor or lymph node metastasis. The patient was discharged from hospital 29 days after surgery with no complications. The patient is alive and has remained cancer-free for 48 months after the surgery. Discussion Systemic chemotherapy for SCCE in combination with surgery was treated after surgery in most reports. Neoadjuvant chemotherapy is advantageous from three viewpoints, namely achievement of downstaging, increasing complete resection rates, and a better completion of treatment compared with postoperative chemotherapy. Neoadjuvant chemotherapy following esophagectomy could be a useful treatment option for patients with limited disease (LD) of SCCE. Conclusion We report a case of SCCE achieving a pathologically complete response with neoadjuvant chemotherapy using CDDP and CPT-11, and long-term survival followed by surgery. PMID:26615446

  12. Thrombotic thrombocytopenic purpura following salvage chemotherapy with paclitaxel, ifosfamide and cisplatin in a patient with a refractory germ cell tumor: A case report and review of the literature

    PubMed Central

    ULAS, ARIFE; SILAY, KAMILE; AKINCI, SEMA; AKINCI, MUHAMMED BULENT; SENDUR, MEHMET ALI; DEDE, DIDEM SENER; POLAT, YUNUS HALIL; YALCIN, BULENT

    2015-01-01

    Thrombotic thrombocytopenic purpura (TTP) is a rare form of thrombotic microangiopathy that is characterized by microvascular thrombosis, thrombocytopenia, hemolysis and end organ damage. An extensive variety of drugs, including certain chemotherapeutic agents, have been associated with TTP. However, paclitaxel, cisplatin and ifosfamide regimen (TIP)-induced TTP has not previously been described. The present study reports the case of a 43-year-old patient with a refractory testicular germ cell tumor who developed acute TTP during TIP chemotherapy. Following the third cycle of TIP chemotherapy, the patient developed fever, anemia, thrombocytopenia and confusion. A diagnosis of TTP was established. Plasmapheresis was initiated as daily treatment in the first week, then continued every other day for 4 weeks. TIP chemotherapy was discontinued. The patient's clinical and neurological symptoms improved markedly after a week. Renal function and hemolysis improved, and the patient was discharged in a stable condition. The patient did not develop any complications and has been in remission for 5 months. The Naranjo adverse drug reaction probability scale indicated a likely association between TTP and the TIP chemotherapy regimen in this patient. This case is also investigated with regard to the associated literature to increase the awareness of TTP following chemotherapy. PMID:26622823

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

    PubMed

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

    2014-05-01

    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

  14. Cisplatin induces stemness in ovarian cancer.

    PubMed

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

    2016-05-24

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

  15. Adjuvant platinum-based chemotherapy for early stage cervical cancer

    PubMed Central

    Rosa, Daniela D; Medeiros, Lídia RF; Edelweiss, Maria I; Pohlmann, Paula R; Stein, Airton T

    2014-01-01

    Background This is an updated version of the original Cochrane review published in The Cochrane Library 2009, Issue 3. Most women with early cervical cancer (stages I to IIA) are cured with surgery or radiotherapy, or both. We performed this review originally because it was unclear whether cisplatin-based chemotherapy after surgery, radiotherapy or both, in women with early stage disease with risk factors for recurrence, was associated with additional survival benefits or risks. Objectives To evaluate the effectiveness and safety of platinum-based chemotherapy after radical hysterectomy, radiotherapy, or both in the treatment of early stage cervical cancer. Search methods For the original 2009 review, we searched the Cochrane Gynaecological Cancer Group Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library 2009, Issue 1), MEDLINE, EMBASE, LILACS, BIOLOGICAL ABSTRACTS and CancerLit, the National Research Register and Clinical Trials register, with no language restriction. We handsearched abstracts of scientific meetings and other relevant publications. We extended the database searches to November 2011 for this update. Selection criteria Randomised controlled trials (RCTs) comparing adjuvant cisplatin-based chemotherapy (after radical surgery, radiotherapy or both) with no adjuvant chemotherapy, in women with early stage cervical cancer (stage IA2-IIA) with at least one risk factor for recurrence. Data collection and analysis Two review authors extracted data independently. Meta-analysis was performed using a random-effects model, with death and disease progression as outcomes. Main results For this updated version, we identified three additional ongoing trials but no new studies for inclusion. Three trials including 368 evaluable women with early cervical cancer were included in the meta-analyses. The median follow-up period in these trials ranged from 29 to 42 months. All women had undergone surgery first. Two trials

  16. 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

  17. International Phase III Trial Assessing Neoadjuvant Cisplatin, Methotrexate, and Vinblastine Chemotherapy for Muscle-Invasive Bladder Cancer: Long-Term Results of the BA06 30894 Trial

    PubMed Central

    2011-01-01

    Purpose This article presents the long-term results of the international multicenter randomized trial that investigated the use of neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) chemotherapy in patients with muscle-invasive urothelial cancer of the bladder treated by cystectomy and/or radiotherapy. Nine hundred seventy-six patients were recruited between 1989 and 1995, and median follow-up is now 8.0 years. Patients and Methods This was a randomized phase III trial of either no neoadjuvant chemotherapy or three cycles of CMV. Results The previously reported possible survival advantage of CMV is now statistically significant at the 5% level. Results show a statistically significant 16% reduction in the risk of death (hazard ratio, 0.84; 95% CI, 0.72 to 0.99; P = .037, corresponding to an increase in 10-year survival from 30% to 36%) after CMV. Conclusion We conclude that CMV chemotherapy improves outcome as first-line adjunctive treatment for invasive bladder cancer. Two large randomized trials (by the Medical Research Council/European Organisation for Research and Treatment of Cancer and Southwest Oncology Group) have confirmed a statistically significant and clinically relevant survival benefit, and neoadjuvant chemotherapy followed by definitive local therapy should be viewed as state of the art, as compared with cystectomy or radiotherapy alone, for deeply invasive bladder cancer. PMID:21502557

  18. Chemotherapy

    MedlinePlus

    ... getting chemotherapy. Chemotherapy is most often given in cycles. These cycles may last one day, several days, or a ... period when no chemotherapy is given between each cycle. A rest period may last for days, weeks, ...

  19. A Phase II Clinical Trial of Concurrent Helical Tomotherapy plus Cetuximab Followed by Adjuvant Chemotherapy with Cisplatin and Docetaxel for Locally Advanced Nasopharyngeal Carcinoma

    PubMed Central

    Zhang, Xinxin; Du, Lei; Zhao, Feifang; Wang, Qiuju; Yang, Shiming; Ma, Lin

    2016-01-01

    Purpose: The present clinical trial was designed to evaluate the efficacy and safety of concurrent helical tomotherapy (HT) with cetuximab followed by adjuvant chemotherapy with docetaxel and cisplatin (TP) in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Materials and Methods: This phase II clinical trial included 43 patients with Stage III/IV LANC (33 Stage III and 10 Stage IV). The treatment consisted of concurrent HT with cetuximab (400 mg/m2 loading dose and weekly 250mg/m2), followed by four cycles of chemotherapy [docetaxel (70 mg/m2 on Day 1) and cisplatin (40 mg/m2 on Days 1 and 2 every 3 weeks). Side effects were evaluated with CTCAE criteria (Common Terminology Criteria for Adverse Events 3.0). Results: The median follow-up duration was 48.0 months [95% confidence interval (CI) 41.7-58.0 months], the 2-year locoregional failure-free rate (LFFR), progression-free survival (PFS), distant failure-free rate (DFFR) and overall survival (OS) were 95.2%, 79.1%, 88.1% and 93.0% respectively; the 3-year LFFR, DFFR, PFS and OS were 92.7%, 85.6%, 72.0% and 85.7% respectively. The most common grade 3 toxicities were oropharyngeal mucositis (81.4%) and RT-related dermatitis (7.0%). No patients had more than grade 3 radiation related toxicities and no patients required nasogastric feeding. One patient experienced grade 3 osteonecrosis at 18 months after treatment. Conclusions: Concurrent HT with cetuximab followed by adjuvant chemotherapy with TP is an effective strategy for the treatment of LANC with encouraging survival rates and minimal side effects. PMID:27019628

  20. Oxaliplatin-Based Doublets Versus Cisplatin or Carboplatin-Based Doublets in the First-Line Treatment of Advanced Nonsmall Cell Lung Cancer.

    PubMed

    Yu, Jing; Xiao, Jing; Yang, Yifan; Cao, Bangwei

    2015-07-01

    The efficacy and toxicity of oxaliplatin-based versus carboplatin/cisplatin-based doublets in patients with previously untreated nonsmall cell lung cancer (NSCLC) have been compared.We searched published randomized controlled trials of oxaliplatin-based or carboplatin/cisplatin-based medications for NSCLC. A fixed effect model was used to analyze outcomes which were expressed as the hazard ratio for overall survival (OS) and time-to-progression (TTP), relative risk, overall response rate (ORR), disease control rate (DCR), 1-year survival, and the odds ratios for toxicity were pooled.Eight studies involving 1047 patients were included. ORR tended to favor carboplatin/cisplatin but the effect was not significantly different compared with oxaliplatin doublets (P = 0.05). The effects of OS, TTP, DCR, and 1-year survival between the 2 regimens were comparable. Oxaliplatin doublets caused less grade 3/4 leukocytopenia and neutropenia. Grades 3 to 4 nonhematological toxicities and grades 3 to 4 hematological toxicities showed little difference between oxaliplatin doublets and carboplatin/cisplatin doublets.Meta-analysis shows that the efficacy of oxaliplatin doublets is similar to that of other currently used platinum doublets. The lack of significant differences in the statistic analysis does not preclude genuine differences in clinical efficacy, because higher diversities between the studies covered differences between the 2 groups in each study. Oxaliplatin combined with a third-generation agent should be considered for use as alternative chemotherapy in patients who cannot tolerate conventional platinum-based regimens because the toxicity profile is much more favorable.

  1. 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.

  2. Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial

    PubMed Central

    Valle, Juan W; Wasan, Harpreet; Lopes, Andre; Backen, Alison C; Palmer, Daniel H; Morris, Karen; Duggan, Marian; Cunningham, David; Anthoney, D Alan; Corrie, Pippa; Madhusudan, Srinivasan; Maraveyas, Anthony; Ross, Paul J; Waters, Justin S; Steward, Will P; Rees, Charlotte; Beare, Sandy; Dive, Caroline; Bridgewater, John A

    2015-01-01

    Summary Background Cisplatin and gemcitabine is the standard first-line chemotherapy regimen for patients with advanced biliary tract cancer; expression of VEGF and its receptors is associated with adverse outcomes. We aimed to assess the effect of the addition of cediranib (an oral inhibitor of VEGF receptor 1, 2, and 3) to cisplatin and gemcitabine on progression-free survival. Methods In this multicentre, placebo-controlled, randomised phase 2 study, we recruited patients aged 18 years or older with histologically confirmed or cytologically confirmed advanced biliary tract cancer from hepatobiliary oncology referral centres in the UK. Patients were eligible if they had an ECOG performance status of 0–1 and an estimated life expectancy of longer than 3 months. Patients were given first-line cisplatin and gemcitabine chemotherapy (25 mg/m2 cisplatin and 1000 mg/m2 gemcitabine [on days 1 and 8 every 21 days, for up to eight cycles]) with either 20 mg oral cediranib or placebo once a day until disease progression. We randomly assigned patients (1:1) with a minimisation algorithm, incorporating the stratification factors: extent of disease, primary disease site, previous treatment, ECOG performance status, and centre. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00939848, and was closed on Sept 30, 2014; results of the final analysis for the primary endpoint are presented. Findings Between April 5, 2011, and Sept 28, 2012, we enrolled 124 patients (62 in each group). With a median follow-up of 12·2 months (IQR 7·3–18·5), median progression-free survival was 8·0 months (95% CI 6·5–9·3) in the cediranib group and 7·4 months (5·7–8·5) in the placebo group (HR 0·93, 80% CI 0·74–1·19, 95% CI 0·65–1·35; p=0·72). Patients who received cediranib had more grade 3–4 toxic effects than did patients who received placebo: hypertension (23 [37%] vs

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

    PubMed

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

    2014-01-01

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

  4. Detouring of cisplatin to access mitochondrial genome for overcoming resistance.

    PubMed

    Marrache, Sean; Pathak, Rakesh K; Dhar, Shanta

    2014-07-22

    Chemoresistance of cisplatin therapy is related to extensive repair of cisplatin-modified DNA in the nucleus by the nucleotide excision repair (NER). Delivering cisplatin to the mitochondria to attack mitochondrial genome lacking NER machinery can lead to a rationally designed therapy for metastatic, chemoresistant cancers and might overcome the problems associated with conventional cisplatin treatment. An engineered hydrophobic mitochondria-targeted cisplatin prodrug, Platin-M, was constructed using a strain-promoted alkyne-azide cycloaddition chemistry. Efficient delivery of Platin-M using a biocompatible polymeric nanoparticle (NP) based on biodegradable poly(lactic-co-glycolic acid)-block-polyethyleneglycol functionalized with a terminal triphenylphosphonium cation, which has remarkable activity to target mitochondria of cells, resulted in controlled release of cisplatin from Platin-M locally inside the mitochondrial matrix to attack mtDNA and exhibited otherwise-resistant advanced cancer sensitive to cisplatin-based chemotherapy. Identification of an optimized targeted-NP formulation with brain-penetrating properties allowed for delivery of Platin-M inside the mitochondria of neuroblastoma cells resulting in ∼17 times more activity than cisplatin. The remarkable activity of Platin-M and its targeted-NP in cisplatin-resistant cells was correlated with the hyperpolarization of mitochondria in these cells and mitochondrial bioenergetics studies in the resistance cells further supported this hypothesis. This unique dual-targeting approach to controlled mitochondrial delivery of cisplatin in the form of a prodrug to attack the mitochondrial genome lacking NER machinery and in vivo distribution of the delivery vehicle in the brain suggested previously undescribed routes for cisplatin-based therapy.

  5. Detouring of cisplatin to access mitochondrial genome for overcoming resistance

    PubMed Central

    Marrache, Sean; Pathak, Rakesh K.; Dhar, Shanta

    2014-01-01

    Chemoresistance of cisplatin therapy is related to extensive repair of cisplatin-modified DNA in the nucleus by the nucleotide excision repair (NER). Delivering cisplatin to the mitochondria to attack mitochondrial genome lacking NER machinery can lead to a rationally designed therapy for metastatic, chemoresistant cancers and might overcome the problems associated with conventional cisplatin treatment. An engineered hydrophobic mitochondria-targeted cisplatin prodrug, Platin-M, was constructed using a strain-promoted alkyne–azide cycloaddition chemistry. Efficient delivery of Platin-M using a biocompatible polymeric nanoparticle (NP) based on biodegradable poly(lactic-co-glycolic acid)-block-polyethyleneglycol functionalized with a terminal triphenylphosphonium cation, which has remarkable activity to target mitochondria of cells, resulted in controlled release of cisplatin from Platin-M locally inside the mitochondrial matrix to attack mtDNA and exhibited otherwise-resistant advanced cancer sensitive to cisplatin-based chemotherapy. Identification of an optimized targeted-NP formulation with brain-penetrating properties allowed for delivery of Platin-M inside the mitochondria of neuroblastoma cells resulting in ∼17 times more activity than cisplatin. The remarkable activity of Platin-M and its targeted-NP in cisplatin-resistant cells was correlated with the hyperpolarization of mitochondria in these cells and mitochondrial bioenergetics studies in the resistance cells further supported this hypothesis. This unique dual-targeting approach to controlled mitochondrial delivery of cisplatin in the form of a prodrug to attack the mitochondrial genome lacking NER machinery and in vivo distribution of the delivery vehicle in the brain suggested previously undescribed routes for cisplatin-based therapy. PMID:25002500

  6. [Disease-free survival in a patient with squamous cell lung carcinoma following complete response with the combination chemotherapy of cisplatin and etoposide].

    PubMed

    Taniwaki, M; Kakusui, M; Imoto, M; Takashima, T; Misawa, S; Kashima, K

    1993-05-01

    Disease-free survival is reported in a patient with non-small cell lung carcinoma successfully treated with the combination chemotherapy of cisplatin and etoposide (CDDP-ETOP). An 80-year-old woman was diagnosed as having squamous cell carcinoma of the lung with bone metastasis. Chest X-ray showed a tumor (64 x 68 mm in size) in the S1/4 segment of the right lobe, and CT scan revealed no apparent metastasis of hilar lymphnode. In March 1989, the patient achieved a complete response (CR) after two courses of CDDP-ETOP therapy, followed by ETOP(100mg) every two weeks and daily UFT (400 mg) for 10 months. Subsequently, a single course of CDDP-ETOP was administered as a consolidation therapy. The patient is alive with no evidence of recurrent disease for 3 years and half after achieving CR.

  7. Cediranib combined with chemotherapy reduces tumor dissemination and prolongs the survival of mice bearing patient-derived ovarian cancer xenografts with different responsiveness to cisplatin.

    PubMed

    Decio, Alessandra; Cesca, Marta; Bizzaro, Francesca; Porcu, Luca; Bettolini, Rossana; Ubezio, Paolo; Taraboletti, Giulia; Belotti, Dorina; Giavazzi, Raffaella

    2015-10-01

    Cediranib is a pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor that affects tumor angiogenesis and is under investigation in clinical studies on ovarian cancer. Using a panel of eleven patient-derived ovarian cancer xenografts (EOC-PDX) growing orthotopically in the peritoneal cavity of nude mice we investigated the effect of cediranib as monotherapy or in combination with chemotherapy on overall survival (primary endpoint, at euthanasia), and tumor dissemination and metastasis in the peritoneal cavity (secondary endpoint, interim analysis). The response of EOC-PDX to cediranib varied (increment of lifespan, ILS between 12 and 85 %) in the different EOC-PDX, independently from tumor responsiveness to cisplatin (DDP). Cediranib combined with DDP and in maintenance regimen prolonged the survival of mice bearing EOC-PDX with different responsiveness to DDP (ILS between 34 and 224 % with only DDP and between 135 and 337 % with DDP plus Cediranib); survival was extended with the addition of paclitaxel to chemotherapy (50-77 % complete remissions). Cediranib reduced ascites of advanced EOC-PDX, but had limited effect on tumor dissemination; only combined with chemotherapy, ascites and metastases were both reduced. The reduction of tumor dissemination was associated to the increase of overall survival. In conclusion, the response to cediranib differs in the various EOC-PDX, reproducing the heterogeneous response of cancer patients to angiogenesis inhibitors. Cediranib potentiated chemotherapy, significantly inhibiting tumor progression and dissemination to metastatic organs, even in tumors poorly responsive to DDP. EOC-PDX preclinical models with different responsiveness to Cediranib may help in identifying determinants of response to cediranib and mechanisms of adaptation to antiangiogenic treatments.

  8. 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

  9. [Platinum-free gemcitabine-based combinations: an alternative to conventional chemotherapy of non-small-cell lung cancers?].

    PubMed

    Pujol, Jean-Louis; Choma, Didier; Jacot, William; Quantin, Xavier

    2002-08-01

    Cisplatin-based combinations are standard regimens in the treatment of advanced non-small cell lung cancer. Survival improvement has been achieved using this therapy. However, the high toxicity induced by cisplatin-based doublets urges the research of alternate treatments. Newest cytotoxic compounds yield a better efficacy/toxicity ratio. Platinum-free doublet regimens based on new drugs are expected to offer the patient an improved survival without decreasing his quality of life. Treatment-allocated time and period with high grade toxicity could be considered as wasted from the patient point of view. Qualy methods based on time without symptoms and toxicity (TWiST) allow the accurate evaluation of this end-point. This brief state-of-the-art deals with methodological statements highlighted by the first publications of randomized studies comparing gemcitabine--navelbine or gemcitabine--taxane combinations with either single-drug chemotherapy or standard chemotherapy based on cisplatin. The choice of end-points is discussed.

  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. Phase II study of a new combined primary chemotherapy regimen, intravenous methotrexate and vincristine and intraarterial adriamycin and cisplatin, for locally advanced urinary bladder cancer: preliminary results.

    PubMed

    Kuroiwa, T; Naito, S; Hasuo, K; Kishikawa, T; Masuda, K; Kumazawa, J

    1995-01-01

    A phase II study of a new combination therapy was performed using intraarterial (i.a.) cisplatin and Adriamycin in combination with i.v. methotrexate and vincristine for 27 patients with invasive urinary bladder carcinoma of stages T2-3NOMO, and the therapeutic effects were assessed. Methotrexate (20 mg/m2) was given i.v. on days 1,15, and 22, and vincristine (0.7 mg/m2) was injected i.v. on day 2 before i.a. infusion therapy and on days 15 and 22. The i.a. chemotherapy was performed after both superior gluteal arteries had been embolized using 3- or 5-mm stainless-steel coils. A mixture of cisplatin (50-70 mg/m2) and Adriamycin (20 mg/m2) was infused i.a. via both internal iliac arteries over a period of 20-30 min. Angiotensin II (mean dose, 21 micrograms) was simultaneously infused i.a. in 15 of 27 patients. In 24 of the 27 patients, at least 2 cycles of full-dose chemotherapy were completed. The dose was decreased in the remaining 3 patients because of their poor health status and advanced age. Among the 27 patients, 9 and 14 had complete (CR) and partial responses (PR), respectively; 3 manifested no change (NC), and 1 had progressive disease (PD). The objective response rate (CR+PR) was 85.2%. Among the 27 patients staged T2-3 NOMO, 6 (CR, 1; PR, 5) underwent total cystectomies and 18 (CR, 8; PR, 8; NC, 2) had transurethral resection of a bladder tumor (TUR-Bt) or partial resections following chemotherapy. The remaining 3 diminished-dose patients had no surgery. Of the 27 patients, 22 were alive after a median follow-up period of 21+ (range, 7-48+) months. No significant side effect was observed except for lower extremity paresthesias in 5 patients (18.5%). These results point to the effectiveness of this therapy and to the possibility of urinary bladder preservation in patients with invasive, advanced urinary bladder cancers. PMID:7850915

  12. Intralesional cisplatin chemotherapy and topical cryotherapy for the control of choanal squamous cell carcinoma in an African penguin (Spheniscus demersus).

    PubMed

    Ferrell, Shannon T; Marlar, Annajane B; Garner, Michael; Lung, Nancy P

    2006-12-01

    A 3.5-yr-old, 2.5-kg female African penguin (Spheniscus demersus) was diagnosed with a choanal squamous cell carcinoma on the basis of biopsy after a history of choanal ulceration and anorexia with weight loss. Therapeutic modalities included the use of intralesional cisplatin followed by localized, topical cryotherapy with liquid nitrogen. The penguin remained free of clinical disease for a period of 9 mo, at which time a second cryotreatment was performed. The patient has remained free of all signs of choanal carcinoma for a period of 13 mo since the second cryotreatment.

  13. FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-κB/Slug-mediated PUMA reduction.

    PubMed

    Wu, D-W; Lee, M-C; Hsu, N-Y; Wu, T-C; Wu, J-Y; Wang, Y-C; Cheng, Y-W; Chen, C-Y; Lee, H

    2015-05-01

    Fragile histidine triad (FHIT) loss by the two-hit mechanism of loss of heterozygosity and promoter hypermethylation commonly occurrs in non-small cell lung cancer (NSCLC) and may confer cisplatin resistance in NSCLC cells. However, the underlying mechanisms of FHIT loss in cisplatin resistance and the response to cisplatin-based chemotherapy in NSCLC patients have not yet been reported. In the present study, inhibition concentration of 50% cell viability induced by cisplatin (IC50) and soft agar growth and invasion capability were increased and decreased in FHIT-knockdown and -overexpressing cells, respectively. Mechanistically, Slug transcription is upregulated by AKT/NF-κB activation due to FHIT loss and, in turn, Slug suppresses PUMA expression; this decrease of PUMA by FHIT loss is responsible for cisplatin resistance. In addition, cisplatin resistance due to FHIT loss can be conquered by AKT inhibitor-perifosine in xenograft tumors. Among NSCLC patients, low FHIT, high p-AKT, high Slug and low PUMA were correlated with shorter overall survival, relapse-free survival and poorer response to cisplatin-based chemotherapy. Therefore, the AKT inhibitor perifosine might potentially overcome the resistance to cisplatin-based chemotherapy in NSCLC patients with low-FHIT tumors, and consequently improve the outcome. PMID:24998847

  14. FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-κB/Slug-mediated PUMA reduction.

    PubMed

    Wu, D-W; Lee, M-C; Hsu, N-Y; Wu, T-C; Wu, J-Y; Wang, Y-C; Cheng, Y-W; Chen, C-Y; Lee, H

    2015-05-01

    Fragile histidine triad (FHIT) loss by the two-hit mechanism of loss of heterozygosity and promoter hypermethylation commonly occurrs in non-small cell lung cancer (NSCLC) and may confer cisplatin resistance in NSCLC cells. However, the underlying mechanisms of FHIT loss in cisplatin resistance and the response to cisplatin-based chemotherapy in NSCLC patients have not yet been reported. In the present study, inhibition concentration of 50% cell viability induced by cisplatin (IC50) and soft agar growth and invasion capability were increased and decreased in FHIT-knockdown and -overexpressing cells, respectively. Mechanistically, Slug transcription is upregulated by AKT/NF-κB activation due to FHIT loss and, in turn, Slug suppresses PUMA expression; this decrease of PUMA by FHIT loss is responsible for cisplatin resistance. In addition, cisplatin resistance due to FHIT loss can be conquered by AKT inhibitor-perifosine in xenograft tumors. Among NSCLC patients, low FHIT, high p-AKT, high Slug and low PUMA were correlated with shorter overall survival, relapse-free survival and poorer response to cisplatin-based chemotherapy. Therefore, the AKT inhibitor perifosine might potentially overcome the resistance to cisplatin-based chemotherapy in NSCLC patients with low-FHIT tumors, and consequently improve the outcome.

  15. Induction chemotherapy with carboplatin-paclitaxel followed by standard radiotherapy with concurrent daily low-dose cisplatin plus weekly paclitaxel for inoperable non-small-cell lung cancer.

    PubMed

    Ardizzoni, Andrea; Scolaro, Tindaro; Mereu, Carlo; Cafferata, Mara Argenide; Tixi, Lucia; Bacigalupo, Almalina; Tiseo, Marcello; Monetti, Francesco; Rosso, Riccardo

    2005-02-01

    Both induction chemotherapy and concurrent platinating agents have been shown to improve results of thoracic irradiation in the treatment of locally advanced non-small-cell lung cancer (NSCLC). This phase II study investigated activity and feasibility of a novel chemoradiation regimen, including platinum and paclitaxel, both as induction chemotherapy and concurrently with thoracic radiotherapy. Previously untreated patients with histologically/cytologically proven unresectable stage I-III NSCLC were eligible. Induction chemotherapy consisted of 2 courses of 200 mg/m2 paclitaxel and carboplatin at AUC of 6 mg/mL/min every 3 weeks. From day 43, continuous thoracic irradiation (60 Gy in 30 fractions radiotherapy for 6 weeks) was given concurrently with daily cisplatin at a dose of 5 mg/m2 intravenously and weekly paclitaxel at a dose of 45 mg/m2 for 6 weeks. Fifteen patients were accrued in the first stage of the trial. According to the previous statistical considerations, accrual at the second stage of the study was halted as a result of the achievement an insufficient number of successes. Major toxicity of combined chemoradiation was grade III-IV esophagitis requiring hospitalization for artificial nutrition, which occurred in 58% of patients. Other toxicities included grade II-IV fatigue in 75% of patients and grade I-IV neuromuscular toxicity in 67%. Only 7 patients completed the treatment program as scheduled. Eight patients (53.3%; 95% confidence interval, 26.5-78.7%) had a major response (5 partial response, 3 complete response), 2 patients had disease progression, and 1 was stable at the end of treatment. Four patients died early. With a median follow up of 38 months, the median survival was 12 months. A combined chemoradiation program, including platinum and paclitaxel, appears difficult to deliver at full dose as a result of toxicity, mainly esophagitis. More active and less toxic combined modality treatments need to be developed for inoperable NSCLC.

  16. Improving Systemic Chemotherapy for Bladder Cancer.

    PubMed

    Rose, Tracy L; Milowsky, Matthew I

    2016-05-01

    Systemic chemotherapy is integral to the management of muscle-invasive and metastatic bladder cancer (BCa). Neoadjuvant chemotherapy has been increasingly utilized for muscle-invasive BCa over the past several years, and several options for cisplatin-based regimens have emerged. Adjuvant chemotherapy may be considered for select patients who did not receive neoadjuvant therapy. Systemic chemotherapy added to radiotherapy is a critical component of a bladder-preserving approach and superior to radiotherapy alone. Cisplatin-based chemotherapy has been the mainstay for metastatic BCa for more than three decades. Novel targeted agents are in development fueled by the recent molecular characterization of BCa. Recent trials of immunotherapy have demonstrated the possibility of a less toxic and potentially more effective treatment for metastatic disease. It is an extremely exciting time for BCa research, and much needed improvements in systemic treatment are most certainly on the horizon. PMID:26984414

  17. Downregulation of HIPK2 Increases Resistance of Bladder Cancer Cell to Cisplatin by Regulating Wip1

    PubMed Central

    Lin, Jun; Zhang, Qiang; Lu, Yi; Xue, Wenrui; Xu, Yue; Zhu, Yichen; Hu, Xiaopeng

    2014-01-01

    Cisplatin-based combination chemotherapy regimen is a reasonable alternative to cystectomy in advanced/metastatic bladder cancer, but acquisition of cisplatin resistance is common in patients with bladder cancer. Previous studies showed that loss of homeodomain-interacting protein kinase-2 (HIPK2) contributes to cell proliferation and tumorigenesis. However, the role of HIPK2 in regulating chemoresistance of cancer cell is not fully understood. In the present study, we found that HIPK2 mRNA and protein levels are significantly decreased in cisplatin-resistant bladder cancer cell in vivo and in vitro. Downregulation of HIPK2 increases the cell viability in a dose- and time-dependent manner during cisplatin treatment, whereas overexpression of HIPK2 reduces the cell viability. HIPK2 overexpression partially overcomes cisplatin resistance in RT4-CisR cell. Furthermore, we showed that Wip1 (wild-type p53-induced phosphatase 1) expression is upregulated in RT4-CisR cell compared with RT4 cell, and HIPK2 negatively regulates Wip1 expression in bladder cancer cell. HIPK2 and Wip1 expression is also negatively correlated after cisplatin-based combination chemotherapy in vivo. Finally, we demonstrated that overexpression of HIPK2 sensitizes chemoresistant bladder cancer cell to cisplatin by regulating Wip1 expression. Conclusions These data suggest that HIPK2/Wip1 signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of bladder cancer. PMID:24846322

  18. 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

  19. Successful personalized chemotherapy for metastatic gastric cancer based on quantitative BRCA1 mRNA expression level: A case report

    PubMed Central

    HUANG, YING; WU, PUYUAN; LIU, BAORUI; DU, JUAN

    2016-01-01

    Personalized chemotherapy is based on the specific genetic profile of individual patients and is replacing the traditional ‘one size fits all’ medicine. Breast cancer 1 (BRCA1) plays a central role in the chemotherapy-induced DNA damage response. It has been repeatedly demonstrated that BRCA1 mRNA levels were negatively associated with cisplatin sensitivity, but positively associated with docetaxel sensitivity in patients with gastric cancer in experimental and clinical studies. This feature leads to customized chemotherapy based on the BRCA1 mRNA expression level and results in a high efficacy of treatment. The present study describes the case of a 77-year-old patient with metastatic gastric cancer who was treated with personalized chemotherapy based on quantitative BRCA1 mRNA expression level. This study and the available literature data suggest that the expression level of BRCA1 mRNA is dynamic to BRCA1-based chemotherapy. More importantly, de novo assessment of BRCA1 status is a preferable option for ciscisplatin- or docetaxel-resistant patients, since the expression levels of BRCA1 mRNA in certain patients may alter significantly following treatment. Therefore, BRCA1 expression should be assessed for predicting differential chemosensitivity and tailoring chemotherapy in gastric cancer. PMID:27313763

  20. Salvage chemotherapy of gemcitabine, dexamethasone, and cisplatin (GDP) for patients with relapsed or refractory peripheral T-cell lymphomas: a consortium for improving survival of lymphoma (CISL) trial.

    PubMed

    Park, Byeong-Bae; Kim, Won Seog; Suh, Cheolwon; Shin, Dong-Yeop; Kim, Jeong-A; Kim, Hoon-Gu; Lee, Won Sik

    2015-11-01

    There is no standard salvage chemotherapy for relapsed or refractory peripheral T-cell lymphomas (PTCLs). Gemcitabine combined with cisplatin has been known as an effective regimen for lymphoma treatment in the salvage setting. We investigated the efficacy and toxicity of gemcitabine, dexamethasone, and cisplatin (GDP) for relapsed or refractory PTCLs in search of a more effective and less toxic therapy. Patients with relapsed or refractory PTCLs with more than one previous regimen were eligible. Treatment consisted of gemcitabine 1000 mg/m(2) intravenously (i.v.) on days 1 and 8, dexamethasone 40 mg orally on days 1-4, and cisplatin 70 mg/m(2) i.v. on day 1, and then every 21 days. Patients could proceed to autologous stem cell transplantation (ASCT) after four cycles of GDP or receive up to six treatment cycles. Twenty-five eligible patients were evaluated for toxicity and response. The diagnoses of participants included 14 cases of PTCL-not otherwise specified (NOS) (56 %) and four cases of angioimmunoblastic T-cell lymphoma (16 %) among others. The median age of the patients was 59 years (range 20-75 years). After treatments with GDP, which delivered a median of four GDP cycles, there were 12 patients with complete responses (CR; 48 %) and six with partial responses (PR; 24 %). The overall response rate (RR) was 72 %. Four patients preceded to ASCT, and three patients finally achieved CR. The median progression free survival was 9.3 months (95 % confidence interval (CI); 4.1-14.6) with a median follow-up duration of 27.1 months. In a total of 86 cycles of GDP, grade 3 or 4 neutropenia and thrombocytopenia occurred in 16.3 and 12.8 % of cycles, respectively. Three patients (3.3 %) experienced febrile neutropenia. GDP is a highly effective and optimal salvage regimen for relapsed or refractory PTCLs and can be administered with acceptable toxicity.

  1. [Experience with combination chemotherapy consisting of methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) in advanced urothelial cancer].

    PubMed

    Nishio, Y; Shirahase, T; Shichiri, Y; Habuchi, T; Matsuda, T; Nishimura, K; Hida, S; Okada, Y; Yoshida, O

    1988-08-01

    The M-VAC (methotrexate, vinblastine, adriamycin and cisplatin) regimen was used to treat 6 patients with metastatic transitional cell carcinoma of the urothelial tract. Three patients showed a partial response, all of them were made surgically disease free. Two of them are still alive 1 year and for 6 months after surgery with no evidence of disease and one other died of disease 11 months after surgery. The response in one case was no change and that in two others was a progressive disease. From our experience, we suggest that treatment with M-VAC is effective but that surgery after M-VAC appears essential for the successful management of the patients with metastatic transitional cell carcinoma of the urothelial tract.

  2. Cisplatin induced paroxysmal supraventricular tachycardia.

    PubMed

    Raja, Waseem; Mir, M Hussain; Dar, Imtiyaz; Banday, Muzamil Ahmad; Ahmad, Irfan

    2013-10-01

    Cisplatin or cis-diamminedichloroplatinum (CDDP) is the first member of a class of platinum-containing anti-cancer drugs that act by binding to and causing cross-linking of deoxyribonucleic acid, which ultimately triggers apoptosis. Cisplatin has a broad-spectrum antineoplastic activity against various types of human tumors. Unfortunately, the optimal usefulness of Cisplatin is limited secondary to its dose related toxicity especially nephrotoxicity. Cisplatin chemotherapy is also associated with cardiotoxic effects that may range from silent arrhythmias to heart failure and even sudden cardiac death. These effects are more pronounced when cisplatin is combined with other cardiotoxic drugs. Here, we report a case of patient of cancer lung who developed paroxysmal supraventricular tachycardia following administration of Cisplatin. A brief review of the literature follows.

  3. The role of additional chemotherapy with oral UFT in intravenous combination chemotherapy with cisplatin and 5-fluorouracil for human gastric cancer xenograft lines of well- and poorly- differentiated adenocarcinomas transplanted in nude mice.

    PubMed

    Tseng, C C; Nio, Y; Tsubono, M; Kawabata, K; Masai, Y; Hayashi, H; Fukumoto, M; Tobe, T

    1992-01-01

    In order to assess the role of maintenance chemotherapy with the oral anticancer agent UFT, a mixture of uracil and futraful, in the intensive intravenous chemotherapy for gastric cancer, nude mice transplanted with human gastric cancer xenografts were treated with intravenous 5-fluorouracil (5-FU) and cisplatin (CDDP), alone or in combination, with or without the oral anticancer agent UFT. UFT was given at its maximal clinical dose of 10 mg/kg of body weight daily for 2 weeks, while 5-FU and/or CDDP was intravenously administered at the dose of 20 mg/kg and 1.8 mg/kg of body weight respectively once a week, alone or in combination, for two weeks. The results revealed that 5-FU or CDDP alone were ineffective for both GC-YN, a well differentiated adenocarcinoma line, and GC-SF, a poorly differentiated adenocarcinoma line; however, UFT was effective for GC-SF. In combinations, only the three-agent combination 5-FU + CDDP + UFT (FPU) was effective for GC-YN; however, all the two-agent combinations and FPU were effective for GC-SF. FPU significantly suppressed the growth of GC-YN much more than all the other treatment groups. In contrast, although all combinations as well as UFT alone were effective for GC-SF, there was no significant difference among these effective groups. Moreover, no side effects were noted in combined use of UFT. This study suggests that oral UFT as a maintenance treatment may be beneficial in the combination chemotherapy for human gastric cancer.

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

    PubMed Central

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

    2015-01-01

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

  6. 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.

  7. Cisplatin Injection

    MedlinePlus

    ... has worsened after treatment with other medications or radiation therapy. Cisplatin is used alone or in combination ... has worsened after treatment with other medications or radiation therapy. Cisplatin is also used alone or in ...

  8. Complete Remission of Acute Myeloid Leukemia following Cisplatin Based Concurrent Therapy with Radiation for Squamous Cell Laryngeal Cancer

    PubMed Central

    Gill, Harpaul S.; Higgins, Kristin A.; Saba, Nabil F.; Kota, Vamsi K.

    2016-01-01

    Acute myeloid leukemia (AML) is a myeloid disorder with several established treatment regimens depending on patient and leukemic factors. Cisplatin is known to have strong leukemogenic potential and is rarely used even as salvage therapy in relapsed or refractory AML. We present a patient simultaneously diagnosed with AML and squamous cell carcinoma of the larynx, who was found to be in complete remission from AML following treatment with cisplatin based chemoradiotherapy for his laryngeal cancer. PMID:27127664

  9. Cisplatin induced sensory neuropathy is prevented by vascular endothelial growth factor-A.

    PubMed

    Vencappa, Samanta; Donaldson, Lucy F; Hulse, Richard P

    2015-01-01

    Increased patient survival is a mark of modern anti-cancer therapy success. Unfortunately treatment side-effects such as neurotoxicity are a major long term concern. Sensory neuropathy is one of the common toxicities that can arise during platinum based chemotherapy. In many cases the current poor understanding of the neurological degeneration and lack of suitable analgesia has led to high incidences of patient drop out of treatment. VEGF-A is a prominent neuroprotective agent thus it was hypothesised to prevent cisplatin induced neuropathy. Systemic cisplatin treatment (lasting 3 weeks biweekly) resulted in mechanical allodynia and heat hyperalgesia in mice when compared to vehicle control. PGP9.5 sensory nerve fibre innervation was reduced in the plantar skin in the cisplatin treated group versus vehicle control mice. The cisplatin induced sensory neurodegeneration was associated with increased cleaved caspase 3 expression as well as a reduction in Activating Transcription Factor 3 and pan VEGF-A expression in sensory neurons. VEGF-A165b expression was unaltered between vehicle and cisplatin treatment. rhVEGF-A165a and rhVEGF-A165b both prevented cisplatin induced sensory neurodegeneration. Cisplatin exposure blunts the regenerative properties of sensory neurons thus leading to sensory neuropathy. However, here it is identified that administration of VEGF-A isoform subtypes induce regeneration and prevent cell death and are therefore a possible adjunct therapy for chemotherapy induced neuropathy. PMID:26279748

  10. Cisplatin induced sensory neuropathy is prevented by vascular endothelial growth factor-A

    PubMed Central

    Vencappa, Samanta; Donaldson, Lucy F; Hulse, Richard P

    2015-01-01

    Increased patient survival is a mark of modern anti-cancer therapy success. Unfortunately treatment side-effects such as neurotoxicity are a major long term concern. Sensory neuropathy is one of the common toxicities that can arise during platinum based chemotherapy. In many cases the current poor understanding of the neurological degeneration and lack of suitable analgesia has led to high incidences of patient drop out of treatment. VEGF-A is a prominent neuroprotective agent thus it was hypothesised to prevent cisplatin induced neuropathy. Systemic cisplatin treatment (lasting 3 weeks biweekly) resulted in mechanical allodynia and heat hyperalgesia in mice when compared to vehicle control. PGP9.5 sensory nerve fibre innervation was reduced in the plantar skin in the cisplatin treated group versus vehicle control mice. The cisplatin induced sensory neurodegeneration was associated with increased cleaved caspase 3 expression as well as a reduction in Activating Transcription Factor 3 and pan VEGF-A expression in sensory neurons. VEGF-A165b expression was unaltered between vehicle and cisplatin treatment. rhVEGF-A165a and rhVEGF-A165b both prevented cisplatin induced sensory neurodegeneration. Cisplatin exposure blunts the regenerative properties of sensory neurons thus leading to sensory neuropathy. However, here it is identified that administration of VEGF-A isoform subtypes induce regeneration and prevent cell death and are therefore a possible adjunct therapy for chemotherapy induced neuropathy. PMID:26279748

  11. Cholesterol reduces the sensitivity to platinum-based chemotherapy via upregulating ABCG2 in lung adenocarcinoma.

    PubMed

    Wu, Yufeng; Si, Ruirui; Tang, Hong; He, Zhen; Zhu, Hui; Wang, Lili; Fan, Yingchao; Xia, Suhua; He, Zelai; Wang, Qiming

    2015-02-20

    Inoperable lung adenocarcinoma is currently treated with platinum-based chemotherapy. However, the effectiveness of these chemotherapeutic agents is not the same for all patients. Patients either show quick chemoresistance (QCR) or delayed chemoresistance (DCR), which are defined by 87 and 242 days of progression-free survival (PFS) after initial platinum-based treatment, respectively. We found that QCR patients displayed an elevated level of serum cholesterol and that their tumors showed upregulated ABCG2 expression. We propose that chemoresistance may be attributed to cholesterol-induced ABCG2 expression and hypothesize that blocking ABCG2 may increase the efficacy of platinum-based chemotherapeutic agents. Using the MTT cell viability assay, we observed that cotreatment with ABCG2 blocker Nicardipine and platinum-based drugs Cisplatin, Oxaliplatin or Carboplatin significantly decreased cell viability of tumor cells. Importantly, our results also showed that incubating cells with cholesterol prior to chemotherapy treatment or cotreatment increased cell viability of tumor cells relative to the controls.

  12. Locally advanced adenocarcinoma and adenosquamous carcinomas of the cervix compared to squamous cell carcinomas of the cervix in Gynecologic Oncology Group trials of cisplatin-based chemoradiation

    PubMed Central

    Rose, Peter G; Java, James J; Whitney, Charles W.; Stehman, Frederick B; Lanciano, Rachelle; Thomas, Gillian M

    2015-01-01

    Objective Conflicting results have been reported for adeno- and adenosquamous carcinomas of the cervix with respect to their response to therapy and prognosis. The current study sought to evaluate impact of adeno- and adenosquamous histology in the randomized trials of primary cisplatin-based chemoradiation for locally advanced cervical cancer. Methods Patients with adeno- and adenosquamous cervical carcinomas were retrospectively studied and compared to squamous cell carcinomas in GOG trials of chemoradiation. Results Among 1671 enrolled in clinical trials of chemoradiation, 182 adeno- and adenosquamous carcinomas were identified (10.9%). A higher percentage of adeno- and adenosquamous carcinomas were stage IB2 (27.5% versus 20.0%) and fewer had stage IIIB (21.4% versus 28.6%). The mean tumor size was larger for squamous than adeno- and adenosquamous. Adeno- and adenosquamous carcinomas were more often poorly differentiated (46.2% versus 26.8%). When treated with radiation therapy alone, the 70 patients with adeno- and adenosquamous carcinoma of the cervix showed a statistically poorer overall survival (p=0.0499) compared to the 647 patients with squamous cell carcinoma of the cervix. However, when treated with radiation therapy with concurrent cisplatin-based chemotherapy, the 112 patients with adeno- and adenosquamous carcinomas had a similar overall survival (p=0.459) compared the 842 patients with squamous cell carcinoma. Adverse effects to treatment were similar across histologies. Conclusion Adeno- and adenosquamous carcinomas of the cervix are associated with worse overall survival when treated with radiation alone but with similar progression-free and overall survival compared to squamous cell carcinomas of the cervix when treated with cisplatin based chemoradiation. PMID:25152438

  13. Cardiovascular Disease Mortality After Chemotherapy or Surgery for Testicular Nonseminoma: A Population-Based Study

    PubMed Central

    Fung, Chunkit; Fossa, Sophie D.; Milano, Michael T.; Sahasrabudhe, Deepak M.; Peterson, Derick R.; Travis, Lois B.

    2015-01-01

    Purpose Increased risks of incident cardiovascular disease (CVD) in patients with testicular cancer (TC) given chemotherapy in European studies were largely restricted to long-term survivors and included patients from the 1960s. Few population-based investigations have quantified CVD mortality during, shortly after, and for two decades after TC diagnosis in the era of cisplatin-based chemotherapy. Patients and Methods Standardized mortality ratios (SMRs) for CVD and absolute excess risks (AERs; number of excess deaths per 10,000 person-years) were calculated for 15,006 patients with testicular nonseminoma reported to the population-based Surveillance, Epidemiology, and End Results program (1980 to 2010) who initially received chemotherapy (n = 6,909) or surgery (n = 8,097) without radiotherapy and accrued 60,065 and 81,227 person-years of follow-up, respectively. Multivariable modeling evaluated effects of age, treatment, extent of disease, and other factors on CVD mortality. Results Significantly increased CVD mortality occurred after chemotherapy (SMR, 1.36; 95% CI, 1.03 to 1.78; n = 54) but not surgery (SMR, 0.81; 95% CI, 0.60 to 1.07; n = 50). Significant excess deaths after chemotherapy were restricted to the first year after TC diagnosis (SMR, 5.31; AER, 13.90; n = 11) and included cerebrovascular disease (SMR, 21.72; AER, 7.43; n = 5) and heart disease (SMR, 3.45; AER, 6.64; n = 6). In multivariable analyses, increased CVD mortality after chemotherapy was confined to the first year after TC diagnosis (hazard ratio, 4.86; 95% CI, 1.25 to 32.08); distant disease (P < .05) and older age at diagnosis (P < .01) were independent risk factors. Conclusion This is the first population-based study, to our knowledge, to quantify short- and long-term CVD mortality after TC diagnosis. The increased short-term risk of CVD deaths should be further explored in analytic studies that enumerate incident events and can serve to develop comprehensive evidence-based approaches

  14. Nephrotoxicity as a Dose-Limiting Factor in a High-Dose Cisplatin-Based Chemoradiotherapy Regimen for Head and Neck Carcinomas

    PubMed Central

    Hoek, Jantien; Bloemendal, Karen M.; van der Velden, Lilly-Ann A.; van Diessen, Judi N.A.; van Werkhoven, Erik; Klop, Willem M.C.; Tesselaar, Margot E.T.

    2016-01-01

    Purpose: Loco-regional control and organ preservation are significantly improved with concomitant cisplatin/radiotherapy and are compromised with less than 5% grade 3 nephrotoxicity (creatinine clearance 15–29 mL/min). However, although clinically important, in none of the randomized trials is grade 2 nephrotoxicity (defined as creatinine clearance 59–30 mL/min) mentioned. In this study, we assessed nephrotoxicity in daily practice among patients treated with high-dose cisplatin (100 mg/m2 on days 1, 22, and 43), concurrently with chemoradiotherapy (CCRT) and the impact on treatment modifications. Methods: 208 patients with advanced-stage malignancies of the head and neck region were evaluated. All patients were treated with high-dose cisplatin CCRT. The main outcome parameters were nephrotoxicity (defined as creatinine clearance grade 2 or more) and cumulative doses of cisplatin and radiation. Results: 133 patients (64%) completed all pre-planned courses of cisplatin. Nephrotoxicity was the main reason to discontinue the chemotherapy. Grade 3 nephrotoxicity was seen in 16 patients (8%) while grade 2 nephrotoxicity was seen in 53 patients (25%). Thirty six patients (17%) could not complete the pre-planned chemotherapy due to nephrotoxicity. Conclusions: In head and neck cancer patients, nephrotoxicity grade 2 is under-reported but is the major factor for discontinuing cisplatin during CCRT. PMID:26891330

  15. PKM2 enhances chemosensitivity to cisplatin through interaction with the mTOR pathway in cervical cancer

    PubMed Central

    Zhu, Haiyan; Wu, Jun; Zhang, Wenwen; Luo, Hui; Shen, Zhaojun; Cheng, Huihui; Zhu, Xueqiong

    2016-01-01

    Pyruvate kinase M2 (PKM2) is a key driver of aerobic glycolysis in cancer cells and has been shown to be up-regulated by mTOR in vitro. Our previous proteomic profiling studies showed that PKM2 was significantly upregulated in cervical cancer tissues after treatment with neoadjuvant chemotherapy (NACT). Whether PKM2 expression predicts cisplatin-based NACT sensitivity and is mTOR dependent in cervical cancer patients remains unclear. Using paired tumor samples (pre- and post-chemotherapy) from 36 cervical cancer patients, we examined mTOR, HIF-1α, c-Myc, and PKM2 expression in cervical cancer samples and investigated the response to cisplatin-based NACT. In addition, we established PKM2 suppressed cervical cancer cell lines and evaluated their sensitivity to cisplatin in vitro. We found that the mTOR/HIF-1α/c-Myc/PKM2 signaling pathway was significantly downregulated in post-chemotherapy cervical cancer tissues. High levels of mTOR, HIF-1α, c-Myc, and PKM2 were associated with a positive chemotherapy response in cervical cancer patients treated with cisplatin-based NACT. In vitro, PKM2 knockdown desensitized cervical cancer cells to cisplatin. Moreover, PKM2 had complex interactions with mTOR pathways. mTOR, HIF1α, c-Myc, and PKM2 expression in cervical cancer may serve as predictive biomarkers to cisplatin-based chemotherapy. PKM2 enhances chemosensitivity to cisplatin through interaction with the mTOR pathway in cervical cancer. PMID:27492148

  16. 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

  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. 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.

  19. [Combination Chemotherapy Using Sorafenib and Hepatic Arterial Infusion with a Fine-Powder Formulation of Cisplatin for Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis--A Case Report].

    PubMed

    Tsukamoto, Tadashi; Kanazawa, Akishige; Shimizu, Sadatoshi; Murata, Akihiro; Sakae, Masayuki; Kurihara, Shigeaki; Tashima, Tetsuzo; Deguchi, Sota; Nakai, Takashi; Kawasaki, Yasuko; Kioka, Kiyohide

    2015-11-01

    Sorafenib has been a standard therapy for advanced hepatocellular carcinoma (HCC) with portal vein thrombosis. Hepatic arterial infusion chemotherapy (HAIC) is still preferably performed in Japan because of its relatively good tumor-shrinking effect. We report a case of advanced multiple HCC with portal thrombus that responded to combination chemotherapy with sorafenib and repeat hepatic arterial infusion with a fine-powder formulation of cisplatin (IA-call®). A 57-year-old man presented for the treatment of HCC with alcoholic cirrhosis. Multiple HCC were found to be rapidly progressing with portal thrombosis. HAIC with IA-call® was performed, but the tumors progressed. TAE was performed 3 times thereafter and the main tumor shrunk to some extent. A month after the last TAE, the HCC was found to progress again, and oral sorafenib was administered. A reservoir and catheter were placed and HAIC with low-dose 5-fluorouracil and cisplatin was performed for 3 cycles following 1 HAIC cycle with epirubicin and mitomycin C, which was not effective. For 10 months after initial therapy, HAIC using IA-call® has been performed once for 6 weeks. After performing HAIC with IA-call® 5 times, the serum levels of HCC tumor markers AFP and PIVKA-Ⅱdecreased, and the tumors continued to shrink and were not stained on enhanced CT scan. The patient has been alive for 23 months after the initial therapy and has maintained stable disease. PMID:26805203

  20. 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.

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

    PubMed

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

    2014-12-01

    Cisplatin/gemcitabine association has been a standard of care for first-line regimen in advanced biliary tract cancer nevertheless oxaliplatin/gemcitabine regimen is frequently preferred. Because comparative effectiveness in clinical outcomes of cisplatin- versus oxaliplatin-containing chemotherapy is not available, a systematic review of studies assessing cisplatin/gemcitabine or oxaliplatin/gemcitabine chemotherapies in advanced biliary tract cancer was performed. Published studies evaluating cisplatin/gemcitabine or oxaliplatin/gemcitabine in advanced biliary tract cancer were included. Each study was weighted according to the number of patients included. The primary objective was to assess weighted median of medians overall survival (mOS) reported for both regimens. Secondary goals were to assess weighted median of medians progression-free survival (mPFS) and toxic effects were pooled and compared within each arm. Thirty-three studies involving 1470 patients were analyzed. In total, 771 and 699 patients were treated by cisplatin/gemcitabine and oxaliplatin/gemcitabine, respectively. Weighted median of mOS was 9.7 months in cisplatin group and 9.5 months in oxaliplatin group. Cisplatin-based chemotherapy was significantly associated with more grade 3 and 4 asthenia, diarrhea, liver toxicity, and hematological toxicity. Sensitivity analysis including only the studies with the standard regimen of cisplatin (25-35 mg/m(2) administered on days 1 and 8) showed that the weighted median of mOS increased from 9.7 to 11.7 months but Gem/CDDP regimen remained more toxic than Gemox regimen. These results suggest that the Gem/CDDP regimen with cisplatin (25-35 mg/m(2)) administered on days 1 and 8 is associated with survival advantage than Gemox regimen but with addition of toxicity.

  2. Cisplatin-Induced Antitumor Immunomodulation: A Review of Preclinical and Clinical Evidence

    PubMed Central

    de Biasi, Andreas R.; Villena-Vargas, Jonathan; Adusumilli, Prasad S.

    2014-01-01

    Contrary to the long held belief that chemotherapy is immunosuppressive, emerging evidence indicates that the anticancer activity of cisplatin is not limited to its ability to inhibit mitosis, but that cisplatin also has important immunomodulatory effects. We therefore methodically examined the relevant preclinical literature and identified four main mechanisms of cisplatin-induced antitumor immunomodulation: (1) MHC class I expression upregulation; (2) recruitment and proliferation of effector cells; (3) upregulation of the lytic activity of cytotoxic effectors; and (4) downregulation of the immunosuppressive microenvironment. Cisplatin-based combination chemotherapy’s antitumor immunomodulatory effects are also beginning to be harnessed in the clinic; we therefore additionally reviewed the applicable clinical literature and discussed how monitoring various components of the immune system (and their responses to cisplatin) can add new levels of sophistication to disease monitoring and prognostication. In summation, this growing body of literature on cisplatin-induced antitumor immunomodulation ultimately highlights the therapeutic potential of synergistic strategies that combine traditional chemotherapy with immunotherapy. PMID:25204552

  3. 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.

  4. 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.

  5. 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.

  6. Involvement of caspase-dependent and -independent apoptotic pathways in cisplatin-induced apoptosis

    NASA Astrophysics Data System (ADS)

    Liu, Lei; Zhang, Yingjie; Wang, Xianwang

    2009-02-01

    Cisplatin, an efficient anticancer agent, can trigger multiple apoptotic pathways in cancer cells. However, the signal transduction pathways in response to cisplatin-based chemotherapy are complicated, and the mechanism is not fully understood. In current study, we showed that, during cisplatin-induced apoptosis of human lung adenocarcinoma cells, both the caspase-dependent and -independent pathways were activated. Herein, we reported that after cisplatin treatment, the activities of caspase-9/-3 were sharply increased; pre-treatment with Z-LEHD-fmk (inhibitor of caspase-9), Z-DEVD-fmk (inhibitor of caspase-3), and Z-VAD-fmk (a pan-caspase inhibitor) increased cell viability and decreased apoptosis, suggesting that caspase-mediated apoptotic pathway was activated following cisplatin treatment. Confocal imaging of the cells transfected with AIF-GFP demonstrated that AIF release occurred about 9 h after cisplatin treatment. The event proceeded progressively over time, coinciding with a nuclear translocation and lasting for more than 2 hours. Down-regulation of AIF by siRNA also significantly increased cell viability and decreased apoptosis, these results suggested that AIF-mediated caspase-independent apoptotic pathway was involved in cispatin-induced apoptosis. In conclusion, the current study demonstrated that both caspase-dependent and -independent apoptotic pathways were involved in cisplatin-induced apoptosis in human lung adenocarcinoma cells.

  7. Engineering of lipid prodrug-based, hyaluronic acid-decorated nanostructured lipid carriers platform for 5-fluorouracil and cisplatin combination gastric cancer therapy

    PubMed Central

    Qu, Chun-Ying; Zhou, Min; Chen, Ying-wei; Chen, Mei-mei; Shen, Feng; Xu, Lei-Ming

    2015-01-01

    Purpose The first-line chemotherapy treatment protocol for gastric cancer is combination chemotherapy of 5-fluorouracil (5-FU) and cisplatin (CDDP). The aim of this study was to engineer prodrug-based nanostructured lipid carriers (NLC) platform for codelivery of 5-FU and CDDP to enhance therapy and decrease toxicity. Methods First, 5-FU-stearic acid lipid conjugate was synthesized by two steps. Second, 5-FU-stearic acid prodrug and CDDP were loaded in NLC. Finally, hyaluronic acid (HA) was coated onto NLC surface. Average size, zeta potential, and drug loading capacity of NLC were evaluated. Human gastric cancer cell line BGC823 (BGC823 cells) was used for the testing of in vitro cytotoxicity assays. In vivo antitumor activity of NLC was evaluated in mice bearing BGC823 cells model. Results HA-coated 5-FU-stearic acid prodrug and CDDP-loaded NLC (HA-FU/C-NLC) showed a synergistic effect in combination therapy and displayed the greatest antitumor activity than all of the free drugs or uncoated NLC in vitro and in vivo. Conclusion This work reveals that HA-coated NLC could be used as a novel carrier to code-liver 5-FU and CDDP for gastric cancer therapy. HA-FU/C-NLC could be a promising targeted and combinational therapy in nanomedicine. PMID:26089667

  8. Cisplatin nephrotoxicity.

    PubMed

    Arany, Istvan; Safirstein, Robert L

    2003-09-01

    Cisplatin remains a major antineoplastic drug for the treatment of solid tumors. Its chief dose-limiting side effect is nephrotoxicity, which evolves slowly and predictably after initial and repeated exposure. The kidney accumulates cisplatin to a higher degree than other organs perhaps via mediated transport. Functionally, reduced renal perfusion and a concentrating defect characterize its nephrotoxicity, whereas morphologically necrosis of the terminal portion of the proximal tubule and apoptosis predominantly in the distal nephron characterize its effects on cell fate. Among the earliest reactions of the kidney to cisplatin is the activation of the MAPK cascade and molecular responses typical of the stress response. Repression of genes characteristic of the mature phenotype of the kidney, especially those serving transport function of the kidney, is also prominent. Metabolic responses, cell cycle events and the inflammatory cascade seem to be important determinants of the degree of renal failure induced by cisplatin. Manipulation of these responses may be exploited to reduce its toxicity clinically.

  9. 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

  10. 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

  11. 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.

  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. 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

  14. Definitive Radiotherapy Following Induction Chemotherapy for Hypopharyngeal Cancer: Selecting Candidates for Organ-Preserving Treatment Based on the Response to Induction Chemotherapy.

    PubMed

    Yanagi, Takeshi; Shibamoto, Yuta; Ogino, Hiroyuki; Baba, Fumiya; Murai, Taro; Nagai, Aiko; Miyakawa, Akifumi; Sugie, Chikao

    2016-01-01

    The outcomes of induction chemotherapy followed by radiotherapy for hypopharyngeal carcinoma were analyzed to determine whether response to induction chemotherapy could be a useful parameter for selecting candidates for organ-preserving therapy.Forty-three patients with hypopharyngeal carcinoma were treated with definitive radiotherapy with or without concurrent chemotherapy following induction chemotherapy. The predominant induction chemotherapy regimens involved cisplatin and 5-fluorouracil with or without docetaxel. The patients that responded to the induction chemotherapy received definitive organ-preserving treatment. Patients who did not respond to induction chemotherapy were considered for surgery, but only those patients who underwent definitive radiotherapy were analyzed in this study. Conventional radiotherapy was administered in all patients. The associations between clinical parameters including age, sex, performance status (PS), tumor site, T-category, N-category, stage, the regimen of induction chemotherapy, the response to induction chemotherapy, the presence/absence of concurrent chemotherapy, overall survival (OS), and local control (LC) were analyzed.Among the surviving patients, the follow-up period ranged from 10-145 months (median: 46 months). The 3-year OS and LC rates for all 43 patients were 61% and 70%, respectively. The 3-year OS and LC rates of the responders were 73% and 81%, respectively, whereas those of the non-responders were 29% and 40%, respectively. In multivariate analysis, only PS was correlated with overall survival (p=0.03). The complication rates were acceptable in all groups.Responders to induction chemotherapy appear to be good candidates for definitive organ-preserving treatment. Chemoselection appears to aid treatment selection in patients with hypopharyngeal carcinoma.

  15. Ghrelin Prevents Cisplatin-Induced Testicular Damage by Facilitating Repair of DNA Double Strand Breaks Through Activation of p53 in Mice.

    PubMed

    Garcia, Jose M; Chen, Ji-an; Guillory, Bobby; Donehower, Lawrence A; Smith, Roy G; Lamb, Dolores J

    2015-07-01

    Cisplatin administration induces DNA damage resulting in germ cell apoptosis and subsequent testicular atrophy. Although 50 percent of male cancer patients receiving cisplatin-based chemotherapy develop long-term secondary infertility, medical treatment to prevent spermatogenic failure after chemotherapy is not available. Under normal conditions, testicular p53 promotes cell cycle arrest, which allows time for DNA repair and reshuffling during meiosis. However, its role in the setting of cisplatin-induced infertility has not been studied. Ghrelin administration ameliorates the spermatogenic failure that follows cisplatin administration in mice, but the mechanisms mediating these effects have not been well established. The aim of the current study was to characterize the mechanisms of ghrelin and p53 action in the testis after cisplatin-induced testicular damage. Here we show that cisplatin induces germ cell damage through inhibition of p53-dependent DNA repair mechanisms involving gamma-H2AX and ataxia telangiectasia mutated protein kinase. As a result, testicular weight and sperm count and motility were decreased with an associated increase in sperm DNA damage. Ghrelin administration prevented these sequelae by restoring the normal expression of gamma-H2AX, ataxia telangiectasia mutated, and p53, which in turn allows repair of DNA double stranded breaks. In conclusion, these findings indicate that ghrelin has the potential to prevent or diminish infertility caused by cisplatin and other chemotherapeutic agents by restoring p53-dependent DNA repair mechanisms. PMID:26019260

  16. BGP-15 - a novel poly(ADP-ribose) polymerase inhibitor - protects against nephrotoxicity of cisplatin without compromising its antitumor activity.

    PubMed

    Racz, Ildiko; Tory, Kalman; Gallyas, Ferenc; Berente, Zoltán; Osz, Erzsebet; Jaszlits, Laszlo; Bernath, Sandor; Sumegi, Balazs; Rabloczky, Gyorgy; Literati-Nagy, Peter

    2002-03-15

    Nephrotoxicity is one of the major dose limiting side effects of cisplatin chemotherapy. The antitumor and toxic effects are mediated in part by different mechanisms, thus, permitting a selective inhibition of certain side effects. The influence of O-(3-piperidino-2-hydroxy-1-propyl)nicotinic amidoxime (BGP-15) - a poly(ADP-ribose) polymerase (PARP) inhibitor - on the nephrotoxicity and antitumor efficacy of cisplatin has been evaluated in experimental models. BGP-15 either blocked or significantly reduced (60-90% in 100-200 mg/kg oral dose) cisplatin induced increase in serum urea and creatinine level in mice and rats and prevented the structural degeneration of the kidney, as well. The nephroprotective effect of BGP-15 treatment was revealed also in living mice by MRI analysis manifesting in the lack of oedema which otherwise developed as a result of cisplatin treatment. The protective effect was accompanied by inhibition of cisplatin-induced poly-ADP-ribosylation and by the restoration of the disturbed energy metabolism. The preservation of ATP level in the kidney was demonstrated in vivo by localized NMR spectroscopy. BGP-15 decreased cisplatin-induced ROS production in rat kidney mitochondria and improved the antioxidant status of the kidney in mice with cisplatin-induced nephropathy. In rat kidney, cisplatin caused a decrease in the level of Bcl-x, a mitochondrial protective protein, and this was normalized by BGP-15 treatment. On the other hand, BGP-15 did not inhibit the antitumor efficacy of cisplatin in cell culture and in transplantable solid tumors of mice. Treatment with BGP-15 increased the mean survival time of cisplatin-treated P-388 leukemia bearing mice from 13 to 19 days. PARP inhibitors have been demonstrated to diminish the consequences of free radical-induced damage, and this is related to the chemoprotective effect of BGP-15, a novel PARP inhibitor. Based on these results, we propose that BGP-15 represents a novel, non-thiol chemoprotective

  17. Chemotherapy for Soft Tissue Sarcomas

    MedlinePlus

    ... drugs may be used as well, including cisplatin, dacarbazine (DTIC), docetaxel (Taxotere ® ), gemcitabine (Gemzar ® ), methotrexate, oxaliplatin, paclitaxel (Taxol ® ), ... such as: MAID (mesna, Adriamycin [doxorubicin], ifosfamide, and dacarbazine). Chemotherapy drugs kill cancer cells but also damage ...

  18. Ototoxicity caused by cisplatin is ameliorated by melatonin and other antioxidants.

    PubMed

    Lopez-Gonzalez, M A; Guerrero, J M; Rojas, F; Delgado, F

    2000-03-01

    The mechanism of the ototoxicity caused by cisplatin is based in the generation of reactive oxygen species, which interferes with the antioxidant protection of the organ of Corti. Conversely, the protection of the cochlea with antioxidants ameliorates the ototoxicity by cisplatin. The ototoxicity produced by cisplatin can be reversible or persistent, depending on the age of the patient, cumulative doses, number of chemotherapy cycles, history of noise exposure, and deteriorating renal function. We have obtained in rats an ototoxic chart utilizing cisplatin (10 mg/kg body weight injected intraperitoneally, once only). Together with this treatment, the animals were treated with melatonin in the drinking water (10 mg/L) or injected subcutaneously (250 microg), and with an antioxidant mixture, injected subcutaneously, composed of 0.25 mg alpha-tocopherol acid succinate, 3 mg ascorbic acid, 1 mg glutathione, and 60 mg N-acetylcysteine. The distortion product otoacoustic emissions were determined for a prolonged period of time for each animal. The ototoxicity produced by cisplatin was maximal from days 7 to 10 post-treatment, returning to normal values in a month. When melatonin and the antioxidant mixture were present, the recovery was between days 10 and 15 post-treatment, independent of the means of administration of the pineal product. We conclude that the ototoxicity caused by cisplatin is ameliorated by melatonin and other antioxidants. PMID:10709968

  19. Simvastatin protects Sertoli cells against cisplatin cytotoxicity through enhanced gap junction intercellular communication.

    PubMed

    Wang, Lingzhi; Peng, Jianxin; Huang, Huansen; Wang, Qin; Yu, Meiling; Tao, Liang

    2015-10-01

    Cisplatin, an important chemotherapeutic agent against testicular germ cell cancer, induces testicular toxicity on Leydig and Sertoli cells, leading to serious side-effects such as azoospermia and infertility. In a previous study, it was found that simvastatin enhanced the sensitivity of Leydig tumor cells to chemotherapeutic toxicity through the enhancement of gap junction functions. In the present study, the effect of simvastatin on the sensitivity of normal Sertoli cells to cisplatin and the role of gap junctions in such effects was investigated. The results showed that, simvastatin attenuated cisplatin toxicity only when cells exhibited high-density culture where gap junctional formation was possible. When gap junction function was decreased by the gap junction inhibitor or by siRNA targeting connexin 43, the protective effect of simvastatin to cisplatin toxicity was substantially attenuated. Simvastatin also enhanced gap junction functions between Sertoli cells. This effect was mediated by the reduction of PKC-mediated connexin phosphorylation, thereby increasing connexin 43 membrane localization. Thus, simvastatin-induced enhancement of gap junction‑mediated intercellular communication attenuated cisplatin toxicity on Sertoli cells. This result indicated that enhancement of gap junction function by simvastatin may have bilateral beneficial effects on cisplatin‑based chemotherapy, enhancing cisplatin killing on cancer while ameliorating the reproduction toxicity.

  20. NM23-H1 expression of head and neck squamous cell carcinoma in association with the response to cisplatin treatment.

    PubMed

    Wang, Yi-Fen; Chang, Chun-Ju; Chiu, Jen-Hwey; Lin, Chin-Ping; Li, Wing-Yin; Chang, Shyue-Yih; Chu, Pen-Yuan; Tai, Shyh-Kuan; Chen, Yu-Jen

    2014-09-15

    We recently reported that low NM23-H1 expression of head and neck squamous cell carcinoma (HNSCC) correlated with poor patients' prognosis. Growing evidence has indicated that high tumor NM23-H1 expression contributes to a good response to chemotherapy. Therefore, we investigated the role of NM23-H1 in susceptibility of HNSCC cells to cisplatin and its clinical significance, as well as the in vitro study for validation was performed. Using immunohistochemistry, we analyzed NM23-H1 expression in surgical specimens from 46 HNSCC patients with cervical metastases receiving surgery and adjuvant chemoradiotherapy. Low tumor NM23-H1 expression correlated with locoregional recurrence of HNSCC following postoperative cisplatin-based therapy (p = 0.056) and poor patient prognosis (p = 0.001). To validate the clinical observation and the effect of NM23-H1 on cisplatin cytotoxicity, we established several stable clones derived from a human HNSCC cell line (SAS) by knockdown and overexpression. Knockdown of NM23-H1 attenuated the chemosensitivity of SAS cells to cisplatin, which was associated with reduced cisplatin-induced S-phase accumulation and downregulation of cyclin E1 and A. Overexpression of NM23-H1 reversed these results, indicating the essential role of NM23-H1 in treatment response to cisplatin. NM23-H1 may participate in HNSCC cell responses to cisplatin and be considered a potential therapeutic target. PMID:25277180

  1. MicroRNA-203 Is a Prognostic Indicator in Bladder Cancer and Enhances Chemosensitivity to Cisplatin via Apoptosis by Targeting Bcl-w and Survivin.

    PubMed

    Zhang, Xin; Zhang, Yanli; Liu, Xinfeng; Fang, Aiju; Li, Peilong; Li, Zewu; Liu, Tong; Yang, Yongmei; Du, Lutao; Wang, Chuanxin

    2015-01-01

    Resistance to cisplatin-based chemotherapy is a major cause of treatment failure in advanced bladder cancer (BC) patients. There is increasing evidence that microRNAs are involved in the development and progression of BC. However, little is known about the function of microRNAs in predicting the effect of adjuvant chemotherapy on BC survival and regulating response to cisplatin. To address this issue, we employed RT-qPCR to evaluate the clinical significance of miR-203 expression in 108 tissues of BC patients receiving cisplatin-based adjuvant chemotherapy, and performed in vitro studies to explore chemotherapeutic sensitivity to cisplatin in miR-203 overexpressing BC cells. We found miR-203 levels were significantly lower in BC progression group than non-progression group (P<0.001). ROC curve analysis illustrated miR-203 could significantly distinguish progressed patients from those without progression (P<0.001), yielding an area under the ROC curve of 0.839 (95% CI, 0.756-0.903). Moreover, low miR-203 expression correlated with shortened progression free survival (PFS) and overall survival (OS) of BC patients, and was an independent prognostic factor. Overexpression of miR-203 in 5637 and T24 BC cells could decrease cell viability, enhance cisplatin cytotoxicity, and promote apoptosis. Western blotting and luciferase reporter assay showed Bcl-w and Survivin were direct downstream targets of miR-203. There was also a significant inverse association between miR-203 and Bcl-w or Survivin expression in BC tissues (r = -0.781, -0.740, both P<0.001). In conclusion, decreased miR-203 predicts progression and poor prognosis for BC patients treated with cisplatin-based chemotherapy while miR-203 overexpression can enhance cisplatin sensitization by promoting apoptosis via directly targeting Bcl-w and Survivin.

  2. Cellular Uptake and Internalization of Hyaluronan-based Doxorubicin and Cisplatin Conjugates

    PubMed Central

    Cai, Shuang; Alhowyan, Adel Ali B; Yang, Qiuhong; Forrest, W.C. Melanie; Shnayder, Yelizaveta; Forrest, M. Laird

    2015-01-01

    Background Hyaluronan (HA) is a ligand for the CD44 receptor which is crucial to cancer cell proliferation and metastasis. High levels of CD44 expression in many cancers have encouraged the development of HA-based carriers for anti-cancer therapeutics. Purpose The objective of this study was to determine whether HA conjugation of anticancer drugs impacts CD44-specific HA-drug uptake and disposition by human head and neck cancer cells. Methods The internalization and cellular disposition of hyaluronan-doxorubicin (HA-DOX), hyaluronan-cisplatin (HA-Pt), and hyaluronan-cyanine7 (HA-Cy7) conjugates were investigated by inhibiting endocytosis pathways, and by inhibiting the CD44–mediated internalization pathways that are known to mediate hyaluronan uptake in vitro. Results Cellular internalization of HA was regulated by CD44 receptors. In mouse xenografts, HA conjugation significantly enhanced tumor cell uptake compared to unconjugated drug. Discussion The results suggested that the main mechanism of HA-based conjugate uptake may be active transport via CD44 in conjunction with a clathrin–dependent endocytic pathway. Other HA receptors, hyaluronan–mediated motility receptor (RHAMM) and lymphatic vessel endothelial hyaluronan receptor (LYVE-1), did not play a significant role in conjugate uptake. Conclusions HA conjugation significantly increased CD44 mediated drug uptake and extended the residence time of drugs in tumor cells. PMID:24892741

  3. Revisiting DNA damage repair, p53-mediated apoptosis and cisplatin sensitivity in germ cell tumors.

    PubMed

    Cavallo, Francesca; Feldman, Darren R; Barchi, Marco

    2013-01-01

    Testicular germ cell tumors (TGCTs), ie, seminomas and nonseminomas, account for 1% to 3% of all neoplasms in men. They are the most common cancer in young white males and are unique in their responsiveness to cisplatin-based chemotherapy. For this reason, TGCTs are considered a model for curative disease. However, up to now, the molecular mechanisms behind this exceptional responsiveness to DNA-damaging agents have remained unclear. A hypersensitive apoptotic response, as well as a reduction in the proficiency to repair cisplatin-induced DNA damage might account for this behavior. In this review, building on recent findings of p53-induced apoptosis and DNA-repair mechanisms in TGCTs, we will discuss the molecular bases that drive tumor sensitivity to cisplatin, emphasizing the new therapeutic approaches proposed to eventually constrain tumor recurrence, and target TGCTs which are unresponsive to standard therapies. PMID:23784838

  4. EGCG Enhances Cisplatin Sensitivity by Regulating Expression of the Copper and Cisplatin Influx Transporter CTR1 in Ovary Cancer.

    PubMed

    Wang, Xuemin; Jiang, Pan; Wang, Pengqi; Yang, Chung S; Wang, Xuerong; Feng, Qing

    2015-01-01

    Cisplatin is one of the first-line platinum-based chemotherapeutic agents for treatment of many types of cancer, including ovary cancer. CTR1 (copper transporter 1), a transmembrane solute carrier transporter, has previously been shown to increase the cellular uptake and sensitivity of cisplatin. It is hypothesized that increased CTR1 expression would enhance the sensitivity of cancer cells to cisplatin (cDDP). The present study demonstrates for the first time that (-)-epigallocatechin-3-gallate (EGCG), a major polyphenol from green tea, can enhance CTR1 mRNA and protein expression in ovarian cancer cells and xenograft mice. EGCG inhibits the rapid degradation of CTR1 induced by cDDP. The combination of EGCG and cDDP increases the accumulation of cDDP and DNA-Pt adducts, and subsequently enhances the sensitivity of ovarian cancer SKOV3 and OVCAR3 cells to the chemotherapeutic agent. In the OVCAR3 ovarian cancer xenograft nude mice model, the combination of the lower concentration of cDDP and EGCG strongly repressed the tumor growth and exhibited protective effect on the nephrotoxicity induced by cisplatin. Overall, these findings uncover a novel chemotherapy mechanism of EGCG as an adjuvant for the treatment of ovarian cancer. PMID:25927922

  5. 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

  6. 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

  7. JWA reverses cisplatin resistance via the CK2—XRCC1 pathway in human gastric cancer cells

    PubMed Central

    Xu, W; Chen, Q; Wang, Q; Sun, Y; Wang, S; Li, A; Xu, S; Røe, O D; Wang, M; Zhang, R; Yang, L; Zhou, J

    2014-01-01

    Gastric cancer is the third most common malignancy in China, with a median 5-year survival of only 20%. Cisplatin has been used in first-line cancer treatment for several types of cancer including gastric cancer. However, patients are often primary resistant or develop acquired resistance resulting in relapse of the cancer and reduced survival. Recently, we demonstrated that the reduced expression of base excision repair protein XRCC1 and its upstream regulator JWA in gastric cancerous tissues correlated with a significant survival benefit of adjuvant first-line platinum-based chemotherapy as well as XRCC1 playing an important role in the DNA repair of cisplatin-resistant gastric cancer cells. In the present study, we demonstrated the role of JWA in cisplatin-induced DNA lesions and aquired cisplatin resistance in five cell-culture models: gastric epithelial cells GES-1, cisplatin-sensitive gastric cancer cell lines BGC823 and SGC7901, and the cisplatin-resistant gastric cancer cell lines BGC823/DDP and SGC7901/DDP. Our results indicated that JWA is required for DNA repair following cisplatin-induced double-strand breaks (DSBs) via XRCC1 in normal gastric epithelial cells. However, in gastric cancer cells, JWA enhanced cisplatin-induced cell death through regulation of DNA damage-induced apoptosis. The protein expression of JWA was significantly decreased in cisplatin-resistant cells and contributed to cisplatin resistance. Interestingly, as JWA upregulated XRCC1 expression in normal cells, JWA downregulated XRCC1 expression through promoting the degradation of XRCC1 in cisplatin-resistant gastric cancer cells. Furthermore, the negative regulation of JWA to XRCC1 was blocked due to the mutation of 518S/519T/523T residues of XRCC1, and indicating that the CK2 activated 518S/519T/523T phosphorylation is a key point in the regulation of JWA to XRCC1. In conclusion, we report for the first time that JWA regulated cisplatin-induced DNA damage and apoptosis through the

  8. 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

  9. A cisplatin slow-release hydrogel drug delivery system based on a formulation of the macrocycle cucurbit[7]uril, gelatin and polyvinyl alcohol.

    PubMed

    Oun, Rabbab; Plumb, Jane A; Wheate, Nial J

    2014-05-01

    The anticancer drug cisplatin was encapsulated within the cucurbit[7]uril macrocycle to form the host-guest complex: cisplatin@CB[7]. This was then incorporated into gelatin and 0-4% w/v polyvinyl alcohol (PVA)-based hydrogels as slow release drug delivery vehicles. The hydrogels demonstrated predicable swelling and disintegration dependent on the PVA concentration. The hydrogel with the highest PVA content was slower to swell and release drug compared with lower concentrations of PVA. The effect of the hydrogel PVA concentration on in vitro cytotoxicity was examined using A2780/CP70 ovarian cancer cells. Over the 24h drug exposure time used, hydrogels containing 4% PVA showed a 20% decrease in viable cells compared to the control, whereas hydrogels containing 0% and 2% PVA induced an 80% and 45% inhibition of cell growth, respectively. There was no measurable difference in the in vitro cytotoxicity of free cisplatin and cisplatin@CB[7] containing hydrogels. Finally, the in vivo effectiveness of a 2%-PVA hydrogel implanted under the skin of nude mice bearing A2780/CP70 xenografts showed that low dose hydrogels containing cisplatin@CB[7] (30 μg equivalent of drug) was just as effective as an intraperitoneal high dose administration of free cisplatin (150 μg) at inhibiting tumour growth.

  10. 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

  11. 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

  12. 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.

  13. Clinical comparative investigation of efficacy and toxicity of cisplatin plus gemcitabine or plus Abraxane as first-line chemotherapy for stage III/IV non-small-cell lung cancer

    PubMed Central

    Ai, Dan; Guan, Yan; Liu, Xiu-Ju; Zhang, Chu-Feng; Wang, Peng; Liang, Hong-Lu; Guo, Qi-Sen

    2016-01-01

    Purpose The purpose of this study was to observe the clinical efficacy and toxicity of cisplatin in combination with gemcitabine or Abraxane as first-line chemotherapy for stage III/IV non-small-cell lung cancer (NSCLC). Patients and methods A total of 200 patients with advanced NSCLC, which was confirmed by pathology or cytology, were enrolled into our research by reviewing previous complete and retrievable medical records data of our hospital. A total of 100 patients were treated with gemcitabine (1,000 mg/m2, day 1 and day 8) in combination with cisplatin (75 mg/m2, days 1–3; GP group) and another 100 patients were treated with Abraxane (260 mg/m2, day 1) in combination with cisplatin (75 mg/m2, days 1–3; TP group). Twenty-one days were required to complete one cycle; at least two cycles were completed by each group. Results For the 100 patients in the GP group, the effective response rate (RR) was 27%, the disease control rate (DCR) was 63%, and the median progression-free survival (PFS) time was 8 months. For the 100 patients in the TP group, the RR was 52%, the DCR was 75%, and the median PFS was 20 months. There was significant difference in RR (P<0.001), but no significant difference in DSR and PFS (P>0.05). Common treatment-related adverse events were hematologic toxicity and gastrointestinal reaction. Hematologic toxicity mainly included decreased white blood cells and platelets. The differences between the two groups were statistically significant (P<0.05). Gastrointestinal reaction mainly included nausea and vomiting. There was no statistical significance between them (P=0.805). For the 85 patients with squamous carcinoma in the TP group, the RR was 60%, the DCR was 78%, and the median PFS was 7.5 months. For the 85 patients with squamous carcinoma in the GP group, the RR was 36%, the DCR was 62%, and the median PFS was 18.5 months. There was significant difference in RR (P=0.024), but no significant difference in DSR and PFS (P>0.05). For the 115

  14. Clinical comparative investigation of efficacy and toxicity of cisplatin plus gemcitabine or plus Abraxane as first-line chemotherapy for stage III/IV non-small-cell lung cancer

    PubMed Central

    Ai, Dan; Guan, Yan; Liu, Xiu-Ju; Zhang, Chu-Feng; Wang, Peng; Liang, Hong-Lu; Guo, Qi-Sen

    2016-01-01

    Purpose The purpose of this study was to observe the clinical efficacy and toxicity of cisplatin in combination with gemcitabine or Abraxane as first-line chemotherapy for stage III/IV non-small-cell lung cancer (NSCLC). Patients and methods A total of 200 patients with advanced NSCLC, which was confirmed by pathology or cytology, were enrolled into our research by reviewing previous complete and retrievable medical records data of our hospital. A total of 100 patients were treated with gemcitabine (1,000 mg/m2, day 1 and day 8) in combination with cisplatin (75 mg/m2, days 1–3; GP group) and another 100 patients were treated with Abraxane (260 mg/m2, day 1) in combination with cisplatin (75 mg/m2, days 1–3; TP group). Twenty-one days were required to complete one cycle; at least two cycles were completed by each group. Results For the 100 patients in the GP group, the effective response rate (RR) was 27%, the disease control rate (DCR) was 63%, and the median progression-free survival (PFS) time was 8 months. For the 100 patients in the TP group, the RR was 52%, the DCR was 75%, and the median PFS was 20 months. There was significant difference in RR (P<0.001), but no significant difference in DSR and PFS (P>0.05). Common treatment-related adverse events were hematologic toxicity and gastrointestinal reaction. Hematologic toxicity mainly included decreased white blood cells and platelets. The differences between the two groups were statistically significant (P<0.05). Gastrointestinal reaction mainly included nausea and vomiting. There was no statistical significance between them (P=0.805). For the 85 patients with squamous carcinoma in the TP group, the RR was 60%, the DCR was 78%, and the median PFS was 7.5 months. For the 85 patients with squamous carcinoma in the GP group, the RR was 36%, the DCR was 62%, and the median PFS was 18.5 months. There was significant difference in RR (P=0.024), but no significant difference in DSR and PFS (P>0.05). For the 115

  15. Chemotherapy in advanced bladder cancer: current status and future

    PubMed Central

    2011-01-01

    Bladder cancer occurs in the majority of cases in males. It represents the seventh most common cancer and the ninth most common cause of cancer deaths for men. Transitional cell carcinoma is the most predominant histological type. Bladder cancer is highly chemosensitive. In metastatic setting, chemotherapy based on cisplatin should be considered as standard treatment of choice for patients with good performance status (0-1) and good renal function-glomerular filtration rate (GFR) > 60 mL/min. The standard treatment is based on cisplatin chemotherapy regimens type MVAC, HD-MVAC, gemcitabine plus cisplatin (GC) or dose dense GC. In unfit patients, carboplatin based regimes; gemcitabine plus carboplatin or methotrexate plus carboplatin plus vinblastine (MCAVI) are reasonable options. The role of targeted therapies when used alone, or in combination with chemotherapy, or in maintenance, was evaluated; targeting angiogenesis seem to be very promising. The purpose of this literature review is to highlight the role of chemotherapy in the management of advanced transitional cell carcinoma of the bladder. PMID:21906310

  16. 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

  17. Development of Chitosan-based Dry Powder Inhalation System of Cisplatin for Lung Cancer

    PubMed Central

    Singh, D. J.; Lohade, A. A.; Parmar, J. J.; Hegde, Darshana D.; Soni, P.; Samad, A.; Menon, Mala D.

    2012-01-01

    Cisplatin, a platinum compound, exerts its cytotoxic effects by coordinating to DNA where it inhibits both replication and transcription, and induces programmed cell death. It is used in the treatment of non-small cell lung cancer. In the present study, an attempt was made to achieve better treatment of lung cancer by direct lung delivery of cisplatin microparticulate systems, which helps to localize the drug in the lungs, and also provide sustained action. Cisplatin-loaded chitosan microspheres were prepared by emulsification and ionotropic gelation method, and characterized for drug content, particle size, densities, flow properties, moisture content, and surface topography by SEM and in vitro drug release was evaluated in simulated lung fluid at 37° at pH 7.4. The respirable or fine particle fraction (FPF) was determined by using twin stage impinger (TSI). Further stability evaluation of cisplatin-loaded DPI systems was carried out at 25°/60% RH and at 40°/75% RH. PMID:23798777

  18. Effect of sorafenib on cisplatin-based chemoradiation in head and neck cancer cells

    PubMed Central

    Möckelmann, Nikolaus; Rieckmann, Thorsten; Busch, Chia-Jung; Becker, Benjamin; Gleißner, Lisa; Hoffer, Konstantin; Omniczynski, Maria; Steinmeister, Leonhard; Laban, Simon; Grénman, Reidar; Petersen, Cordula; Rothkamm, Kai; Dikomey, Ekkehard; Knecht, Rainald; Kriegs, Malte

    2016-01-01

    Despite aggressive chemoradiation (CRT) protocols in the treatment of patients with head and neck squamous cell carcinomas (HNSCC), the outcome is still unfavorable. To improve therapy efficacy we had already successfully tested the multikinase inhibitor sorafenib in combination with irradiation (IR) in previous studies on HNSCC cell lines. In this study we investigated its effect on combined CRT treatment using cisplatin.Radio- and chemosensitivity with and without sorafenib was measured in four HNSCC cell lines and normal fibroblasts (NF) by colony formation assay. Apoptosis and cell cycle analysis were performed by flow cytometry. In HNSCC cells, sorafenib enhanced the antiproliferative effect of cisplatin without affecting apoptosis induction and with only minor effects on cell inactivation. Sorafenib added prior to irradiation enhanced cellular radiosensitivity in three of the tested HNSCC cell lines and caused massive overall cell inactivation when combined with CRT. In contrast, sorafenib did not radiosensitize NF and reduced cisplatin-induced cell inactivation. Cell inactivation by IR and cisplatin is further increased by the addition of sorafenib in HNSCC, but not in NF cells. Therefore, sorafenib is a promising candidate to improve therapy efficacy for HNSCC. PMID:27015558

  19. Second-line chemotherapy with bleomycin, methotrexate, and vinorelbine (BMV) for patients with squamous cell carcinoma of the head, neck and esophagus (SCC-HN&E) pretreated with a cisplatin-containing regimen: a phase II study.

    PubMed

    Moroni, M; Giannetta, L; Gelosa, G; Secondino, S; Chillura, G; Colombo, E; Siena, S

    2003-08-01

    We evaluated the toxicity and activity of bleomycin, methotrexate and vinorelbine (BMV) combination chemotherapy in cisplatin-pretreated patients with squamous cell carcinoma of the head, neck and esophagus (SCC-HN&E) with the aim of identifying a second-line therapy combination and schedule that might offer an improved therapeutic index. BMV (bleomycin 15 I.U., total dose, methotrexate 30 mg/m2, and vinorelbine 30 mg/m2) was administered intravenously every 2 weeks until disease progression, to 26 consecutive patients. Clinical and CT-scan evaluations revealed 7 partial responses (PR) 127%, 95% confidence interval: 9.6%-44.4%], and 13 patients with stable disease (SD) [50%]. The mean progression-free survival for patients who achieved a PR or SD was 6.47 months (range 4-13 months), with 75% of these patients experiencing partial relief of symptoms, mainly pain and dysphagia. BMV, administered second-line in an outpatient setting, has activity similar to that of the taxanes, but with a more acceptable toxicity profile including an absence of alopecia.

  20. Delayed Emotional Recovery After Taxane-based Chemotherapy

    PubMed Central

    Thornton, Lisa M.; Carson, William E.; Shapiro, Charles L.; Farrar, William B.; Andersen, Barbara L.

    2009-01-01

    Background There are few patient-reported data regarding quality of life after taxane-based adjuvant chemotherapy and none regarding mental health outcomes. Methods This was a naturalistic, longitudinal study that used a case–control design. Data were derived from a randomized clinical trial in patients who had stage II/III breast cancer (N = 227). Paclitaxel (Taxol) was approved for use midway during the accrual period (1994–1999). Patients who received taxanes as part of their adjuvant chemotherapy (the taxane group; n = 55) were matched with patients receiving regimens without taxanes (the no-taxane group; n = 83) on trial arm, lymph node status, surgery type, menopausal status, and partner status. Mixed-effects models tested for group differences in nurse evaluations of patients' symptoms and Karnofsky performance status and in patient-reported quality of life (the 36-item Medical Outcomes Study Short Form) and emotional distress (Profile of Mood States; Center for Epidemiological Studies Depression scale). Results As expected, patients in the taxane group experienced significantly higher rates of selected toxicities, including arthralgia/myalgia (45% vs 26%) and ataxia (20% vs 5%). Patients in the taxane group also had significantly worse emotional distress and mental quality of life throughout adjuvant treatment. Rates of probable clinical depression also were high. In contrast, these outcomes were improving for patients in the no-taxane group (all P <.023). Emotional recovery for patients in the taxane group required 2 years on average versus 6 to 12 months for patients in the no-taxane group. During Years 3 through 5, the groups had similar outcomes. Conclusions These data suggested that taxane-based chemotherapies confer risk for significant psychological symptoms. Depression, in particular, should be monitored. PMID:18521922

  1. EGCG synergizes the therapeutic effect of cisplatin and oxaliplatin through autophagic pathway in human colorectal cancer cells.

    PubMed

    Hu, Fen; Wei, Fei; Wang, Yulei; Wu, Bibo; Fang, Yuan; Xiong, Bin

    2015-05-01

    Application of the platinum-based chemotherapy for colorectal cancer is restricted due to its severe cytotoxic effects. In this study we used synergistic strategies by combining (-)-Epigallocatechin gallate (EGCG) with cisplatin or oxaliplatin to minimize the ill effects of platinum-based therapy. MTS assay was used to examine the effect of EGCG, cisplatin and oxaliplatin on the proliferation of human colorectal cancer DLD-1 and HT-29 cells. Autophagic process was evaluated by detection of LC3-II protein, autophagosome formation, and quantification of Acidic Vesicular. Treatment of DLD-1 and HT-29 cells with EGCG plus cisplatin or oxaliplatin showed a synergistic effect on inhibition of cell proliferation and induction of cell death. EGCG enhanced the effect of cisplatin and oxaliplatin-induced autophagy in DLD-1 and HT-29 cells, as characterized by the accumulation of LC3-II protein, the increase of acidic vesicular organelles (AVOs), and the formation of autophagosome. In addition, transfection of DLD-1 and HT-29 cells with siRNA against ATG genes reduced EGCG synergistic effect. Our findings suggest that combining EGCG with cisplatin or oxaliplatin could potentiate the cytotoxicity of cisplatin and oxaliplatin in colorectal cancer cells through autophagy related pathway.

  2. Self-assembled nanoscale coordination polymers carrying siRNAs and cisplatin for effective treatment of resistant ovarian cancer.

    PubMed

    He, Chunbai; Liu, Demin; Lin, Wenbin

    2015-01-01

    Resistance to the chemotherapeutic agent cisplatin is a major limitation for the successful treatment of many cancers. Development of novel strategies to overcome intrinsic and acquired resistance to chemotherapy is of critical importance to effective treatment of ovarian cancer and other types of cancers. We have sought to re-sensitize resistant ovarian cancer cells to chemotherapy by co-delivering chemotherapeutics and pooled siRNAs targeting multi-drug resistance (MDR) genes using self-assembled nanoscale coordination polymers (NCPs). In this work, NCP-1 particles with trigger release properties were first constructed by linking cisplatin prodrug-based bisphosphonate bridging ligands with Zn(2+) metal-connecting points and then coated with a cationic lipid layer, followed by the adsorption of pooled siRNAs targeting three MDR genes including survivin, Bcl-2, and P-glycoprotein via electrostatic interactions. The resulting NCP-1/siRNA particles promoted cellular uptake of cisplatin and siRNA and enabled efficient endosomal escape in cisplatin-resistant ovarian cancer cells. By down-regulating the expression of MDR genes, NCP-1/siRNAs enhanced the chemotherapeutic efficacy as indicated by cell viability assay, DNA ladder, and flow cytometry. Local administration of NCP-1/siRNAs effectively reduced tumor sizes of cisplatin-resistant SKOV-3 subcutaneous xenografts. This work shows that the NCP-1/siRNA platform holds great promise in enhancing chemotherapeutic efficacy for the effective treatment of drug-resistant cancers.

  3. Self-assembled Nanoscale Coordination Polymers Carrying siRNAs and Cisplatin for Effective Treatment of Resistant Ovarian Cancer

    PubMed Central

    He, Chunbai; Liu, Demin; Lin, Wenbin

    2014-01-01

    Resistance to the chemotherapeutic agent cisplatin is a major limitation for the successful treatment of many cancers. Development of novel strategies to overcome intrinsic and acquired resistance to chemotherapy is of critical importance to effective treatment of ovarian cancer and other types of cancers. We have sought to re-sensitize resistant ovarian cancer cells to chemotherapy by co-delivering chemotherapeutics and pooled siRNAs targeting multi-drug resistance (MDR) genes using self-assembled nanoscale coordination polymers (NCPs). In this work, NCP-1 particles with trigger release properties were first constructed by linking cisplatin prodrug-based bisphosphonate bridging ligands with Zn2+ metal-connecting points and then coated with a cationic lipid layer, followed by the adsorption of pooled siRNAs targeting three MDR genes including survivin, Bcl-2, and P-glycoprotein via electrostatic interactions. The resulting NCP-1/siRNA particles promoted cellular uptake of cisplatin and siRNA and enabled efficient endosomal escape in cisplatin-resistant ovarian cancer cells. By down-regulating the expression of MDR genes, NCP-1/siRNAs enhanced the chemotherapeutic efficacy as indicated by cell viability assay, DNA ladder, and flow cytometry. Local administration of NCP-1/siRNAs effectively reduced tumor sizes of cisplatin-resistant SKOV-3 subcutaneous xenografts. This work shows that the NCP-1/siRNA platform holds great promise in enhancing chemotherapeutic efficacy for the effective treatment of drug-resistant cancers. PMID:25315138

  4. 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.

  5. Co-Delivery of Cisplatin Prodrug and Chlorin e6 by Mesoporous Silica Nanoparticles for Chemo-Photodynamic Combination Therapy to Combat Drug Resistance.

    PubMed

    Zhang, Wei; Shen, Jianliang; Su, Hua; Mu, Ge; Sun, Jing-Hua; Tan, Cai-Ping; Liang, Xing-Jie; Ji, Liang-Nian; Mao, Zong-Wan

    2016-06-01

    Combination therapy shows great promise in circumventing cisplatin resistance. We report herein the development of a novel nanoscale drug delivery system (nDDS) based nanotherapeutic that combines chemotherapy and photodynamic therapy (PDT) into one single platform to achieve synergistic anticancer capacity to conquer cisplatin resistance. Mesoporous silica nanoparticle (MSNs) was used as the drug delivery vector to conjugate cisplatin prodrug and to load photosensitizer chlorin e6 (Ce6) to afford the dual drug loaded delivery system MSNs/Ce6/Pt. The hybrid nanoparticles have an average diameter of about 100 nm and slightly positive surface charge of about 18.2 mV. The MSNs/Ce6/Pt nanoparticles can be efficiently internalized by cells through endocytosis, thereby achieving much higher cellular Pt uptake than cisplatin in cisplatin-resistant A549R lung cancer cells. After 660 nm light irradiation (10 mW/cm(2)), the cellular reactive oxygen species (ROS) level in MSNs/Ce6/Pt treated cells was elevated dramatically. As a result of these properties, MSNs/Ce6/Pt exhibited very potent anticancer activity against A549R cells, giving a half-maximal inhibitory concentration (IC50) value for the combination therapy of 0.53 μM, much lower than that of cisplatin (25.1 μM). This study suggests the great potential of nDDS-based nanotherapeutic for combined chemo-photodynamic therapy to circumvent cisplatin resistance.

  6. SKA1 regulates the metastasis and cisplatin resistance of non-small cell lung cancer

    PubMed Central

    SHEN, LIHUA; YANG, MIN; LIN, QIONGHUA; ZHANG, ZHONGWEI; MIAO, CHANGHONG; ZHU, BIAO

    2016-01-01

    Currently, chemotherapy with platinum-based drugs including cisplatin is the most effective therapy for the treatment of non-small cell lung carcinoma (NSCLC). However, the efficacy of chemotherapy is limited due to commonly developed drug resistance. Spindle and kinetochore-associated complex subunit 1 (SKA1) is part of a complex essential for stabilizing the attachment of spindle microtubules to kinetochores and for maintaining the metaphase plate during mitosis. In the present study, we aimed to investigate the role of SKA1 in the process of metastasis and drug resistance of NSCLC. We completed a series of experiments to investigate the function of SKA1 in NSCLC metastasis and drug resistance including qRT-PCR, immunohistochemistry and western blotting, as well as MTT, BrdU, wounded healing, Transwell and gelatin zymography assays. We demonstrated that the expression levels of SKA1 were elevated in NSCLC and were correlated with cancer progression and malignancy. We also reported that SKA1 positively regulated the proliferation and metastatic ability of NSCLC cells. In addition, we determined that SKA1 contributed to cisplatin resistance in NSCLC cells by protecting these cells from cisplatin-induced cell apoptosis. SKA1 also appeared to regulate the ERK1/2 and the Akt-mediated signaling pathways in NSCLC cells. SKA1 is required for metastasis and cisplatin resistance of non-small cell lung cancer. PMID:26985856

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

    PubMed Central

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

    2015-01-01

    Preventing chemotherapy-induced thrombocytopenia could avoid chemotherapy dose reductions and delays. The safety and maximum tolerated dose of eltrombopag, an oral thrombopoietin receptor agonist, with gemcitabine-based therapy was evaluated. Patients with advanced solid tumors and platelets ≤300 × 109/L receiving gemcitabine plus cisplatin or carboplatin (Group A) or gemcitabine monotherapy (Group B) were randomized 3:1 to receive eltrombopag or placebo at a starting dose of 100 mg daily administered on days −5 to −1 and days 2–6 starting from cycle 2 of treatment. Nineteen patients (Group A, n = 9; Group B, n = 10) received eltrombopag 100 mg and seven (Group A, n = 3; Group B, n = 4) received matching placebo. Nine eltrombopag patients in Group A and eight in Group B had 38 and 54 occurrences of platelet counts ≥400 × 109/L, respectively. Mean platelet nadirs across cycles 2–6 were 115 × 109/L and 143 × 109/L for eltrombopag-treated patients versus 53 × 109/L and 103 × 109/L for placebo-treated patients in Groups A and B, respectively. No dose-limiting toxicities were reported for eltrombopag; however, due to several occurrences of thrombocytosis, a decision was made not to dose-escalate eltrombopag to >100 mg daily. In Groups A and B, 14% of eltrombopag versus 50% of placebo patients required chemotherapy dose reductions and/or delays for any reason across cycles 3–6. Eltrombopag 100 mg once daily administered 5 days before and after day 1 of chemotherapy was well tolerated with an acceptable safety profile, and will be further tested in a phase II trial. Fewer patients receiving eltrombopag required chemotherapy dose delays and/or reductions compared with those receiving placebo. PMID:25165041

  8. Development of Cell-Based High-Throughput Chemical Screens for Protection Against Cisplatin-Induced Ototoxicity.

    PubMed

    Teitz, Tal; Goktug, Asli N; Chen, Taosheng; Zuo, Jian

    2016-01-01

    Various compounds have been tested in recent years for protection against cisplatin-induced hearing loss, but no compound has yet been FDA approved for clinical use in patients. Towards this goal, we developed an unbiased, high-throughput, mammalian cochlear cell-based chemical screen that allowed quantification of the protection ability of bioactive compounds and ranked them for future testing ex vivo in cochlear explant cultures and in vivo in animal models. In our primary screens, protection in the HEI-OC1 organ of Corti immortalized cell line was measured by the ability of each compound to inhibit caspase-3/7 activity triggered by cisplatin treatment (50 μM cisplatin for 22 h). A total of 4385 unique bioactive compounds were tested in a single dose of 8 μM and promising compounds were validated by dose response curves covering ten, 1:3 serial diluted concentrations. Primary hits were defined as having more than 60 % inhibition of the caspase-3/7 activity. Toxicity of the top compounds was measured by a CellTiter-Glo (CTG) assay that measured the viability of the cells in the presence of compound alone in similar dose responsive analysis. A combination of the caspase-3/7 inhibition activity assay (as measured by IC50) and the CTG viability assay (as determined by LD50) identified the top protective compounds in the HEI-OC1 cells. In the future, the top hits in our screens will be tested for their protective ability ex vivo in mouse cochlear explants and in vivo in animal models. Our mammalian cochlear cell-based, high-throughput chemical screening assays described here can be further modified and represent an initial successful step towards therapeutic intervention of hearing disorders, an unmet medical need of our society. PMID:27259939

  9. Neoadjuvant M-VAC (methotrexate, vinblastine, adriamycin, and cisplatin) chemotherapy and bladder preservation for muscle-infiltrating transitional cell carcinoma of the bladder.

    PubMed

    Sternberg, C N; Pansadoro, V; Lauretti, S; Platania, A; Giannarelli, D; Rossetti, A; De Carli, P; Arena, M G; Cancrini, A

    1995-01-01

    A group of 66 patients with locally advanced T2-T4 NOMO TCC of the bladder were treated with three cycles of neo-adjuvant M-VAC chemotherapy. Of 65 evaluable patients, 18 (28%) were T2, 22 (34%) were T3a, 21 (33%) were T3b, and 4 (6%) were T4a. Patients were restaged clinically by repeat CT scan and TURB and were to undergo pathologic staging. Partial cystectomy was to be performed in patients with initial monofocal lesions who responded to therapy. As the study evolved, many patients who responded to M-VAC underwent clinical restaging only. Clinical response incorporated the results of the CT scan, cytology, and TURB. The overall clinical response rate was 82%. A cCr was attained in 28 of the 65 (43%) patients, and 25 of the 65 (38%) patients attained a cPR; 7 patients (11%) had stable disease, and 5 (8%) had progression. The median follow-up is 36(+) months (6(+)-78(+) months). The overall survival for all patients is 82% at 2 years, and 3 year survival is 73%. Of 65 patients, 44 (68%) were managed with conservative therapy (TURB or partial cystectomy). Of 44, 34 (77%) are alive, 28 (64%) with a functional bladder. Patients who had downstaging of their tumors to absence of disease (TO) or superficial disease have 2 and 3 year survival of 86 and 83%. For patients with muscle-infiltrating tumors after M-VAC, 2 and 3 year survival is 89 and 32%. Of 65 patients treated in this study, 28 (43%) have conserved normal bladder function. Response to chemotherapy may be the most important predictor of survival. Although bladder conservation is feasible in selected patients, they remain at risk for recurrence. PMID:21224105

  10. Anti-tumour activity of two novel compounds in cisplatin-resistant testicular germ cell cancer

    PubMed Central

    Nitzsche, B; Gloesenkamp, C; Schrader, M; Hoffmann, B; Zengerling, F; Balabanov, S; Honecker, F; Höpfner, M

    2012-01-01

    Background: Resistance to cisplatin-based chemotherapy is associated with poor prognosis in testicular germ cell cancer, emphasising the need for new therapeutic approaches. In this respect, the therapeutic concept of anti-angiogenesis is of particular interest. In a previous study, we presented two novel anti-angiogenic compounds, HP-2 and HP-14, blocking the tyrosine kinase activity of angiogenic growth factor receptors, such as vascular endothelial growth factor receptor-2 (VEGFR-2), and related signalling pathways in testicular cancer. In this study, we investigated the efficacy of these new compounds in platinum-resistant testicular germ cell tumours (TGCTs), in vitro and in vivo. Methods and results: Drug-induced changes in cell proliferation of the cisplatin-sensitive TGCT cell line 2102EP and its cisplatin-resistant counterpart 2102EP-R, both expressing the VEGFR-2, were evaluated by crystal violet staining. Both compounds inhibited the growth of cisplatin-resistant TGCT cells in a dose-dependent manner. In combination experiments with cisplatin, HP-14 revealed additive growth-inhibitory effects in TGCT cells, irrespective of the level of cisplatin resistance. Anti-angiogenic effects of HP compounds were confirmed by tube formation assays with freshly isolated human umbilical vein endothelial cells. Using TGCT cells inoculated onto the chorioallantoic membrane of fertilised chicken eggs (chicken chorioallantoic membrane assay), the anti-angiogenic and anti-proliferative potency of the novel compounds was also demonstrated in vivo. Gene expression profiling revealed changes in the expression pattern of genes related to DNA damage detection and repair, as well as in chaperone function after treatment with both cisplatin and HP-14, alone or in combination. This suggests that HP-14 can revert the lost effectiveness of cisplatin in the resistant cells by altering the expression of critical genes. Conclusion: The novel compound HP-14 effectively inhibits the

  11. 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.

  12. Modified Cisplatin/Interferon α-2b/Doxorubicin/Fluorouracil (PIAF) chemotherapy in patients with no hepatitis or cirrhosis is associated with improved response rate, resectability and survival of initially unresectable hepatocellular carcinoma

    PubMed Central

    Kaseb, Ahmed O.; Shindoh, Junichi; Patt, Yehuda Z.; Roses, Robert E.; Zimmitti, Giuseppe; Lozano, Richard D.; Hassan, Manal M.; Hassabo, Hesham M.; Curley, Steven A.; Aloia, Thomas A.; Abbruzzese, James L.; Vauthey, Jean-Nicolas

    2013-01-01

    Purpose The purposes of this study was to evaluate the factors associated with response rate, resectability, and survival after cisplatin/interferon α-2b/doxorubicin/5-flurouracil (PIAF) combination therapy in patients with initially unresectable hepatocellular carcinoma (HCC). Patients and Methods The study included two groups of patients treated with conventional high-dose PIAF (n=84) between 1994 and 2003 and those without hepatitis or cirrhosis treated with modified PIAF (n=33) between 2003 and 2012. Tolerance of chemotherapy, best radiographic response, rate of conversion to curative surgery, and overall survival were analyzed and compared between the two groups, and multivariate and logistic regression analyses were applied to identify predictors of response and survival. Results The modified PIAF group had a higher median number of PIAF cycles (4 vs. 2, P = .049), higher objective response rate (36% vs. 15%, P = .013), higher rate of conversion to curative surgery (33% vs. 10%, P = .004), and longer median overall survival (21.3 vs. 10.6 months, P = .002). Multivariate analyses confirmed that positive hepatitis B serology (hazard ratio [HR], 1.68; 95% CI, 1.08 to 2.59) and Eastern Cooperative Oncology Group performance status ≥2 (HR, 1.75; 95% CI 1.04 to 2.93) were associated with worse survival while curative surgical resection after PIAF treatment (HR, 0.15; 95% CI, 0.07 to 0.35) was associated with improved survival. Conclusions In patients with initially unresectable HCC, the modified PIAF regimen in patients with no hepatitis or cirrhosis is associated with improved response, resectability, and survival. PMID:23821538

  13. Knockdown of retinoblastoma protein may sensitize glioma cells to cisplatin through inhibition of autophagy.

    PubMed

    Liu, Xiangyu; Sun, Kangjian; Wang, Handong; Dai, Yuyuan

    2016-05-01

    Glioblastoma multiforme (GBM) is one of the deadliest forms of cancer due to its limited sensitivity to chemotherapy and radiotherapy. Cisplatin (CCDP) is a widely used chemotherapeutic agent for tumors, but the agent often results in the development of chemo-resistance. In several cancers, cisplatin resistance is associated with autophagy induction. Here, we found that in glioma cells cisplatin treatment induced autophagy. Our data indicates that the autophagy induction plays a critical role in cisplatin resistance of glioma cells, knockdown of RB inhibited autophagy induced by cisplatin, and inhibition of autophagy improved cisplatin-induced apoptosis. It suggests that a combination of autophagy inhibitors with cisplatin may improve the therapeutic efficiency of cisplatin towards GBM with acquired resistance. PMID:27048711

  14. A Very Rare Cerebral Complication of Chemotherapy in a Young Girl: A Difficult Diagnosis.

    PubMed

    Kridis, Wala B; Khanfir, Afef; Kammoun, Fatma; Mahfoudh, Kheireddine B; Triki, Chahinez; Frikha, Mounir

    2015-01-01

    Sagittal sinus thrombosis (SST) induced by chemotherapy is exceptional. We describe here a new case following the fourth cure of chemotherapy based on cisplatin, bleomycin and etoposide in a 16-year-old patient with no obvious risk factors. Through this uncommon case which forms part of cerebral venous sinus thrombosis (CVST), we propose to study the pathophysiology, the diagnosis and the management of this entity. The exclusion of the other causes of CVST is important not only for the therapeutic implication but also for the prognosis. Then, accurate documentation of each case induced by chemotherapy is needed to further understanding.

  15. 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

  16. Oridonin effectively reverses cisplatin drug resistance in human ovarian cancer cells via induction of cell apoptosis and inhibition of matrix metalloproteinase expression.

    PubMed

    Ma, Shihong; Tan, Wenhua; Du, Botao; Liu, Wei; Li, Weijia; Che, Dehong; Zhang, Guangmei

    2016-04-01

    Cisplatin is a first generation platinum‑based chemotherapeutic agent, however, the extensive application of cisplatin inevitably results in drug resistance, which is a major obstacle in cancer chemotherapy. The aim of the present study was to investigate the efficiency of reversing cisplatin‑resistance with the use of combination therapy with oridonin and cisplatin in human ovarian cancer cells, and attempt to reduce the side effects of the therapeutic agents when used alone. The half maximal inhibitory concentration (IC50) values of cisplatin were determined in cisplatin‑sensitive and cisplatin‑resistant ovarian cancer cells using an MTT assay. IC50 values of cisplatin in A2780, A2780/DDP, SKOV3 and SKOV3/DDP cells were significantly decreased in a time‑dependent manner. The antitumor effect of oridonin in A2780/DDP cells was also detected by the MTT assay and the inhibitory effects of oridonin increased in a dose‑ and time‑dependent manner. A2780/DDP cells were treated with 20 µM oridonin in combination with increasing concentrations of cisplatin for 48 h, and the result demonstrated that oridonin synergistically increased the antitumor effects of cisplatin in A2780/DDP cells. Notably, the combination treatment of oridonin and cisplatin effectively reversed cisplatin resistance and the IC50 values were significantly decreased from 50.97 µM and 135.20 to 26.12 µM and 73.00 µM in A2780/DDP and SKOV3/DDP cells at 48 h, respectively. Furthermore, oridonin induced cell apoptosis in a dose‑dependent manner and promoted cell‑cycle arrest at the G0/G1 phase in ovarian cancer cells. Oridonin and cisplatin synergistically increased the cell apoptosis rate of A2780/DDP cells, which was detected by fluorescence‑activated cell sorting analysis. Downregulated expression levels of Bcl‑2 and upregulated the expression of Bax protein were demonstrated by western blot analysis, further indicating increased apoptosis. In addition, the expression levels of

  17. PIM2 kinase is induced by cisplatin in ovarian cancer cells and limits drug efficacy.

    PubMed

    Musiani, Daniele; Hammond, Dean E; Cirillo, Luca; Erriquez, Jessica; Olivero, Martina; Clague, Michael J; Di Renzo, Maria Flavia

    2014-11-01

    Platinum-based chemotherapy is widely used to treat various cancers, but many patients ultimately relapse due to drug resistance. We employed phosphoproteomic analysis and functional assays of the response of SK-OV-3 ovarian cancer cells to cisplatin as a strategy to identify kinases as candidate druggable targets to sensitize cells to platinum. A SILAC-based approach combined with TiO2-based phosphopeptide enrichment allowed the direct identification of ERK1/2, p90RSK, and ERBB2 as kinases whose phosphorylation is regulated by cisplatin. Bioinformatic analysis revealed enrichment in linear phosphorylation motifs predicted to be targets of p38MAPK, CDK2, and PIM2. All three PIM kinases were found expressed in a panel of 10 ovarian cancer cell lines, with the oncogenic PIM2 being the most commonly induced by cisplatin. Targeting PIM2 kinase by either biochemical inhibitors or RNA interference impaired cell growth, decreased cisplatin-triggered BAD phosphorylation, and sensitized ovarian cancer cells to drug-induced apoptosis. Overexpression of PIM2 triggered anchorage-independent growth and resulted in increased BAD phosphorylation and cell resistance to DNA damaging agents. The data show that the PIM2 kinase plays a role in the response of ovarian cancer cells to platinum drugs and suggest that PIM inhibitors may find clinical application as an adjunct to platinum-based therapies. PMID:25099161

  18. New strategies against prostate cancer--Pt(II)-based chemotherapy.

    PubMed

    Matos, C S; de Carvalho, A L M B; Lopes, R P; Marques, M P M

    2012-01-01

    Prostate cancer is the second most common cancer worldwide and the sixth cause of cancer-related death in men. When hormone therapy fails to control tumour growth, castration-resistant prostate cancer (CRPC) occurs and chemotherapy drugs must be administered. Since 2004, docetaxel administration is the standard of care in metastatic CRPC, although it presents severe limitations such as acquired resistance and poor prognosis. An analogue (cabazitaxel) was approved by the FDA in 2010 as a second-line chemotherapeutic agent. Novel immuno- and hormonal therapy agents, as well as tumour vaccines, have been recently developed, but new strategies are still needed for effectively handling this type of neoplasia. Platinum compounds, in particular, have been the object of a growing interest, despite the former belief that they should have modest activity against prostate cancer. Compounds such as carboplatin, oxaliplatin or satraplatin, either alone or in combination, have lately shown promising results. In order to overcome the deleterious side-effects usually associated to these metal-based agents, several approaches have been followed with a view to optimise drug delivery and targeting, some of which showed considerable success in CRPC. Platinum drugs may therefore have an important role in the chemotherapeutic management of human metastatic castration-resistant prostate cancer, mostly in second-line strategies. The present review addresses the most relevant studies on platinum-based antineoplastic agents towards CRPC in the last decade--from first--and second-generation complexes to newly developed compounds.

  19. Silencing of PKC-α, TRPC1 or NF-κB expression attenuates cisplatin-induced ICAM-1 expression and endothelial dysfunction.

    PubMed

    Bodiga, Vijaya Lakshmi; Kudle, Madhukar Rao; Bodiga, Sreedhar

    2015-11-01

    Platinum-based chemotherapy has been associated with increased long-term cardiovascular events. Also noteworthy is the accumulating awareness of early vascular toxicity occurring at the time of chemotherapy or immediately thereafter. The objective of the study was to delineate the molecular mechanisms associated with the early vascular toxicity and test the molecular silencing approach towards attenuating the endothelial dysfunction during platinum-based chemotherapy. Human umbilical vein endothelial cells (HUVECs) were treated with varying concentrations of cisplatin (1.0-10.0μg/ml) or vehicle control (0.1% dimethyl sulfoxide) for monitoring the changes in Intercellular adhesion molecule-1 (ICAM-1) mRNA and protein expression viz. a viz. altered activation of protein kinase C (PKC) isoforms, transient receptor potential channel (TRPC) 1 expression, Nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NF-κB), Store Operated Ca(2+) Entry (SOCE) in cisplatin-induced endothelial permeability and adherence of the activated endothelial cells to human monocyte-like U937 cells. Silencing of either PKC-α, TRPC1 or p65 subunit of NF-κB, all resulted in significant alleviation of cisplatin-induced endothelial dysfunction. At concentrations ≥8μg/ml, cisplatin induced a significant increase in the expression of ICAM-1 mRNA as well as protein. This was mediated by changes in PKC-α membrane translocation, NF-κB activation, increased expression as well as phosphorylation of TRPC1 and enhanced SOCE, leading to hyperpermeability and leakage of albumin. Increased adherence of U937 monocytes to cisplatin-activated endothelial cells was evident. Cisplatin challenge activates PKC-α, which in turn phosphorylated TRPC1 resulting in enhanced Ca(2+) entry. Increased Ca(2+) flux is required for activation of NF-κB and ICAM-1 expression. Enhanced ICAM-1 expression promotes monocyte binding to endothelial cells and increased endothelial hyperpermeability. PMID:26300057

  20. Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: results from the Eastern Cooperative Oncology Group

    PubMed Central

    Catalano, P.; Gibson, M. K.; Skaar, T. C.; Philips, S.; Montgomery, E. A.; Hafez, M. J.; Powell, M.; Liu, G.; Forastiere, A. A.; Benson, A. B.; Kleinberg, L. R.; Murphy, K. M.

    2013-01-01

    Purpose Germline genetic variations may partly explain the clinical observation that normal tissue tolerance to radiochemotherapy varies by individual. Our objective was to evaluate the association between single-nucleotide polymorphisms (SNPs) in radiation/platinum pathways and serious treatment-related toxicity in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy. Methods In a multicenter clinical trial (E1201), 81 eligible treatment-naïve subjects with resectable esophageal adenocarcinoma received cisplatin-based chemotherapy concurrent with radiotherapy, with planned subsequent surgical resection. Toxicity endpoints were defined as grade ≥3 radiation-related or myelosuppressive events probably or definitely related to therapy, occurring during or up to 6 weeks following the completion of radiochemotherapy. SNPs were analyzed in 60 subjects in pathways related to nucleotide/base excision- or double stranded break repair, or platinum influx, efflux, or detoxification. Results Grade ≥3 radiation-related toxicity (mostly dysphagia) and myelosuppression occurred in 18 and 33% of subjects, respectively. The variant alleles of the XRCC2 5′ flanking SNP (detected in 28% of subjects) and of GST-Pi Ile-105-Val (detected in 65% of subjects) were each associated with higher odds of serious radiation-related toxicity compared to the major allele homozygote (47% vs. 9%, and 31% vs. 0%, respectively; P = 0.005). No SNP was associated with myelosuppression. Conclusions This novel finding in a well-characterized cohort with robust endpoint data supports further investigation of XRCC2 and GST-Pi as potential predictors of radiation toxicity. PMID:21286719

  1. 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. PMID:26952500

  2. 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.

  3. Evaluation of nanoparticle delivered cisplatin in beagles

    NASA Astrophysics Data System (ADS)

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

    2015-08-01

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

  4. 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.

  5. Neurotrophin-3 transduction attenuates cisplatin spiral ganglion neuron ototoxicity in the cochlea.

    PubMed

    Bowers, William J; Chen, Xiaowei; Guo, Huang; Frisina, D Robert; Federoff, Howard J; Frisina, Robert D

    2002-07-01

    Ototoxicity is a major dose-limiting side effect of cisplatin chemotherapy for cancer patients. We previously demonstrated in vitro that herpes simplex type 1 (HSV-1) amplicon-mediated delivery of a neurotrophin-3 (NT-3)/myc chimera protects spiral ganglion neurons (SGNs) in murine cochlear cultures from cisplatin-induced ototoxicity. To extend these findings, a newly constructed amplicon vector (HSVnt-3myc/SV40lac) that expresses the NT-3myc chimera and the Escherichia coli beta-galactosidase (lacZ) reporter gene under separate transcriptional control was initially tested in vitro and then was delivered to the cochlea of aged mice that were subsequently treated with cisplatin. Successful transduction with the new amplicon was observed in vitro as determined by its capacity to infect SGNs and to express NT-3myc mRNA and protein. To determine whether amplicon-directed NT-3myc overexpression could abrogate the ototoxicity in vivo, two groups of aged mice (CBA) were inoculated with HSVnt-3myc/SV40lac or control vector, HSVSV40lac, preceding administration of cisplatin. Cochleas inoculated with HSVnt-3myc/SV40lac harbored significantly greater numbers of surviving SGNs and showed lower incidence of cisplatin-induced apoptosis or necrosis than those injected with the control virus. These data demonstrate that HSV amplicon-mediated NT-3 delivery can attenuate the ototoxic actions of cisplatin in the peripheral auditory system of the aged mouse. The potency of NT-3 in SGN neuroprotection suggests that in vivo neurotrophin-based gene therapy is a promising preventative treatment for chemical-induced hearing disorders, and potentially for hearing degeneration due to normal aging.

  6. A poly(γ, L-glutamic acid)-citric acid based nanoconjugate for cisplatin delivery.

    PubMed

    Xiong, Yerong; Jiang, Weiwei; Shen, Yan; Li, Huiyi; Sun, Chunmeng; Ouahab, Ammar; Tu, Jiasheng

    2012-10-01

    A cisplatin-loaded nanoconjugate, poly(γ, L-glutamic acid)-citric acid-cisplatin [γ-PGA-CA-CDDP], as a tumor-targeted drug delivery system with sustained release capacity was successfully synthesized and characterized, and its antitumor activity was evaluated. The particle size (107 ± 6.3 nm) and average molecular weight (66 kDa) were determined by dynamic light scattering (DLS) and gel permeation chromatography (GPC), respectively. The nanoconjugate delivery system released platinum in a sustained manner in PBS at 37 °C with an initial burst release during the first 8 h and 50% cumulative release within 48 h. Both in-vitro and in-vivo studies showed that the toxicity of γ-PGA-CA-CDDP nanoconjugate significantly decreased by comparison to that of unconjugated CDDP. The maximum tolerated dose (MTD) of γ-PGA-CA-CDDP nanoconjugate was about 38 mg/kg versus 8 mg/kg for CDDP. No apathy or acute adverse reactions were observed in γ-PGA-CA-CDDP nanoconjugate groups while mice expressed apathy at all dose levels with CDDP treatment. In ICR mice, the area under the curve and total body clearance values for γ-PGA-CA-CDDP nanoconjugate were 9-fold and one-twentieth of the values for CDDP, respectively. With the aid of near-infrared fluorescence (NIRF) imaging system, it was demonstrated that γ-PGA-CA-CDDP nanoconjugate gradually accumulated at the tumor site within 15 min postinjection and exhibited prolonged retention for more than 8 h. In H22-implanted mice, γ-PGA-CA-CDDP showed a significantly higher antitumor activity versus CDDP. These results reveal that γ-PGA-CA-CDDP nanoconjugate with improved stability, reduced toxicity and prolonged in-vivo retention time holds great potential in terms of clinical application to cancer therapy.

  7. 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

  8. 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.

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

    PubMed

    Wu, Fei; Li, Yi; Song, Haibo; Zhang, Yuan; Zhang, Yuzhu; Jiang, Miao; Wang, Fang; Mu, Qian; Zhang, Wen; Li, Liang; Tang, Dongqi

    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

  10. 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

  11. 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.

  12. MKP1 mediates chemosensitizer effects of E1a in response to cisplatin in non-small cell lung carcinoma cells

    PubMed Central

    Pascual-Serra, Raquel; García-Cano, Jesus; Garcia-Gil, Elena; De la Cruz-Morcillo, Miguel; Ortega-Muelas, Marta; Serrano-Oviedo, Leticia; Gutkind, J. Silvio; Sánchez-Prieto, Ricardo

    2015-01-01

    The adenoviral gene E1a is known to enhance the antitumor effect of cisplatin, one of the cornerstones of the current cancer chemotherapy. Here we study the molecular basis of E1a mediated sensitivity to cisplatin in an experimental model of Non-small cell lung cancer. Our data show how E1a blocks the induction of autophagy triggered by cisplatin and promotes the apoptotic response in resistant cells. Interestingly, at the molecular level, we present evidences showing how the phosphatase MKP1 is a major determinant of cisplatin sensitivity and its upregulation is strictly required for the induction of chemosensitivity mediated by E1a. Indeed, E1a is almost unable to promote sensitivity in H460, in which the high expression of MKP1 remains unaffected by E1a. However, in resistant cell as H1299, H23 or H661, which display low levels of MKP1, E1a expression promotes a dramatic increase in the amount of MKP1 correlating with cisplatin sensitivity. Furthermore, effective knock down of MKP1 in H1299 E1a expressing cells restores resistance to a similar extent than parental cells. In summary, the present work reinforce the critical role of MKP1 in the cellular response to cisplatin highlighting the importance of this phosphatase in future gene therapy approach based on E1a gene. PMID:26689986

  13. Expression of p53 protein as a predictor of the response to 5-fluorouracil and cisplatin chemotherapy in human gastrointestinal cancer cell lines evaluated with apoptosis by use of thin layer collagen gel.

    PubMed

    Matsuhashi, Nobuhisa; Saio, Masanao; Matsuo, Atsushi; Sugiyama, Yasuyuki; Saji, Shigetoyo

    2004-04-01

    Apoptosis of the target cells is an important index in the assessment of the efficacy of cancer chemotherapy. We previously established a new experimental technique in which cancer cells are distributed in thin collagen gel as one or two cell layers, and cultured with anti-cancer drugs. The cells are stained with fluorescent Hoechst 33258 (Ho) and photographed, then with hematoxylin and eosin (H&E) and again photographed. The results show that most cell death patterns can be determined by combining observations of Ho and H&E-stained cells without the necessity for judging the apoptosis by electron microscopy. 5-fluorouracil (5-FU) and cisplatin (CDDP) are important anti-cancer drugs in the treatment of a variety of cancers. 5-FU or CDDP alone have shown significant effects in the treatment of gastric and colon cancers, and in addition, it has been shown that the combination of 5-FU plus CDDP (FP) therapy produces synergism greater than 5-FU or CDDP alone in gastrointestinal cancer. In this study, we evaluated the efficacy and toxicity of FP therapy in the gastric cancer cell lines MKN45, MKN28, and KATOIII and the colon cancer cell lines HCT116 and COLO320, and examined the relationship between the response to FP therapy and apoptosis. Additionally, we performed transfection of normal p53 gene into p53 mutant MKN28 cells and analyzed the impact of the p53 gene on a sensitivity test. Wild-type p53 in MKN45, HCT116, and COLO320 cells underwent significantly (p<0.01) more apoptosis than MKN28 and KATOIII cells possessing p53 mutant- and deficient-type, respectively, in FP therapy. Transfection of p53 to MKN28 cells resulted in a significantly (p<0.01) higher apoptotic index. From these results, we conclude that the p53 pathway allows induction of apoptosis in gastrointestinal cancers in FP therapy treatment, and that identification of the p53 type of a patient's cancer can be used to predict the success of FP therapy. PMID:15010816

  14. Activation of surrogate death receptor signaling triggers peroxynitrite-dependent execution of cisplatin-resistant cancer cells

    PubMed Central

    Seah, S; Low, I C C; Hirpara, J L; Sachaphibulkij, K; Kroemer, G; Brenner, C; Pervaiz, S

    2015-01-01

    Platinum-based drugs remain as the cornerstone of cancer chemotherapy; however, development of multidrug resistance presents a therapeutic challenge. This study aims at understanding the molecular mechanisms underlying resistance to cisplatin and unraveling surrogate signaling networks that could revert sensitivity to apoptosis stimuli. We made use of three different sets of cell lines, A549 and H2030 non-small-cell lung cancer (NSCLC) and A2780 ovarian cancer cells and their cisplatin-resistant variants. Here we report that cisplatin-resistant cell lines displayed a multidrug-resistant phenotype. Changes in mitochondrial metabolism and defective mitochondrial signaling were unraveled in the resistant cells. More interestingly, a marked increase in sensitivity of the resistant cells to death receptor-induced apoptosis, in particular TRAIL (TNF-related apoptosis-inducing ligand)-mediated execution, was observed. Although this was not associated with an increase in gene transcription, a significant increase in the localization of TRAIL death receptor, DR4, to the lipid raft subdomains of plasma membrane was detected in the resistant variants. Furthermore, exposure of cisplatin-resistant cells to TRAIL resulted in upregulation of inducible nitric oxide synthase (iNOS) and increase in nitric oxide (NO) production that triggered the generation of peroxynitrite (ONOO−). Scavenging ONOO− rescued cells from TRAIL-induced apoptosis, thereby suggesting a critical role of ONOO− in TRAIL-induced execution of cisplatin-resistant cells. Notably, preincubation of cells with TRAIL restored sensitivity of resistant cells to cisplatin. These data provide compelling evidence for employing strategies to trigger death receptor signaling as a second-line treatment for cisplatin-resistant cancers. PMID:26492363

  15. Induction of Activating Transcription Factor 3 Is Associated with Cisplatin Responsiveness in Non-Small Cell Lung Carcinoma Cells.

    PubMed

    Bar, Jair; Hasim, Mohamed S; Baghai, Tabassom; Niknejad, Nima; Perkins, Theodore J; Stewart, David J; Sekhon, Harmanjatinder S; Villeneuve, Patrick J; Dimitroulakos, Jim

    2016-09-01

    Non-small cell lung carcinoma (NSCLC) is the most common cause of cancer deaths, with platin-based combination chemotherapy the most efficacious therapies. Gains in overall survival are modest, highlighting the need for novel therapeutic approaches including the development of next-generation platin combination regimens. The goal of this study was to identify novel regulators of platin-induced cytotoxicity as potential therapeutic targets to further enhance platin cytotoxicity. Employing RNA-seq transcriptome analysis comparing two parental NSCLC cell lines Calu6 and H23 to their cisplatin-resistant sublines, Calu6cisR1 and H23cisR1, activating transcription factor 3 (ATF3) was robustly induced in cisplatin-treated parental sensitive cell lines but not their resistant sublines, and in three of six tumors evaluated, but not in their corresponding normal adjacent lung tissue (0/6). Cisplatin-induced JNK activation was a key regulator of this ATF3 induction. Interestingly, in both resistant sublines, this JNK induction was abrogated, and the expression of an activated JNK construct in these cells enhanced both cisplatin-induced cytotoxicity and ATF3 induction. An FDA-approved drug compound screen was employed to identify enhancers of cisplatin cytotoxicity that were dependent on ATF3 gene expression. Vorinostat, a histone deacetylase inhibitor, was identified in this screen and demonstrated synergistic cytotoxicity with cisplatin in both the parental Calu6 and H23 cell lines and importantly in their resistant sublines as well that was dependent on ATF3 expression. Thus, we have identified ATF3 as an important regulator of cisplatin cytotoxicity and that ATF3 inducers in combination with platins are a potential novel therapeutic approach for NSCLC. PMID:27659012

  16. Squalamine treatment of human tumors in nu/nu mice enhances platinum-based chemotherapies.

    PubMed

    Williams, J I; Weitman, S; Gonzalez, C M; Jundt, C H; Marty, J; Stringer, S D; Holroyd, K J; Mclane, M P; Chen, Q; Zasloff, M; Von Hoff, D D

    2001-03-01

    Squalamine, an antiangiogenic aminosterol, is presently undergoing Phase II clinical trials in cancer patients. To broaden our understanding of the clinical potential for squalamine, this agent was evaluated in nu/nu mouse xenograft models using the chemoresistant MV-522 human non-small cell lung carcinoma and the SD human neuroblastoma lines. Squalamine was studied alone and in combination with either cisplatin or paclitaxel plus carboplatin. Squalamine alone produced a modest MV-522 tumor growth inhibition (TGI) and yielded a TGI with cisplatin that was better than cisplatin alone. Squalamine also significantly enhanced the activity of paclitaxel/carboplatin combination therapy in the MV-522 tumor model. Squalamine similarly improved the effectiveness of cisplatin in producing TGI when screened against the SD human neuroblastoma xenograft. Xenograft tumor shrinkage was seen for the MV-522 tumor in combination treatments including squalamine, whereas no tumor shrinkage was seen when squalamine was omitted from the treatment regimen. To gain a greater understanding of the mechanism by which squalamine inhibited tumor growth in the xenograft studies, in vitro experiments were carried out with vascular endothelial growth factor-stimulated human umbilical vein endothelial cells in culture exposed to squalamine. Squalamine treatment was found to retard two cellular events necessary for angiogenesis, inducing disorganization of F-actin stress fibers and causing a concomitant reduction of detectable cell the surface molecular endothelial cadherin (VE-cadherin). We propose that the augmentation by squalamine of cytotoxicity from platinum-based therapies is attributable to interference by squalamine with the ability of stimuli to promote endothelial cell movement and cell-cell communication necessary for growth of new blood vessels in xenografts after chemotherapeutic injury to the tumor. PMID:11297269

  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. PMID:27184186

  18. MEK Inhibition Overcomes Cisplatin Resistance Conferred by SOS/MAPK Pathway Activation in Squamous Cell Carcinoma.

    PubMed

    Kong, Li Ren; Chua, Kian Ngiap; Sim, Wen Jing; Ng, Hsien Chun; Bi, Chonglei; Ho, Jingshan; Nga, Min En; Pang, Yin Huei; Ong, Weijie Richard; Soo, Ross Andrew; Huynh, Hung; Chng, Wee Joo; Thiery, Jean-Paul; Goh, Boon Cher

    2015-07-01

    Genomic analyses of squamous cell carcinoma (SCC) have yet to yield significant strategies against pathway activation to improve treatment. Platinum-based chemotherapy remains the mainstay of treatment for SCC of different histotypes either as a single-agent or alongside other chemotherapeutic drugs or radiotherapy; however, resistance inevitably emerges, which limits the duration of treatment response. To elucidate mechanisms that mediate resistance to cisplatin, we compared drug-induced perturbations to gene and protein expression between cisplatin-sensitive and -resistant SCC cells, and identified MAPK-ERK pathway upregulation and activation in drug-resistant cells. ERK-induced resistance appeared to be activated by Son of Sevenless (SOS) upstream, and mediated through Bim degradation downstream. Clinically, elevated p-ERK expression was associated with shorter disease-free survival in patients with locally advanced head and neck SCC treated with concurrent chemoradiation. Inhibition of MEK/ERK, but not that of EGFR or RAF, augmented cisplatin sensitivity in vitro and demonstrated efficacy and tolerability in vivo. Collectively, these findings suggest that inhibition of the activated SOS-MAPK-ERK pathway may augment patient responses to cisplatin treatment.

  19. Radiochemotherapy for locally advanced squamous cell carcinoma of the head and neck: Higher-dose cisplatin every 3 weeks versus cisplatin/5-fluorouracil every 4 weeks.

    PubMed

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

    2016-09-01

    Many patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) receive cisplatin-based radiochemotherapy. The optimal regimen is still unclear when considering both efficacy and feasibility. This study compared two regimens for locoregional control (LRC), overall survival (OS), and adverse events. Data of 329 patients with LASCCHN receiving definitive or postoperative radiochemotherapy were retrospectively analyzed. A total of 131 patients received 100 mg/m(2) cisplatin on days 1, 22, and 43 (group A), and 198 patients received 20 mg/m(2) cisplatin plus 600/1000 mg/m(2) 5-FU on days 1-5 and days 29-33 (group B). Radiochemotherapy regimens plus nine factors were compared for LRC and OS, and radiochemotherapy regimens additionally for adverse events. On univariate analysis, chemotherapy type was not associated with LRC (p = 0.36). On multivariate analysis, performance score (p = 0.039), N-category (p = 0.007), histologic grade (p = 0.007), upfront surgery (p = 0.030), and pre-radiochemotherapy hemoglobin levels (p < 0.001) were associated with LRC. On univariate analysis, chemotherapy type had no impact on OS (p = 0.64). On multivariate analysis, performance score (p < 0.001), T-category (p = 0.025), N-category (p < 0.001), histologic grade, and hemoglobin levels (p < 0.001) were associated with OS. Renal failure occurred significantly more often in group A (p = 0.008). Otherwise, adverse events were not significantly different. Thus, both radiochemotherapy regimens appeared similarly effective for LASCCHN. Patients receiving 100 mg/m(2) of cisplatin require close monitoring of their renal function. PMID:27499514

  20. Enhancement of Cisplatin Nephrotoxicity by Morphine and Its Attenuation by the Opioid Antagonist Naltrexone.

    PubMed

    Aminian, Atefeh; Javadi, Shiva; Rahimian, Reza; Dehpour, Ahmad Reza; Asadi Amoli, Fahimeh; Moghaddas, Payman; Ejtemaei Mehr, Shahram

    2016-07-01

    Nephrotoxicity is a major side effect of cisplatin, a widely used chemotherapy agent. Morphine and other opioids are also used extensively in different types of cancer for the clinical management of pain associated with local or metastatic neoplastic lesions. In addition to its analgesic effects, morphine has also been reported to possess potential immunomodulatory and antioxidant properties. Herein, we investigated the effects of morphine in a rat model of cisplatin-induced nephrotoxicity. Following administration of a single dose of cisplatin (5 mg/kg), animals received intraperitoneal injections of morphine (5 mg/kg/day) and/or naltrexone (20 mg/kg/day), an opioid antagonist, for 5 days. Cisplatin-induced nephrotoxicity was detected by a significant increase in plasma urea and creatinine levels in addition to alterations in kidney tissue morphology. Levels of TNF-α and IL-1β were significantly increased in the renal tissue in cisplatin group. Moreover, glutathione (GSH) concentration and superoxide dismutase activity were significantly reduced in renal tissue in cisplatin group compared with control animals. Treatment with morphine aggravated the deleterious effects of cisplatin at clinical, biochemical and histopathological levels; whereas naltrexone diminished the detrimental effects of morphine in animals receiving morphine and cisplatin. Morphine or naltrexone alone had no effect on the mentioned parameters. Our findings indicate that concomitant treatment with morphine might intensify cisplatin-induced renal damage in rats. These findings suggest that morphine and other opioids should be administered cautiously in patients receiving cisplatin chemotherapy. PMID:27424012

  1. Estimation of an optimal chemotherapy utilisation rate for cancer: setting an evidence-based benchmark for quality cancer care.

    PubMed

    Jacob, S A; Ng, W L; Do, V

    2015-02-01

    There is wide variation in the proportion of newly diagnosed cancer patients who receive chemotherapy, indicating the need for a benchmark rate of chemotherapy utilisation. This study describes an evidence-based model that estimates the proportion of new cancer patients in whom chemotherapy is indicated at least once (defined as the optimal chemotherapy utilisation rate). The optimal chemotherapy utilisation rate can act as a benchmark for measuring and improving the quality of care. Models of optimal chemotherapy utilisation were constructed for each cancer site based on indications for chemotherapy identified from evidence-based treatment guidelines. Data on the proportion of patient- and tumour-related attributes for which chemotherapy was indicated were obtained, using population-based data where possible. Treatment indications and epidemiological data were merged to calculate the optimal chemotherapy utilisation rate. Monte Carlo simulations and sensitivity analyses were used to assess the effect of controversial chemotherapy indications and variations in epidemiological data on our model. Chemotherapy is indicated at least once in 49.1% (95% confidence interval 48.8-49.6%) of all new cancer patients in Australia. The optimal chemotherapy utilisation rates for individual tumour sites ranged from a low of 13% in thyroid cancers to a high of 94% in myeloma. The optimal chemotherapy utilisation rate can serve as a benchmark for planning chemotherapy services on a population basis. The model can be used to evaluate service delivery by comparing the benchmark rate with patterns of care data. The overall estimate for other countries can be obtained by substituting the relevant distribution of cancer types. It can also be used to predict future chemotherapy workload and can be easily modified to take into account future changes in cancer incidence, presentation stage or chemotherapy indications.

  2. Estimation of an optimal chemotherapy utilisation rate for cancer: setting an evidence-based benchmark for quality cancer care.

    PubMed

    Jacob, S A; Ng, W L; Do, V

    2015-02-01

    There is wide variation in the proportion of newly diagnosed cancer patients who receive chemotherapy, indicating the need for a benchmark rate of chemotherapy utilisation. This study describes an evidence-based model that estimates the proportion of new cancer patients in whom chemotherapy is indicated at least once (defined as the optimal chemotherapy utilisation rate). The optimal chemotherapy utilisation rate can act as a benchmark for measuring and improving the quality of care. Models of optimal chemotherapy utilisation were constructed for each cancer site based on indications for chemotherapy identified from evidence-based treatment guidelines. Data on the proportion of patient- and tumour-related attributes for which chemotherapy was indicated were obtained, using population-based data where possible. Treatment indications and epidemiological data were merged to calculate the optimal chemotherapy utilisation rate. Monte Carlo simulations and sensitivity analyses were used to assess the effect of controversial chemotherapy indications and variations in epidemiological data on our model. Chemotherapy is indicated at least once in 49.1% (95% confidence interval 48.8-49.6%) of all new cancer patients in Australia. The optimal chemotherapy utilisation rates for individual tumour sites ranged from a low of 13% in thyroid cancers to a high of 94% in myeloma. The optimal chemotherapy utilisation rate can serve as a benchmark for planning chemotherapy services on a population basis. The model can be used to evaluate service delivery by comparing the benchmark rate with patterns of care data. The overall estimate for other countries can be obtained by substituting the relevant distribution of cancer types. It can also be used to predict future chemotherapy workload and can be easily modified to take into account future changes in cancer incidence, presentation stage or chemotherapy indications. PMID:25455844

  3. Systemic chemotherapy in inoperable or metastatic bladder cancer.

    PubMed

    Bamias, A; Tiliakos, I; Karali, M-D; Dimopoulos, M A

    2006-04-01

    Urothelial cancer is a common malignancy. The management of patients with recurrent disease after cystectomy or initially metastatic or unresectable disease represents a therapeutic challenge. Systemic chemotherapy prolongs survival but long-term survival remains infrequent. During recent years there has been improvement due to the use of novel chemotherapeutic agents, mainly gemcitabine and the taxanes. The long-considered-standard MVAC has been challenged by combinations showing more favourable toxicity profiles and equal (gemcitabine-cisplatin) or even improved (dose-dense, G-CSF-supported MVAC) efficacy. Specific interest has also been generated in specific groups of patients (elderly patients, patients with renal function impairment or comorbidities), who are not fit for the standard cisplatin-based chemotherapy but can derive significant benefit from carboplatin- or taxane-based treatment. Retrospective analyses have enabled the identification of groups of patients with different prognoses, who possibly require different therapeutic approaches. Modern chemotherapy offers a chance of long-term survival in patients without visceral metastases, possibly in combination with definitive local treatment. Finally, the progress of targeted therapies in other neoplasms seems to be reflected in advanced bladder cancer by recent studies indicating that biological agents can be combined with modern chemotherapy. The true role of such therapies is currently being evaluated. PMID:16303860

  4. 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. PMID:27116414

  5. In-depth identification of pathways related to cisplatin-induced hepatotoxicity through an integrative method based on an informatics-assisted label-free protein quantitation and microarray gene expression approach.

    PubMed

    Cho, Young-Eun; Singh, Thoudam S K; Lee, Hyun-Chul; Moon, Pyong-Gon; Lee, Jeong-Eun; Lee, Myung-Hoon; Choi, Eung-Chil; Chen, Yu-Ju; Kim, Sang-Hyun; Baek, Moon-Chang

    2012-01-01

    Cisplatin is used widely for treatment of a variety of cancer diseases. Recently, however, the use of cisplatin is restricted because of its adverse effects such as hepatotoxicity. There is no study with current proteomics technology to evaluate cisplatin-induced hepatotoxicity, even if some studies have reported on the hepatotoxicity. In this study, proteomic as well as genomic analyses have been used for identification of proteins and genes that respond to cisplatin treatment in rat primary hepatocytes. To investigate the hepatotoxic effects of cisplatin, rat primary hepatocytes were treated with an IC(20) concentration for 24 h. From proteomic analysis based on label-free quantitation strategy, cisplatin induced 76 up-regulated and 19 down-regulated proteins among 325 distinct proteins. In the mRNA level, genomic analysis revealed 72 up-regulated and 385 down-regulated genes in the cisplatin-treated group. Based on these two analyses, 19 pathways were commonly altered, whereas seven pathways were identified only by proteomic analysis, and 19 pathways were identified only by genomic analysis. Overall, this study explained the mechanism of cisplatin-induced hepatotoxicity with two points of view: well known pathways including drug metabolism, fatty acid metabolism, and glycolysis/TCA cycle and little known pathways including urea cycle and inflammation metabolism, for hepatotoxicity of other toxic agents. Up-regulated proteins detected by proteomic analysis in the cisplatin-treated group: FBP1 (fructose 1,6-bisphosphatase 1), FASN (fatty acid synthase), CAT (catalase), PRDX1 (peroxiredoxin-1), HSPD1 (60-kDa heat shock protein), MDH2 (malate dehydrogenase 2), and ARG1 (arginase 1), and also down-regulated proteins in the cisplatin-treated group: TPM1 (tropomyosin 1), TPM3 (tropomyosin 3), and CTSB (cathepsin B), were confirmed by Western blot analysis. In addition, up-regulated mRNAs detected by microarray analysis in the cisplatin-treated group: GSTA2, GSTT2, YC2

  6. A Case of Neurotoxicity Following 5-Fluorouracil-based Chemotherapy

    PubMed Central

    Ki, Seung Seog; Jeong, Jin Mo; Kim, Seong Ho; Jeong, Sook Hyang; Lee, Jin Hyuk; Han, Chul Ju; Kim, You Cheol; Lee, Jhin Oh; Hong, Young Joon

    2002-01-01

    5-Fluorouracil (5-FU) is a commonly used chemotherapeutic agent. However, its neurotoxicity is rare and not well recognized. We report a case of 5-FU neurotoxicity with organic brain syndrome and progression to multifocal leukoencephalopathy in a 44-year-old male patient having malignant gastrointestinal stromal tumor. 5-FU-induced neurotoxicity should, therefore, be considered as an important differential diagnosis in cancer patients with neurological abnormality and history of chemotherapy. PMID:12014219

  7. 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.

  8. Biodegradable polymeric system for cisplatin delivery: development, in vitro characterization and investigation of toxicity profile.

    PubMed

    Alam, Noor; Khare, Vaibhav; Dubey, Ravindra; Saneja, Ankit; Kushwaha, Manoj; Singh, Gurdarshan; Sharma, Neelam; Chandan, Balkrishan; Gupta, Prem N

    2014-05-01

    Cisplatin is one of the most potent anticancer agent used in the treatment of various solid tumors, however, its clinical use is limited due to severe adverse effects including nephrotoxicity. In this investigation cisplatin loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles were developed and characterized for various in vitro characteristics including size distribution, zeta potential, drug loading and release profile. PLGA nanoparticles were successfully developed as investigated using scanning electron microscopy and exhibited average particles size and zeta potential as 284.8 nm and -15.8 mV, respectively. Fourier transform infrared spectroscopy and differential scanning calorimetry indicated an absence of any polymer-drug interactions. Cisplatin nanoparticles exhibited in vitro anticancer activity against A549 cells comparable to that of cisplatin solution. The biodistribution study in mice indicated that the kidney cisplatin level was significantly (p<0.01) lower with cisplatin nanoparticles than cisplatin solution. Following two cycles of cisplatin treatment, a week apart, blood urea nitrogen level was found to be higher in case of cisplatin solution as compared to cisplatin nanoparticles. Further, there was a significant (p<0.01) increase in plasma creatinine level in case of cisplatin solution as compared to cisplatin nanoparticles. Histopathological examination of kidney from cisplatin nanoparticles treated group revealed no kidney damage, however, a sign of nephrotoxicity was observed in the case of cisplatin solution. The results suggest that PLGA nanoparticle based formulation could be a potential option for cisplatin delivery. PMID:24656356

  9. Gene Polymorphisms and Chemotherapy in Non-small Cell Lung Cancer.

    PubMed

    Osawa, Kayo

    2009-08-20

    The phamacogenetics is being used to predict whether the selected chemotherapy will be really effective and tolerable to the patient. Irinotecan, oxidized by CYP3A4 to produce inactive compounds, is used for treatment of various cancers including advanced non small cell lung cancer (NSCLC) patients. CYP3A4(*)16B polymorphism was associated with decreased metabolism of irrinotecan. Irinotecan is also metabolized by carboxylesterase to its principal active metabolite, SN-38, which is subsequently glucuronidated by UGT1As to form the inactive compound SN-38G. UGT1A1(*)28 and UGT1A1(*)6 polymorphisms were useful for predicting severe toxicity with NSCLC patients treated with irinotecan-based chemotherapy. Platinum-based compounds (cisplatin, carboplatin) are being used in combination with new cytotoxic drugs such as gemcitabine, paclitaxel, docetaxel, or vinorelbine in the treatment of advanced NSCLC. Cisplatin activity is mediated through the formation of cisplatin-DNA adducts. Gene polymorphisms of DNA repair factors are therefore obvious candidates for determinants of repair capacity and chemotherapy efficacy. ERCC1, XRCC1 and XRCC3 gene polymorphisms were a useful marker for predicting better survival in advanced NSCLC patients treated with platinum-based chemotherapy. XPA and XPD polymorphisms significantly increased response to platinum-based chemotherapy. These DNA repair gene polymorphisms were useful as a predictor of clinical outcome to the platinum-based chemotherapy. EGFR kinase inhibitors induce dramatic clinical responses in NSCLC patients with advanced disease. EGFR gene polymorphism in intron 1 contains a polymorphic single sequence dinucleotide repeat (CA-SSR) showed a statistically significant correlation with the gefitinib response and was appeared to be a useful predictive marker of the development of clinical outcome containing skin rashes with gefitinib treatment. The other polymorphisms of EGFR were also associated with increased EGFR promoter

  10. Increase of intracellular cisplatin levels and radiosensitization by ultrasound in combination with microbubbles.

    PubMed

    Lammertink, Bart H A; Bos, Clemens; van der Wurff-Jacobs, Kim M; Storm, Gert; Moonen, Chrit T; Deckers, Roel

    2016-09-28

    The possibility to enhance drug delivery by using ultrasound in combination with microbubbles (USMB) is extensively studied. So far, these studies have focused on the delivery and efficacy of a single drug, e.g. in chemotherapy. In this study, we investigated the intracellular delivery of cisplatin by USMB and the subsequent increased efficacy in combination with radiotherapy in a head and neck cancer cell line in vitro. After USMB-mediated intracellular delivery was verified using the model-drug SYTOX® Green, we investigated the efficacy of cisplatin when combined with USMB and radiotherapy and measured whether intracellular cisplatin concentration was enhanced after applying USMB. In addition, the effect of USMB on cisplatin and radiotherapy-induced DNA damage was studied. Flow cytometry showed that USMB treatment increased the average percentage SYTOX® Green positive cells from 2.2% to 34.5%. Clonogenic assays demonstrated that exposure to USMB significantly increased the efficacy of cisplatin combined with radiotherapy. The enhanced efficacy was associated with increased intracellular cisplatin levels, which were 2.7-fold higher when cisplatin was combined with USMB. As a result, an 82% increase in levels of DNA double strand breaks was found when cisplatin was combined with USMB, compared to cisplatin only (p<0.05). In conclusion, cisplatin uptake was significantly increased by USMB, which resulted in enhanced levels of DNA damage and increased efficacy of cisplatin in combination with radiotherapy in vitro. PMID:27476609

  11. How to calculate the dose of chemotherapy

    PubMed Central

    Gurney, H

    2002-01-01

    Body surface area-dosing does not account for the complex processes of cytotoxic drug elimination. This leads to an unpredictable variation in effect. Overdosing is easily recognised but it is possible that unrecognised underdosing is more common and may occur in 30% or more of patients receiving standard regimen. Those patients who are inadvertently underdosed are at risk of a significantly reduced anticancer effect. Using published data, it can be calculated that there is an almost 20% relative reduction in survival for women receiving adjuvant chemotherapy for breast cancer as a result of unrecognised underdosing. Similarly, the cure rate of cisplatin-based chemotherapy for advanced testicular cancer may be reduced by as much as 10%. The inaccuracy of body surface area-dosing is more than an inconvenience and it is important that methods for more accurate dose calculation are determined, based on the known drug elimination processes for cytotoxic chemotherapy. Twelve rules for dose calculation of chemotherapy are given that can be used as a guideline until better dose-calculation methods become available. Consideration should be given to using fixed dose guidelines independent of body surface area and based on drug elimination capability, both as a starting dose and for dose adjustment, which may have accuracy, safety and financial advantages. British Journal of Cancer (2002) 86, 1297–1302. DOI: 10.1038/sj/bjc/6600139 www.bjcancer.com © 2002 Cancer Research UK PMID:11953888

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

    PubMed

    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. 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

  14. Late relapse of testicular cancer: Recurrence after 24 years and treatment with chemotherapy alone.

    PubMed

    Akar, Emre; Tural, Deniz; Arslan, Deniz; Başsorgun, Cumhur İbrahim; Yıldız, Özcan

    2015-01-01

    Late relapse of testicular cancer, defined as >2 years interval between initial treatment and recurrence, is a rare disease with the incidence rate of 2.6%. Due to its chemoresistant features, treatment options of late relapses are controversial while surgical approach and cisplatin-based chemotherapies can be considered. We report here a patient with nonseminomatous germ cell tumor who experienced relapse 24 years after his first diagnosis. After detecting left supraclavicular lymphadenopathy and absence of any other malignant lesion in positron emission tomography-computerized tomography, patient was treated with three cycles of VeIP regimen (vinblastine/ifosfamide/cisplatin). Second complete response to this treatment was achieved with chemotherapy alone.

  15. Late relapse of testicular cancer: Recurrence after 24 years and treatment with chemotherapy alone.

    PubMed

    Akar, Emre; Tural, Deniz; Arslan, Deniz; Başsorgun, Cumhur İbrahim; Yıldız, Özcan

    2015-01-01

    Late relapse of testicular cancer, defined as >2 years interval between initial treatment and recurrence, is a rare disease with the incidence rate of 2.6%. Due to its chemoresistant features, treatment options of late relapses are controversial while surgical approach and cisplatin-based chemotherapies can be considered. We report here a patient with nonseminomatous germ cell tumor who experienced relapse 24 years after his first diagnosis. After detecting left supraclavicular lymphadenopathy and absence of any other malignant lesion in positron emission tomography-computerized tomography, patient was treated with three cycles of VeIP regimen (vinblastine/ifosfamide/cisplatin). Second complete response to this treatment was achieved with chemotherapy alone. PMID:26458676

  16. Renal Medullary Carcinoma Response to Chemotherapy: a Referral Center Experience in Brazil

    PubMed Central

    Maroja Silvino, Marina Cavalcanti; Venchiarutti Moniz, Camila Motta; Munhoz Piotto, Gustavo Henrique; Siqueira, Sheila; Galapo Kann, Ariel; Dzik, Carlos

    2013-01-01

    Renal medullary carcinoma (RMC) is rare, accounting for less than 1% of all renal neoplasms. Case reports suggest RMC is highly aggressive, poorly responsive to chemotherapy, often metastatic at diagnosis, affects young men with sickle cell trait, and median overall survival (mOS) is less than 12 months. We report the epidemiological characteristics, treatments performed, response rate to each treatment and mOS of five patients with RMC. All patients had sickle cell trait, four were male, three had metastatic disease at diagnosis and mean age at diagnosis was 25 years. Non-metastatic patients were submitted to nephrectomy. Two patients had partial response to first line chemotherapy including cisplatin and gemcitabine. There was no response to sunitinib or second line chemo - therapy; mOS was 6 months. Due to its rarity, case series are the only evidence available to discuss the treatment for RMC. In our experience, only cisplatin and gemcitabine based regimen offered response. PMID:24179656

  17. 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

  18. A new optimization based approach to experimental combination chemotherapy.

    PubMed

    Pereira, F L; Pedreira, C E; de Sousa, J B

    1995-01-01

    A new approach towards the design of optimal multiple drug experimental cancer chemotherapy is presented. Once an adequate model is specified, an optimization procedure is used in order to achieve an optimal compromise between after treatment tumor size and toxic effects on healthy tissues. In our approach we consider a model including cancer cell population growth and pharmacokinetic dynamics. These elements of the model are essential in order to allow less empirical relationships between multiple drug delivery policies, and their effects on cancer and normal cells. The desired multiple drug dosage schedule is computed by minimizing a customizable cost function subject to dynamic constraints expressed by the model. However, this additional dynamic wealth increases the complexity of the problem which, in general, cannot be solved in a closed form. Therefore, we propose an iterative optimization algorithm of the projected gradient type where the Maximum Principle of Pontryagin is used to select the optimal control policy.

  19. VEGF-C inhibition reverses resistance of bladder cancer cells to cisplatin via upregulating maspin.

    PubMed

    Zhu, Haipeng; Yun, Feng; Shi, Xiaoxue; Wang, Dong

    2015-08-01

    The aim of the current study was to elucidate the association between vascular endothelial growth factor C (VEGF-C) and resistance of bladder cancer cells to cisplatin and the underlying mechanism involving maspin. A total of 32 bladder cancer tissue samples from patients (18 males and 14 females with an average age of 65.9 years) were collected from the Fifth Affiliated Hospital of Zhengzhou University (Zhengzhou, China). All patients had undergone cisplatin-based combination chemotherapy. In addition, the BIU87 human bladder cancer cell line was cultured and a cisplatin-resistant subline (BIU87-CisR) was established by continuous exposure to cisplatin. The mRNA expression levels of VEGF-C and maspin in tissue samples, BIU87 cells and BIU87-CisR cells were analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Targeted inhibition of VEGF-C in BIU87-CisR cells was performed using small interfering (si)RNA technology and the alteration in levels of maspin was confirmed by RT-qPCR and western blot analysis. siRNA-treated and -untreated BIU87-CisR cells were divided into the following four groups: Control group (no drug treatment), 3 μM cisplatin treated group, 3 μM cisplatin + siRNA treated group and the siRNA treated group. Cell viability following treatment in each group was evaluated by the cell counting kit 8 assay. The cell cycle and apoptotic rate of BIU87-CisR cells was analyzed by propidium iodide (PI) staining and Annexin V-PI double staining with flow cytometry. Furthermore, pcDNA-maspin transfected BIU78-CisR cells were used to establish the effect of maspin on the sensitivity to cisplatin. VEGF-C expression in chemoresistant patients and BIU87-CisR cells was significantly increased compared with chemosensitive patients and normal BIU87 cells, respectively. By contrast, maspin levels were lower in chemoresistant patients and BIU87-CisR cells. Subsequent to VEGF-C inhibition, maspin expression was markedly increased. Cisplatin

  20. Pharmacokinetics and pharmacogenomics in gastric cancer chemotherapy.

    PubMed

    Nishiyama, Masahiko; Eguchi, Hidetaka

    2009-05-20

    Despite extensive efforts, treatment of gastric cancer by chemotherapy, the globally accepted standard, is yet undetermined, and uncertainty remains regarding the optimal regimen. Recent introduction of active "new generation agents" offers hope for improving patient outcomes. Current chemotherapeutic trials provided several regimens that may become a possible standard treatment, including docetaxel/cisplatin/5-FU (TCF) and cisplatin/S-1 for advanced and metastatic cancer and S-1 monotherapy in the adjuvant setting. Along with the development of novel active regimens, individual optimization of cancer chemotherapy has been attempted in order to reduce toxicity and enhance tumor response. Unlike the rare and limited contribution of pharmacokinetic studies, pharmacogenomic studies are increasing the potential to realize the therapeutics against gastric cancer. Despite the limited data, pharmacogenomics in gastric cancer have provided a number of putative biomarkers for the prediction of tumor response to chemotherapies and of toxicity.

  1. 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

  2. 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

  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

    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. 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

  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. 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

  7. 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

  8. 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.

  9. 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

  10. Pirarubicin-based chemotherapy displayed better clinical outcomes and lower toxicity than did doxorubicin-based chemotherapy in the treatment of non-metastatic extremity osteosarcoma

    PubMed Central

    Zheng, Shuier; Zhou, Shuhui; Qiao, Guanglei; Yang, Qingcheng; Zhang, Zhichang; Lin, Feng; Min, Daliu; Tang, Lina; Li, Hongtao; Sun, Yuanjue; Zhao, Hui; Shen, Zan; Yao, Yang

    2015-01-01

    Pirarubicin (THP) is a newer generation anthracycline anticancer drug with antineoplastic efficacy against numerous tumors. Few studies have reported its application and efficiency in anti-osteosarcoma chemotherapeutic strategies. Ninety-six non-metastatic extremity osteosarcoma patients treated with THP or doxorubicin (DOX) in combination with high-dose methotrexate (HDMTX), cisplatin (DDP) and ifosfamide (IFO) within the past 9 years at our hospital were evaluated retrospectively to compare efficacy and side effects. Among the patients, 55.2% were male, 36.5% were ≤14 years old and 59.4% presented with a large tumor (≥1/3 of bone) to our department. The 5-year disease-free survival (DFS) rate of the patients treated with the THP-based chemotherapeutic regimen was 70.2%, significantly higher than that of the DOX-based regimen-treated group (53.1%). The THP-based chemotherapeutic regimen decreased the lung metastatic rate significantly compared with the DOX-based regimen (19.1% vs. 36.7%, P=0.045), as well as the relapse rate (31.9% vs. 49.0%, P=0.067). Both regimens were generally well tolerated. However, while the THP-based chemotherapeutic regimen did not alter toxicity in the hematologic system, liver or kidneys compared with the DOX-based regimen, it showed lower rates of alopecia (63.8% vs. 85.7%, P=0.012), nausea and vomiting (51.1% vs. 79.6%, P=0.003), and mucositis (48.9% vs. 75.6%, P=0.003). THP also resulted in lower cardiac toxicity. Our data demonstrate that the THP-based regimen is better than the DOX-based regimen in terms of the 5-year DFS rate, pulmonary metastasis rate, relapse rate and side effects. PMID:25628949

  11. Galectin-1-Induced Autophagy Facilitates Cisplatin Resistance of Hepatocellular Carcinoma.

    PubMed

    Su, Yu-Chi; Davuluri, Goutham Venkata Naga; Chen, Cheng-Hao; Shiau, Dong-Che; Chen, Chien-Chin; Chen, Chia-Ling; Lin, Yee-Shin; Chang, Chih-Peng

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers in Taiwan. Although chemotherapy is the primary treatment for HCC patients, drug resistance often leads to clinical failure. Galectin-1 is a beta-galactoside binding lectin which is up-regulated in HCC patients and promotes tumor growth by mediating cancer cell adhesion, migration and proliferation, but its role in chemoresistance of HCC is poorly understood. In this study we found that galectin-1 is able to lead to chemoresistance against cisplatin treatment, and subsequent inhibition has reversed the effect of cell death in HCC cells. Moreover, galectin-1 was found to induce autophagic flux in HCC cells. Inhibition of autophagy by inhibitors or knockdown of Atg5 cancels galectin-1-induced cisplatin resistance in HCC cells. Increase of mitophagy triggered by galectin-1 was found to reduce the mitochondrial potential loss and apoptosis induced by cisplatin treatment. Finally, using an in situ hepatoma mouse model, we clearly demonstrated that inhibition of galectin-1 by thiodigalactoside could significantly augment the anti-HCC effect of cisplatin. Taken together, our findings offer a new insight into the chemoresistance galectin-1 causes against cisplatin treatment, and points to a potential approach to improve the efficacy of cisplatin in the treatment of HCC patients. PMID:26859293

  12. [INTRAVENOUS CHEMOTHERAPY VERSUS INTRAPERITONEAL CHEMOTHERAPY IN ADVANCED OVARIAN CANCER: UPDATE ON THE SITUATION WORLDWIDE AND IN ISRAEL].

    PubMed

    Binyamin, Sivan; Segev, Yakir; Auslender, Ron; Bitterman, Arie; Lavie, Ofer

    2015-09-01

    Ovarian cancer is the second in incidence and the first cause of death. As much as 70% of ovarian cancer patients are diagnosed with advanced disease. The standard treatment of advanced ovarian cancer is a combination of primary optimal debulking (POD) followed by a combined adjuvant chemotherapy treatment. Another optional treatment includes neoadjuvant chemotherapy followed by optimal debulking and then adjuvant chemotherapy. The common adjuvant chemotherapy includes a combination of platinum and taxol compounds given intravenously. Other possible treatments which had been evaluated in the past decades include a combination of chemotherapy given intravenously and intraperitoneally. The rationale behind delivering the chemotherapy intraperitoneally is to provide a much higher concentrations of cytotoxic agents in the peritoneal cavity and to reduce the systemic side effects. A number of randomized trials have shown that the combination of IV and IP chemotherapy entails a survival advantage. Most studies included treatment based on cisplatin treatments with/ without taxol given intravenously versus a combined treatment (intravenously and intraperitoneally) of those agents. An advantage of up to 8 months in disease-free survival and 11 months in overall survival was noted in the IP group. On the other hand, this treatment led to a higher rate of side effects, including abdominal pain, electrolyte imbalance and catheter related complications. Despite the inconsistency in the treatment protocols between the different trials comparing intravenous and intra-peritoneal treatment, one cannot ignore the statistical significance between the groups, for disease-free survival and overall survival. That is why, when addressing patients who completed optimal surgery, one needs to conduct a thorough evaluation regarding the complementary chemotherapy treatment. Due to the broad side effect profile, special notice should be taken as to the patient's age, medical history, and

  13. Dose and schedule-finding study of oral topotecan and weekly cisplatin in patients with recurrent ovarian cancer

    PubMed Central

    Gelderblom, H; Sparreboom, A; Jonge, M J A de; Loos, W J; Wilms, E; Mantel, M A; Hennis, B; Camlett, I; Verweij, J; Burg, M E L van der

    2001-01-01

    Both weekly cisplatin chemotherapy and single agent topotecan have proven to be effective in recurrent ovarian cancer. Preclinical data show synergism between cisplatin and topotecan. Side effects for this combination are drug sequence dependent and predominantly haematologic. Since preclinical data suggest that Cremophor EL (CrEL), the formulation vehicle of paclitaxel, has a protective effect on haematological toxicity of cisplatin, CrEL was added to the combination cisplatin and topotecan. In this phase I study, escalating doses of oral topotecan administered on day 1, 2, 8, 9, 15, 16, 29, 30, 36, 37, 43, 44 were combined with weekly cisplatin 70 mg m−2d−1on day 1, 8, 15, 29, 36, 43 (scheme A) or with the presumably less myelotoxic sequence weekly cisplatin day 2, 9, 16, 30, 37, 44 (scheme B). In scheme C, CrEL 12 ml was administered prior to cisplatin in the sequence of Scheme A. 18 patients have received a total of 85 courses. In scheme A 4/10 patients, all treated with topotecan 0.45 mg m−2d−1, experienced DLT: 1 patient had vomiting grade 4, 1 patient had grade 4 neutropenia >5 days, 1 patient had >2 weeks delay due to thrombocytopenia and 1 patient due to neutropenia. Both patients in scheme B (topotecan 0.45 mg m−2d−1) had DLT due to a delay > 2 weeks because of prolonged haematological toxicity. No DLT was observed in the first 3 patients in scheme C (topotecan 0.45 mg m−2d−1). However, 2 out of 3 patients treated at dose level topotecan 0.60 mg m−2d−1in scheme C experienced DLT due to >2 weeks delay because of persistent thrombocytopenia or neutropenia. We conclude that there is a modest clinical effect of CrEL on haematological toxicity for this cisplatin-based combination regimen, which seems to reduce these side effects but does not really enable an increase of the oral topotecan dose. © 2001 Cancer Research Campaign  http://www.bjcancer.com PMID:11710824

  14. Treatment of invasive bladder cancer by cisplatin and radiation in patients unsuited for surgery

    SciTech Connect

    Shipley, W.U.; Prout, G.R. Jr.; Einstein, A.B.; Coombs, L.J.; Wajsman, Z.; Soloway, M.S.; Englander, L.; Barton, B.A.; Hafermann, M.D.

    1987-08-21

    Seventy patients with muscle-invading bladder carcinoma (clinical stages T2 to T4) who were not candidates for cystectomy were treated with combined cisplatin and full-dose external-beam radiation on a multi-institutional prospective protocol from 1980 through 1985. Thirty-six patients are alive, all but three without evidence of cancer. The complete response rate is 77% in the 62 patients completing planned irradiation and 70% for all patients. Among the complete responders, 73% are currently maintained, and this group has a significantly higher four-year survival than those not having a complete response and those with recurrence of disease - 57% vs 11%. The observed high complete response rates in patients in all stages and the high survival rates suggest irradiation plus cisplatin therapy offers an important therapeutic gain over radiation therapy alone for invasive cancer of the bladder. These results encourage further evaluation of combining cisplatin-based, multidrug chemotherapy with irradiation in patients with locally very-advanced bladder tumors who are not suited for surgery.

  15. 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.

  16. A chemotherapy response classifier based on support vector machines for high-grade serous ovarian carcinoma

    PubMed Central

    Zhou, Bo; Guo, En-Song; Yang, Zong-Yuan; Liao, Jing; Ding, Dong; Xu, Qin; Lu, Hao; Meng, Li; Wang, Shi-Xuan; Zhou, Jian-Feng; Xing, Hui; Weng, Dan-Hui; Ma, Ding; Chen, Gang

    2016-01-01

    Long-term outcome of high-grade serous epithelial ovarian carcinoma (HGSOC) remains poor as a result of recurrence and the emergence of drug resistance. Almost all the patients were given the same platinum-based chemotherapy after debulking surgery even though some of them are naturally resistant to the first-line chemotherapy. No method could verify this part of patients right after the surgery currently. In this study, we used 156 paraffin-embedded high-grade HGSOC specimens for immunohistochemical analysis with 37 immunology markers, and association between the expression levels of these markers and the chemoresponse were evaluated. A support vector machine (SVM)-based HGSOC prognostic classifier was then established, and was validated by a 95-patient independent cohort. The classifier was strongly predictive of chemotherapy resistance, and divided patients into low- and high-risk groups with significant differences progression-free survival (PFS) and overall survival (OS). This classifier may provide a potential way to predict the chemotherapy resistance of HGSOC right after the surgery, and then allow clinicians to make optimal clinical decision for those potentially chemoresistant patients. The potential clinical application of this classifier will benefit those patients with primary drug resistance. PMID:26675546

  17. 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

  18. Emodin mitigates the oxidative stress induced by cisplatin in osteosarcoma MG63 cells

    PubMed Central

    Yan, Li; Hu, Rui; Tu, Song; Cheng, Wen-Jun; Zheng, Qiong; Wang, Jun-Wen; Kan, Wu-Sheng; Ren, Yi-Jun

    2016-01-01

    Previously, the application of cisplatin in chemotherapy was limited due to the significant side effects on normal cell growth. In the present study, the concomitant application of emodin with cisplatin was demonstrated to ameliorate cisplatin-induced oxidative stress and markedly suppress tumor cell proliferation for the first time. Human osteosarcoma MG-63 cells were treated with cisplatin alone or in combination with emodin. The cell viability was determined by MTS assays and the augmentation of reactive oxygen species were determined by fluorogenic probes; in addition, a stable MG-63 subline bearing antioxidant response element (ARE)-driven luciferase expression was developed to monitor the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-ARE signaling pathway. The results indicated that cisplatin or emodin may inhibit MG-63 cell proliferation in a time- or dose-dependent manner, respectively. Concomitant treatment with cisplatin and emodin demonstrated synergic anti-tumor effects. Cisplatin augmented reactive oxygen species in the MG-63 cells, followed by the translocation of Nrf2 from the cytoplasm into the nucleus, which triggered ARE-driven luciferase expression. The addition of emodin diminished the previously described phenomenon, resulting in decreased ROS augmentation, translocation of Nrf2 and ARE-driven luciferase activity. In conclusion, emodin could ameliorate cisplatin-induced oxidative stress and protect the cells from oxidative stress-induced damage. The findings of the present study provide a novel strategy for the treatment of osteosarcoma using emodin and cisplatin.

  19. Emodin mitigates the oxidative stress induced by cisplatin in osteosarcoma MG63 cells

    PubMed Central

    Yan, Li; Hu, Rui; Tu, Song; Cheng, Wen-Jun; Zheng, Qiong; Wang, Jun-Wen; Kan, Wu-Sheng; Ren, Yi-Jun

    2016-01-01

    Previously, the application of cisplatin in chemotherapy was limited due to the significant side effects on normal cell growth. In the present study, the concomitant application of emodin with cisplatin was demonstrated to ameliorate cisplatin-induced oxidative stress and markedly suppress tumor cell proliferation for the first time. Human osteosarcoma MG-63 cells were treated with cisplatin alone or in combination with emodin. The cell viability was determined by MTS assays and the augmentation of reactive oxygen species were determined by fluorogenic probes; in addition, a stable MG-63 subline bearing antioxidant response element (ARE)-driven luciferase expression was developed to monitor the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-ARE signaling pathway. The results indicated that cisplatin or emodin may inhibit MG-63 cell proliferation in a time- or dose-dependent manner, respectively. Concomitant treatment with cisplatin and emodin demonstrated synergic anti-tumor effects. Cisplatin augmented reactive oxygen species in the MG-63 cells, followed by the translocation of Nrf2 from the cytoplasm into the nucleus, which triggered ARE-driven luciferase expression. The addition of emodin diminished the previously described phenomenon, resulting in decreased ROS augmentation, translocation of Nrf2 and ARE-driven luciferase activity. In conclusion, emodin could ameliorate cisplatin-induced oxidative stress and protect the cells from oxidative stress-induced damage. The findings of the present study provide a novel strategy for the treatment of osteosarcoma using emodin and cisplatin. PMID:27602124

  20. Primary malignant mediastinal germ cell tumours: improved prognosis with platinum-based chemotherapy and surgery.

    PubMed Central

    Childs, W. J.; Goldstraw, P.; Nicholls, J. E.; Dearnaley, D. P.; Horwich, A.

    1993-01-01

    A retrospective analysis was performed of 18 patients with primary malignant germ cell tumours of the mediastinum treated with platinum-based chemotherapy between 1977 and 1990. All seven patients with pure seminoma were treated initially with chemotherapy and four of these patients received additional mediastinal radiotherapy. Only one patient relapsed; his initial therapy had included radiotherapy and single-agent carboplatin and he was successfully salvaged with combination chemotherapy. With a follow-up of 11 to 117 months (median 41 months) all seven patients with seminoma remain alive and disease free giving an overall survival of 100%. Eleven patients had malignant non seminoma; following chemotherapy eight of these had elective surgical resection of residual mediastinal masses. Complete remission was achieved in nine (82%) patients, however, one of these patients died from bleomycin pneumonitis. With a follow-up of 12 to 113 months (median 55 months) eight of 11 (73%) patients with malignant mediastinal teratoma remain alive and disease free. PMID:8494705

  1. 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

  2. Feasibility of radiotherapy or chemoradiotherapy after taxane-based induction chemotherapy for nonoperated locally advanced head and neck squamous cell carcinomas.

    PubMed

    Levy, Antonin; Blanchard, Pierre; Bellefqih, Sara; Brahimi, Nacéra; Guigay, Joël; Janot, François; Temam, Stéphane; Daly-Schveitzer, Nicolas; Bourhis, Jean; Tao, Yungan

    2014-11-01

    To assess the use of radiotherapy (RT) or concurrent chemoradiotherapy (CRT) following taxane-based induction chemotherapy (T-ICT) in locally advanced head and neck squamous cell carcinoma (LAHNSCC) and to evaluate the tolerability of CRT after T-ICT. From 01/2006 to 08/2012, 173 LAHNSCC patients treated as a curative intent by T-ICT, followed by definitive RT/CRT were included in this analysis. There was an 86% objective response (OR) after ICT among 154 evaluable patients. Forty-four patients received less than three cycles (25%) and 20 received only one cycle of T-ICT. The 3-year actuarial overall survival (OS) was 49% and there was no OS difference according to the type of ICT (regimen or number of cycle) or the addition of concurrent CT (cisplatin, carboplatin, or cetuximab) to RT. In multivariate analysis (MVA), clinically involved lymph node (cN+), age more than 60 years, the absence of OR after ICT, and performance status of at least 1 predicted for a decreased OS, with hazard ratios (HR) of 2.8, 2.2, 2.1, and 2, respectively. The 3-year actuarial locoregional control (LRC) and distant control (DC) rates were 52 and 73%, respectively. In MVA, the absence of OR after ICT (HR: 3.2), cN+ (HR: 3), and age more than 60 years (HR: 1.7) were prognostic for a lower LRC whereas cN+ (HR: 4.2) and carboplatin-based T-ICT (HR: 2.9) were prognostic for a lower DC. The number of cycles (≤ 2) received during ICT was borderline significant for DC in the MVA (P=0.08). Among patients receiving less than or equal to three cycles of ICT, higher outcomes were observed in patients who received cisplatin-based T-ICT (vs. carboplatin-based T-ICT) or subsequent CRT (vs. RT). T-ICT in our experience, followed by RT or CRT, raises several questions on the role and type of induction, and the efficacy of CRT over RT. The role of RT or CRT following induction, although feasible in these advanced patients, awaits answers from randomized trials.

  3. 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.

  4. Bioresorbable polymersomes for targeted delivery of cisplatin.

    PubMed

    Petersen, Matthew A; Hillmyer, Marc A; Kokkoli, Efrosini

    2013-04-17

    Nontoxic bioresorbable polymersomes have been developed that efficiently and site-selectively tether targeting peptides under mild conditions with no toxic catalysts. The binding and release properties of these polymersomes have been evaluated when targeting DLD-1 human colon cancer cells overexpressing the α(5)β(1) integrin. The delivery efficacy to these cells is markedly improved over commonly used RGD targeting peptides by use of an α(5)β(1)-specific targeting peptide, PR_b. Release profiles in buffered solution from pH 7.4 to 4.5 were evaluated and compared to release after binding to cells, and enzymatic degradation was identified as a major cause of rapid payload release in the cell. Intracellular trafficking and release were imaged via confocal microscopy in live cells and colocalization with organelles was evaluated quantitatively over time. Finally, the anticancer drug cisplatin was encapsulated in the PR_b functionalized polymersomes and the presence of PR_b greatly improved delivery efficacy, with increased cisplatin-induced losses to targeted DLD-1 colon cancer cell viability. When delivered to CACO-2 model human epithelial cells expressing low levels of α(5)β(1) integrin, low toxicity was maintained, suggesting that targeting was specific to α(5)β(1) overexpressing cells. These results demonstrate that PR_b-functionalized bioresorbable polymersomes may be an attractive route to minimizing the dose-limiting side effects associated with existing approaches to cisplatin chemotherapy.

  5. Altered localisation of the copper efflux transporters ATP7A and ATP7B associated with cisplatin resistance in human ovarian carcinoma cells

    PubMed Central

    Kalayda, Ganna V; Wagner, Christina H; Buß, Irina; Reedijk, Jan; Jaehde, Ulrich

    2008-01-01

    Background Copper homeostasis proteins ATP7A and ATP7B are assumed to be involved in the intracellular transport of cisplatin. The aim of the present study was to assess the relevance of sub cellular localisation of these transporters for acquired cisplatin resistance in vitro. For this purpose, localisation of ATP7A and ATP7B in A2780 human ovarian carcinoma cells and their cisplatin-resistant variant, A2780cis, was investigated. Methods Sub cellular localisation of ATP7A and ATP7B in sensitive and resistant cells was investigated using confocal fluorescence microscopy after immunohistochemical staining. Co-localisation experiments with a cisplatin analogue modified with a carboxyfluorescein-diacetate residue were performed. Cytotoxicity of the fluorescent cisplatin analogue in A2780 and A2780cis cells was determined using an MTT-based assay. The significance of differences was analysed using Student's t test or Mann-Whitney test as appropriate, p values of < 0.05 were considered significant. Results In the sensitive cells, both transporters are mainly localised in the trans-Golgi network, whereas they are sequestrated in more peripherally located vesicles in the resistant cells. Altered localisation of ATP7A and ATP7B in A2780cis cells is likely to be a consequence of major abnormalities in intracellular protein trafficking related to a reduced lysosomal compartment in this cell line. Changes in sub cellular localisation of ATP7A and ATP7B may facilitate sequestration of cisplatin in the vesicular structures of A2780cis cells, which may prevent drug binding to genomic DNA and thereby contribute to cisplatin resistance. Conclusion Our results indicate that alterations in sub cellular localisation of transport proteins may contribute to cisplatin resistance in vitro. Investigation of intracellular protein localisation in primary tumour cell cultures and tumour tissues may help to develop markers of clinically relevant cisplatin resistance. Detection of resistant

  6. Improving Taxane-Based Chemotherapy in Castration-Resistant Prostate Cancer.

    PubMed

    Kroon, Jan; Kooijman, Sander; Cho, Nam-Joon; Storm, Gert; van der Pluijm, Gabri

    2016-06-01

    Currently, the clinical utility of taxane-based drug formulations in castration-resistant prostate cancer (CRPC) is severely limited by acquired chemotherapy resistance, dose-limiting toxicities, and nonresponders. Therefore, approaches to improve taxane-based chemotherapy are desperately required. In this review, we highlight the strategies that aim to overcome these limitations, such as bypassing therapy resistance, targeted drug delivery, and adequate prediction of therapy response. The involvement of the apoptotic pathway, ABC transporters, the glucocorticoid receptor (GR) axis, androgen receptor (AR) splicing, epithelial plasticity, and cancer stem cells in mediating taxane-resistance are outlined. Furthermore, passive and active targeted nanomedicinal drug delivery strategies and the use of circulating tumor cells in predicting docetaxel responses are discussed. Finally, recent advances towards clinical translation of these approaches in CRPC are reviewed. PMID:27068431

  7. Effect of leuprolide acetate on ovarian function after cyclophosphamide-doxorubicin-based chemotherapy in premenopausal patients with breast cancer: results from a phase II randomized trial.

    PubMed

    Song, Guiping; Gao, Hui; Yuan, Zhixiang

    2013-01-01

    Previous studies provided inconclusive evidence for the effectiveness of gonadotropin-releasing hormone analogue on ovarian function protection against chemotherapy-induced genotoxicity in premenopausal patients. This study was designed to examine the efficacy of leuprolide acetate on ovarian function preservation in patients with breast cancer. A total of 220 patients were recruited in this prospective clinical trial and were assigned randomly to receive cyclophosphamide-doxorubicin-based chemotherapy only or chemotherapy plus leuprolide acetate. Resumption of menses or premenopausal levels of both follicle-stimulating hormone (FSH) and estradiol (E2) within 12 months after the end of chemotherapy were considered as effective ovarian preservation. A total of 183 patients were considered evaluable (94 in chemotherapy-only group and 89 in chemotherapy plus leuprolide acetate group). At the end of follow-up, 27 patients in chemotherapy group and 15 in chemotherapy plus leuprolide acetate group resumed menses; seven patients in chemotherapy group and 14 in chemotherapy plus leuprolide acetate group restored premenopausal levels of FSH and E2. The median time to resume menses was 9.2 months for patients in chemotherapy plus leuprolide acetate group and was not reached in chemotherapy-only group. In addition, our results demonstrated that age and chemotherapy doses made no significant difference in the occurrence of premature menopause. The leuprolide acetate treatment simultaneously with cyclophosphamide-doxorubicin-based chemotherapy reduced the risk of developing premature menopause in premenopausal patients with breast cancer.

  8. 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.

  9. Early Decreases in α-Fetoprotein and Des-γ-carboxy Prothrombin Predict the Antitumor Effects of Hepatic Transarterial Infusion Chemotherapy with Cisplatin (CDDP) Powder in Patients with Advanced Hepatocellular Carcinoma.

    PubMed

    Hatanaka, Takeshi; Kakizaki, Satoru; Shimada, Yasushi; Takizawa, Daichi; Katakai, Kenji; Yamazaki, Yuichi; Sato, Ken; Kusano, Motoyasu; Yamada, Masanobu

    2016-01-01

    Objective We retrospectively investigated the relationship between the tumor response and serial changes in α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) during hepatic arterial infusion of a cisplatin powder formulation (CDDP powder) in patients with advanced hepatocellular carcinoma (HCC). Methods Seventy-six advanced HCC patients were analyzed. All HCC patients received high-concentration cisplatin (1.43 mg/mL) via the haptic artery at a dose of 65 mg/m(2). AFP and DCP were measured at baseline and four to eight weeks after treatment, and the antitumor responses were evaluated according to the response evaluation criteria in solid tumours (RECIST) criteria after one or two courses of treatment. The patients were classified into two groups, a decreased group and a non-decreased group, according to the change in the serum levels of AFP and DCP at four to eight weeks compared to baseline. Results The response to treatment of the decreased group (n=16) and non-decreased group (n=60) was complete response/partial response/stable disease/progressive disease (CR/PR/SD/PD) in 4/4/5/3 and 1/11/8/40 patients, respectively. The response rate and disease control rate of the decreased group were significantly higher than those of the non-decreased group (p=0.016 and p<0.001, respectively). The median survival time (MST) of the decreased/non-decreased groups were 25.9/10.6 months, respectively. The cumulative survival rates for the decreased group were significantly higher than those of the non-decreased group (p=0.042). In the multivariate analysis, vascular invasion and the decreased group were significant factors that affected the therapeutic efficacy. Conclusion A decrease in the levels of AFP and DCP after the first treatment with CDDP powder is a good predictor for the antitumor effect and the prognosis. PMID:27522991

  10. Successful conservative treatment of neutropenic enterocolitis complicating taxane-based chemotherapy: a report of five cases.

    PubMed

    Kouroussis, C; Samonis, G; Androulakis, N; Souglakos, J; Voloudaki, A; Dimopoulos, M A; Kotsakis, T; Kakolyris, S; Kalbakis, K; Georgoulias, V

    2000-06-01

    Five cases of acute neutropenic enterocolitis complicating taxane-based chemotherapy are described. During a 34-month period, our department administered 4,600 courses of taxane-based (paclitaxel and docetaxel) chemotherapy to 800 cancer patients. Seven to 10 days postchemotherapy in five patients (0.1% of the given courses), neutropenic fever, abdominal pain, rebound tenderness, and grade II-IV diarrhea (bloody in two cases) developed. Two patients had oral candidiasis, and in two others septic shock developed. Computed tomography scans of the abdomen revealed in all patients thickening of the colon wall and pericolic edema, and a pericolic abscess was revealed in three of them. Both clinical and radiologic findings supported the diagnosis of acute neutropenic enterocolitis. All patients were successfully treated with broad-spectrum antibiotics and recombinant human granulocyte colony-stimulating factor. In conclusion, acute neutropenic enterocolitis is a severe complication of taxane-based chemotherapy. Early diagnosis and appropriate conservative treatment leads to complete recovery. Although rare, this infection is less often associated with other chemotherapeutic regimens.

  11. Overexpression of long non-coding RNA PVT1 in ovarian cancer cells promotes cisplatin resistance by regulating apoptotic pathways.

    PubMed

    Liu, Enling; Liu, Zheng; Zhou, Yuxiu; Mi, Ruoran; Wang, Dehua

    2015-01-01

    Ovarian cancer is the most lethal gynecologic malignancy. Cisplatin is a very effective cancer chemotherapy drug, but cisplatin resistance is a crucial problem of therapy failure. Overexpression of PVT1 has been demonstrated in ovarian cancer. The mRNA level of PVT1 in ovarian cancer tissues of cisplatin-resistant patients and cisplatin-sensitive patients, cisplatin-resistant cells SKOV-3/DDP and A2780/DDP, cisplatin-sensitive cells SKOV-3 and A2780 were determined by qRT-PCR. The influence of the knockdown or overexpression of PVT1 on cisplatin resistance was measured by measuring the cytotoxicity of cisplatin and the apoptotic rate of ovarian cancer cells was detected by CCK-8 assay and flow cytometry, respectively. The mRNA levels and protein expression of TGF-β1, Smad4, p-Smad4 and Caspase-3 in apoptotic pathways were determined. The mRNA level of PVT1 was significantly higher in ovarian cancer tissues of cisplatin-resistant patients and cisplatin-resistant cells. SKOV-3/DDP and A2780/DDP cell viability and the percentage of apoptotic cells after transfection with PVT-1 siRNA and treated with cisplatin was markedly lower and higher than the control, respectively. Moreover, the overexpression of PVT1 exhibited the anti-apoptotic property in SKOV-3 and A2780 cells after transfection with LV-PVT1-GFP and treated with cisplatin. The mRNA levels and protein expression of TGF-β1, p-Smad4 and Caspase-3 were much higher in cisplatin-resistant cells transfected with siPVT1. Overexpression of LncRNA PVT1 in ovarian cancer promotes cisplatin resistance by regulating apoptotic pathways. PMID:26884974

  12. Swelling and diffusion of PNIPA-based gels for localized chemotherapy and hyperthermia.

    PubMed

    Oni, Y; Soboyejo, W O

    2012-01-01

    This paper presents the results of an experimental study of the swelling and diffusion of poly(N-iso-propyl-acrylamide) PNIPA-based gels with the potential for applications in bio-micro-electro-mechanical systems (BioMEMS) for localized cancer treatment that involves both chemotherapy and hyperthermia. The swelling due to the uptake of water, rhodamine dye and the cancer drug, paclitaxel, are studied using weight gain experiments that are conducted over a range of temperatures in which hyperthermia can occur during drug delivery. The release of rhodamine dye and paclitaxel is also elucidated by considering their diffusion through the gels. The underlying mechanisms of diffusion and swelling are discussed over a temperature range in which synergistic cancer treatment can be effected by the combined use of hyperthermia and chemotherapy. PMID:23177767

  13. Drug scheduling of cancer chemotherapy based on natural actor-critic approach.

    PubMed

    Ahn, Inkyung; Park, Jooyoung

    2011-11-01

    Recently, reinforcement learning methods have drawn significant interests in the area of artificial intelligence, and have been successfully applied to various decision-making problems. In this paper, we study the applicability of the NAC (natural actor-critic) approach, a state-of-the-art reinforcement learning method, to the drug scheduling of cancer chemotherapy for an ODE (ordinary differential equation)-based tumor growth model. ODE-based cancer dynamics modeling is an active research area, and many different mathematical models have been proposed. Among these, we use the model proposed by de Pillis and Radunskaya (2003), which considers the growth of tumor cells and their interaction with normal cells and immune cells. The NAC approach is applied to this ODE model with the goal of minimizing the tumor cell population and the drug amount while maintaining the adequate population levels of normal cells and immune cells. In the framework of the NAC approach, the drug dose is regarded as the control input, and the reward signal is defined as a function of the control input and the cell populations of tumor cells, normal cells, and immune cells. According to the control policy found by the NAC approach, effective drug scheduling in cancer chemotherapy for the considered scenarios has turned out to be close to the strategy of continuing drug injection from the beginning until an appropriate time. Also, simulation results showed that the NAC approach can yield better performance than conventional pulsed chemotherapy. PMID:21839140

  14. Right heart function deteriorates in breast cancer patients undergoing anthracycline-based chemotherapy

    PubMed Central

    Boczar, Kevin Emery; Aseyev, Olexiy; Sulpher, Jeffrey; Johnson, Christopher; Burwash, Ian G; Turek, Michele; Dent, Susan

    2016-01-01

    Background Cardiotoxicity from anthracycline-based chemotherapy is an important cause of early and late morbidity and mortality in breast cancer patients. Left ventricular (LV) function is assessed for patients receiving anthracycline-based chemotherapy to identify cardiotoxicity. However, animal studies suggest that right ventricular (RV) function may be a more sensitive measure to detect LV dysfunction. The purpose of this pilot study was to determine if breast cancer patients undergoing anthracycline-based chemotherapy experience RV dysfunction. Methods Forty-nine breast cancer patients undergoing anthracycline-based chemotherapy at the Ottawa Hospital between November 2007 and March 2013 and who had 2 echocardiograms performed at least 3months apart were retrospectively identified. Right atrial area (RAA), right ventricular fractional area change (RV FAC) and RV longitudinal strain of the free wall (RV LSFW) were evaluated according to the American Society of Echocardiography guidelines. Results The majority (48/49) of patients were females with an average age of 53.4 (95% CI: 50.1–56.7years). From baseline to follow-up study, average LV ejection fraction (LVEF) decreased from 62.22 (95% CI: 59.1–65.4) to 57.4% (95% CI: 54.0–60.9) (P=0.04). During the same time period, the mean RAA increased from 12.1cm2 (95% CI: 11.1–13.0cm2) to 13.8cm2 (95% CI: 12.7–14.9cm2) (P=0.02), mean RV FAC decreased (P=0.01) from 48.3% (95% CI: 44.8–51.74) to 42.1% (95% CI: 38.5–45.6%), and mean RV LSFW worsened from −16.2% (95% CI: −18.1 to −14.4%) to −13.81% (95% CI: −15.1 to −12.5%) (P=0.04). Conclusion This study demonstrates that breast cancer patients receiving anthracycline-based chemotherapy experience adverse effects on both right atrial size and RV function. Further studies are required to determine the impact of these adverse effects on right heart function and whether this represents an earlier marker of cardiotoxicity. PMID:27457966

  15. Fenofibrate reduces cisplatin-induced apoptosis of renal proximal tubular cells via inhibition of JNK and p38 pathways.

    PubMed

    Thongnuanjan, Penjai; Soodvilai, Sirima; Chatsudthipong, Varanuj; Soodvilai, Sunhapas

    2016-01-01

    Cisplatin is widely used as a standard chemotherapy for solid tumors. The major adverse effect of cisplatin is nephrotoxicity in proximal tubular cells, via oxidative stress, DNA damage, cell apoptosis, and inflammation. The aim of this study was to investigate the pharmacological effect and mechanism of fibrate drugs on cisplatin-induced renal proximal tubular cell death. Cisplatin decreased cell viability of LLC-PK1 and HK-2 cells in a dose-dependent manner. Cisplatin-induced apoptosis was attenuated by co-treatment with fenofibrate while less so with clofibrate and bezafibrate. Fenofibrate's protective effect was not complimented by co-treatment with GW6471, a PPARα antagonist, indicating the protective effect occurred via a PPARα-independent mechanism. Treating cells with cisplatin induced reactive oxygen species (ROS), c-JUN N-terminal kinase (JNK), and p38 kinase (p38), but not extracellular signal-regulated kinase (ERK). Fenofibrate reversed cisplatin-induced JNK and p38 activation, but had no effect on ROS production. The findings suggest fenofibrate's protective effect on cisplatin-induced cytotoxicity is mediated by inhibition of JNK and p38. Moreover, fenofibrate did not alter cisplatin's antitumor effect on cancer cell lines including T84, SW-480, HepG2, and SK-LU-1 cells. Therefore, fenofibrate may be a candidate agent for further development as an adjuvant to cisplatin treatment. PMID:27193727

  16. 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

  17. Innovative therapies: intraoperative intracavitary chemotherapy.

    PubMed

    Chang, Michael Y; Sugarbaker, David J

    2004-11-01

    Both phase I studies demonstrated that high-dose cisplatin can be delivered safely with acceptable complication rates. The maximum tolerated doses of 225 mg/m2 and 250 mg/m2 cisplatin, respectively, are higher than any other published report of intrapleural cisplatin. The intrapleural cisplatin doses reported in other trials have been 80 mg/m2, 100 mg/m2, and 200 mg/m2. Despite the use of high-dose intraoperative chemotherapy, the group of 50 patients who underwent EPP experienced mortality and morbidity comparable to the contemporaneous group of 41 patients who did not participate in the protocol, except for increased rates of deep venous thrombosis and diaphragmatic patch failure. The 44 patients who underwent P/D experienced a slightly higher mortality rate and creatinine toxicity rate than the first phase I trial. Given the demographics of this patient cohort (higher age, lower FEV1, and inability to withstand pneumonectomy because of limited cardiopulmonary reserve), however, the mortality and morbidity rates seem acceptable. The pharmacologic data from both studies support our hypothesis that high regional doses of cisplatin can be delivered with less systemic absorption than can be achieved with intravenous administration (data not shown). With the maximum tolerated dose of intracavitary cisplatin and safety of intraoperative administration after surgical resection firmly established by these phase I trials, we are prepared to implement phase II and III studies of EPP and P/D with intraoperative cisplatin lavage. We aim to monitor tumor recurrence and patient survival prospectively and compare these results with historic controls. We also intend to document prospectively the morbidity and mortality of the treatment protocols. Finally, we plan to evaluate the pharmacokinetics of cisplatin by measuring tissue and perfusate levels of active and inactive cisplatin. By approaching the problem of local recurrence after resection of MPM in a careful and methodical

  18. Post-chemotherapy lymph node histology in radiologically normal patients with metastatic nonseminomatous testicular cancer.

    PubMed

    Fosså, S D; Ous, S; Lien, H H; Stenwig, A E

    1989-03-01

    A total of 37 patients with initially advanced metastatic nonseminomatous testicular cancer underwent retroperitoneal lymph node dissection after cisplatin-based combination chemotherapy. Abdominal computerized tomography was negative at retroperitoneal lymphadenectomy (lymph nodes not exceeding 10 mm. in the transverse computerized tomography plane). Complete necrosis and fibrosis were found in 25 patients. In 11 patients the retroperitoneal lymphadenectomy specimen showed a mature teratoma. Residual vital malignant tumor was observed in 1 patient. Neither the initial size of the retroperitoneal mass nor the histological status of the primary tumor was predictive of the histological findings in the retroperitoneal lymphadenectomy specimen. The high frequency of mature teratoma raises the question whether omitting post-chemotherapy surgery is a safe routine policy in patients with negative computerized tomography, especially if long-term followup is not feasible. We recommend a post-chemotherapy retroperitoneal operation as routine treatment even in patients with negative computerized tomography.

  19. In situ injection of phenylboronic acid based low molecular weight gels for efficient chemotherapy.

    PubMed

    Gao, Wenxia; Liang, Yan; Peng, Xinyu; Hu, Yalong; Zhang, Longgui; Wu, Huayue; He, Bin

    2016-10-01

    Injectable low molecular weight gels (LMWGs) based on the derivatives of phenylboronic acid were prepared and used as substrates for efficient in situ chemotherapy. The gelators as well as LMWGs were characterized by (1)H NMR, UV-vis, FTIR, MS and SEM. Anticancer drug doxorubicin hydrochloride (DOX) was encapsulated in the gels. The rheological properties and rapid recovery capability of both blank and drug-loaded gels were tested. The LMWGs were non-toxic to both 3T3 fibroblasts and 4T1 breast cancer cells. The gels were formed rapidly after injected in vivo. The in vivo anticancer activities of DOX-loaded LMWGs were investigated in breast cancer bearing mice. The intratumoral injection of DOX loaded LMWGs with dose of 30 mg/kg revealed that the gels could coat around the tumor tissues to release DOX sustainingly and maintain effective DOX concentration for chemotherapy. The systemic toxicity of DOX was reduced significantly with the in situ administration of LMWGs formulations. The injectable LMWGs exhibited excellent therapeutic efficacy and low side effects in local chemotherapy. PMID:27497056

  20. Optimizing Glioblastoma Temozolomide Chemotherapy Employing Lentiviral-based Anti-MGMT shRNA Technology

    PubMed Central

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

    2013-01-01

    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. PMID:23319055

  1. Protocol consisting of cisplatin, etoposide and irinotecan induced complete pathological remission of primary small cell carcinoma of the bladder.

    PubMed

    Kawahara, Takashi; Nishiyama, Hiroyuki; Yamamoto, Shingo; Kamoto, Toshiyuki; Ogawa, Osamu

    2006-09-01

    A 73-year-old man with primary small-cell carcinoma of the bladder was treated by radical cystectomy with neoadjuvant chemotherapy. Pathological complete remission was achieved by combination chemotherapy composed of cisplatin, etoposide and irinotecan. The patient is free of disease 19 months after surgery.

  2. S-1-based vs non-S-1-based chemotherapy in advanced gastric cancer: A meta-analysis

    PubMed Central

    Yang, Jian; Zhou, Yan; Min, Ke; Yao, Qiang; Xu, Chun-Ni

    2014-01-01

    AIM: To assess the efficacy and tolerability of S-1-based vs non-S-1-based chemotherapy in advanced gastric cancer (AGC). METHODS: We extracted reported endpoints, including overall survival (OS), progression-free survival (PFS), time-to-treatment failure (TTF), objective response rate (ORR) and adverse effects, from randomized controlled trials identified in PubMed, the Cochrane library, Science Direct, EMBASE and American Society of Clinical Oncology meetings. Stata software was used to calculate the pooled values. RESULTS: Seven randomized controlled trials involving 2176 patients were included in this meta-analysis. Compared to non-S-1-based regimens, the use of S-1-based regimens were associated with an increase in ORR (RR = 1.300; 95%CI: 1.028-1.645); OS (HR = 0.89; 95%CI: 0.81-0.99; P = 0.025), TTF (HR = 0.83; 95%CI: 0.75-0.92; P = 0.000), and a lower risk of febrile neutropenia (RR = 0.225; P = 0.000) and stomatitis (RR = 0.230; P = 0.032). OS, PFS and TTF were prolonged, especially in the Asian population. In subgroup analysis, statistically significant increases in ORR (RR = 1.454; P = 0.029), OS (HR = 0.895; P = 0.041) and TTF (HR = 0.832; P = 0.000) were found when S-1-based chemotherapy was compared to 5-fluorouracil (5-FU)-based chemotherapy. The incidence of leukopenia (RR = 0.584; P = 0.002) and stomatitis (RR = 0.230; P = 0.032) was higher in the 5-FU-based arm. S-1-based regimens had no advantage in ORR, OS, PFS, TTF and grade 3 or 4 adverse events over capecitabine-based regimens. CONCLUSION: S-1-based chemotherapy may be a good choice for AGC because of longer survival times, better tolerance and more convenient use. PMID:25206296

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

    PubMed Central

    Barrera, Ivan; Metrakos, Peter; Kavan, Petr

    2015-01-01

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

  4. A phase II study of cisplatin, vindesine and continuously infused 5-fluorouracil in the treatment of advanced non-small-cell lung cancer. Osaka Lung Cancer Chemotherapy Study Group.

    PubMed Central

    Nakano, T.; Ikegami, H.; Nakamura, S.; Kawase, T.; Nishikawa, H.; Yokota, S.; Yoshida, M.; Tachibana, T.; Igarashi, T.; Komuta, K.; Higashino, K.

    1996-01-01

    Fifty-two previously untreated patients with advanced non-small-cell lung cancer (NSCLC) were treated on a 14 day cycle with cisplatin (60 mg m-2 i.v.) and vindesine (3 mg m-2 i.v.) on day 1, followed by a 3 day continuous infusion of 5-fluorouracil (800 mg m-2 day-1) starting on day 8. An overall response rate of 40.4% was observed in 47 evaluable patients, which included one complete response and 18 partial responses. Responses were achieved in 61.1% of stage 3 patients and 27.6% of stage 4 patients. The median progression-free interval was 19.3 weeks, and median survival time was 41.6 weeks (47.1 weeks for patients with stage 3 disease and 38.7 weeks for those with stage 4 disease). Toxicity was well tolerated. Gastrointestinal and renal toxicities did not exceed WHO grade 2. Grade 3 or 4 leucopenia and anaemia occurred in nine (19%) and four (9%) patients respectively, but only grade 2 thrombocytopenia was observed. Phlebitis at the infusion site was observed in 24 patients (53%). This treatment programme achieved a response rate similar to other active combination regimens for the treatment of advanced NSCLC, and was less toxic. PMID:8624270

  5. 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

  6. 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.

  7. 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

  8. Exosomes derived from gefitinib-treated EGFR-mutant lung cancer cells alter cisplatin sensitivity via up-regulating autophagy

    PubMed Central

    Fan, Lu-Lu; Liu, Yu; Cheng, Liang; Wang, Fang; Yu, Han-Qing; Gao, Jian; Wei, Wei; Wang, Hua; Sun, Guo-Ping

    2016-01-01

    Several clinical trials indicate that concurrent administration of tyrosine kinase inhibitors (TKIs, such as gefitinib or erlotinib) with chemotherapy agents fails to improve overall survival in advanced non-small cell lung cancer (NSCLC) patients. However, the precise mechanisms underlying the antagonistic effects remain unclear. In the present study, we investigated the role of exosomes in the antagonistic effects of concurrent administration of chemotherapy and TKIs. Exosomes derived from gefitinib-treated PC9 cells (Exo-GF) decreased the antitumor effects of cisplatin, while exosomes derived from cisplatin-treated PC9 cells (Exo-DDP) did not significantly affect the antitumor effects of gefitinib. Additionally, inhibition of exosome secretion by GW4869 resulted in a modest synergistic effect when cisplatin and gefitinib were co-administered. Furthermore, Exo-GF co-incubation with cisplatin increased autophagic activity and reduced apoptosis, as demonstrated by an upregulation of LC3-II and Bcl-2 protein levels and downregulation of p62 and Bax protein levels. Thus, the antagonistic effects of gefitinib and cisplatin were mainly attributed to Exo-GF, which resulted in upregulated autophagy and increased cisplatin resistance. These results suggest that inhibition of exosome secretion may be a helpful strategy to overcome the antagonistic effects when TKIs and chemotherapeutic agents are co-administered. Before administering chemotherapy, introducing a washout period to completely eliminate TKI-related exosomes, may be a better procedure for administering chemotherapy and TKIs. PMID:27029054

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

    NASA Astrophysics Data System (ADS)

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

    2014-03-01

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

  10. Platinum-containing compound platinum pyrithione is stronger and safer than cisplatin in cancer therapy.

    PubMed

    Zhao, Chong; Chen, Xin; 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

    2016-09-15

    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

  11. Neoadjuvant chemotherapy in advanced sinonasal teratocarcinosarcoma with intracranial extension: Report of two cases with literature review.

    PubMed

    Joshi, Amit; Noronha, Vanita; Sharma, Mansi; Dhumal, Sachin; Juvekar, Shashikant; Patil, Vijay Maruti; Pai, Prathamesh; Prabhash, Kumar

    2015-01-01

    Sinonasal teratocarcinosarcoma (SNTCS) is a highly aggressive rare tumor of the nasal cavity. Surgery followed by concurrent chemoradiation is the mainstay of treatment in SNTCS. However, intracranial extension may complicate surgical resection, with difficulty in achieving R0 resection. Here we present two cases of SNTCS with intracranial extension; both patients were seen in skull base clinic of our hospital and deemed unsuitable for surgery. These patients then were offered neoadjuvant chemotherapy (NACT), both patients had a partial response with cisplatin and etoposide protocol; subsequently they underwent R0 resection (no macroscopic residual tumor at surgery with all margins were negative for tumor on microscopy). The present cases highlight the fact that NACT with cisplatin and etoposide protocol may be considered in technically unresectable SNTCS. PMID:26881569

  12. 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.

  13. Personalized peptide vaccination for cervical cancer patients who have received prior platinum-based chemotherapy.

    PubMed

    Kawano, Kouichiro; Tsuda, Naotake; Waki, Kayoko; Matsueda, Satoko; Hata, Yoshiro; Ushijima, Kimio; Itoh, Kyogo; Yamada, Akira; Kamura, Toshiharu

    2015-09-01

    A feasibility study was performed to evaluate the immunological efficacy and safety of a personalized peptide vaccine (PPV) for cervical cancer patients who have received platinum-based chemotherapy. A total of 24 patients with standard chemotherapy-resistant cervical cancer, including 18 recurrent cases, were enrolled in this study and received a maximum of 4 peptides based on HLA-A types and IgG levels to the vaccine candidate peptides in pre-vaccination plasma. The parental protein expression of most of the vaccine peptides was confirmed in the cervical cancer tissues. No vaccine-related systemic grade 3 or 4 adverse events were observed in any patients. Due to disease progression, 2 patients failed to complete the first cycle of vaccinations (sixth vaccination). Cytotoxic T-lymphocyte (CTL) or IgG responses specific for the peptides used for vaccination were augmented in half of cases after the first cycle. The median overall survival was 8.3 months. The clinical responses of the evaluable 18 cases consisted of 1 case with a partial response and 17 cases with disease progression; the remaining 6 cases were not evaluable. Performance status, injection site skin reaction and circulating PD-1(+) CD4(+) T-cells were significantly prognostic of overall survival, and multivariate analysis also indicated that the performance status and circulating PD-1(+) CD4(+) T-cells were prognostic. Because of the safety and immunological efficacy of PPV and the possible prolongation of overall survival, further clinical trials of PPV at a larger scale in advanced or recurrent cervical cancer patients who have received prior platinum-based chemotherapy are recommended.

  14. Pharmacogenomics of platinum-based chemotherapy sensitivity in NSCLC: toward precision medicine.

    PubMed

    Yin, Ji-Ye; Li, Xi; Zhou, Hong-Hao; Liu, Zhao-Qian

    2016-08-01

    Lung cancer is one of the leading causes of cancer-related death in the world. Platinum-based chemotherapy is the first-line treatment for non-small-cell lung cancer (NSCLC), however, the therapeutic efficiency varies remarkably among individuals. A large number of pharmacogenomics studies aimed to identify genetic variations which can be used to predict platinum response. Those studies are leading NSCLC treatment to the new era of precision medicine. In the current review, we provided a comprehensive update on the main recent findings of genetic variations which can be used to predict platinum sensitivity in the NSCLC patients.

  15. Pharmacogenomics of platinum-based chemotherapy sensitivity in NSCLC: toward precision medicine.

    PubMed

    Yin, Ji-Ye; Li, Xi; Zhou, Hong-Hao; Liu, Zhao-Qian

    2016-08-01

    Lung cancer is one of the leading causes of cancer-related death in the world. Platinum-based chemotherapy is the first-line treatment for non-small-cell lung cancer (NSCLC), however, the therapeutic efficiency varies remarkably among individuals. A large number of pharmacogenomics studies aimed to identify genetic variations which can be used to predict platinum response. Those studies are leading NSCLC treatment to the new era of precision medicine. In the current review, we provided a comprehensive update on the main recent findings of genetic variations which can be used to predict platinum sensitivity in the NSCLC patients. PMID:27462924

  16. Adjuvant chemotherapy for non-small cell lung cancer: a New Zealand perspective.

    PubMed

    Sasidharan, Rita; Gibbs, David; Sullivan, Richard; Simpson, Andrew; Perez, David; Christmas, Timothy; McKeage, Mark

    2006-01-01

    This article reviews recent developments with the use of adjuvant chemotherapy for resected early-stage non-small cell lung cancer (NSCLC) and the implications of these developments for healthcare in New Zealand (NZ). Non-small cell lung cancer is a major cause of mortality and morbidity in NZ, and is greatly over-represented among Maori and socioeconomically deprived populations. Early-stage NSCLC is potentially curable by surgery, but long-term outcome after surgical resection is limited by disease recurrence locally or at sites distant from the primary disease. Three recent large randomised controlled phase III trials using modern platinum-based combination chemotherapy protocols have shown significant survival benefits for the use of postoperative adjuvant chemotherapy after resection of early-stage NSCLC. Cisplatin plus vinorelbine was used as the adjuvant chemotherapy regimen in two of these trials resulting in improvements in 5-year survival of 51.2% versus 42.6% (p=0.013) and 69% versus 54% (p=0.03), respectively. In NZ, adjuvant chemotherapy for NSCLC is expected to prevent up to 15 lung cancer deaths each year for relatively low drug expenditure and has the potential to benefit Maori and the economically-deprived disproportionately more than other populations. In conclusion, it is the opinion of this group of NZ lung cancer specialists that adjuvant chemotherapy with cisplatin plus vinorelbine should now be adopted as a standard of care for patients with resected stage II and III NSCLC. For this to occur, current PHARMAC policies preventing its use for these eligible patients will need to be revised.

  17. 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.

  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. ATR-Chk1 signaling inhibition as a therapeutic strategy to enhance cisplatin chemosensitivity in urothelial bladder cancer.

    PubMed

    Li, Ching-Chia; Yang, Juan-Cheng; Lu, Mei-Chin; Lee, Chia-Lin; Peng, Chieh-Yu; Hsu, Wei-Yu; Dai, Yun-Hao; Chang, Fang-Rong; Zhang, Da-Yong; Wu, Wen-Jeng; Wu, Yang-Chang

    2016-01-12

    DNA damage responses contribute to cisplatin resistance; however, therapeutic strategies to overcome cisplatin resistance have not yet been established. Here, we demonstrate that inhibition of ATR-Chk1 pathway with the potent inhibitor WYC0209 sensitizes bladder cancer cells to cisplatin. In the clinical microarray profile, high ATR expression is associated with poor prognosis in bladder cancer patients who receive chemotherapy. We show that pharmacological and genetic suppressing of ATR sensitized cells to cisplatin. Treatment with WYC0209 or siATR increased levels of cisplatin-DNA adducts, concomitant with decreased levels of p-glycoprotein expression. Additionally, Combinations of cisplatin and WYC0209 show synergistic activity against bladder cancer. Ultimately, WYC0209 enhanced the anti-tumor effects of cisplatin and suppressed p-glycoprotein expression in bladder cancer xenografts. These results indicate that inhibiting ATR-Chk1 activation with WYC0209 suppresses p-glycoprotein expression and increases cisplatin activity in bladder cancer. Our findings collectively suggest that ATR-Chk1 is a target for improving the efficacy of cisplatin in bladder cancer. PMID:26657501

  20. Infrasound sensitizes human glioblastoma cells to cisplatin-induced apoptosis.

    PubMed

    Rachlin, Kenneth; Moore, Dan H; Yount, Garret

    2013-11-01

    The development of nontoxic agents that can selectively enhance the cytotoxicity of chemotherapy is an important aim in oncology. This study evaluates the ability of infrasound exposure to sensitize glioblastoma cells to cisplatin-induced apoptosis. The infrasound was delivered using a device designed to replicate the unique infrasound emissions measured during external Qigong treatments. Human glioblastoma cell lines harboring wild-type p53 (U87) or mutant p53 (U251, SF210, and SF188) were treated in culture with cisplatin, infrasound emissions, or the combination of the 2 agents. Induction of apoptosis was quantified after 24 hours by flow cytometry following annexin V/propidium iodide staining. Infrasound emissions alone, delivered at moderate levels (~10 mPa) with dynamic frequency content (7-13 Hz), did not induce apoptosis, yet combining infrasound with cisplatin augmented the induction of apoptosis by cisplatin in all the 4 cell lines (P < .05). Increased cellular uptake of the fluorophore calcein associated with infrasound exposure was quantified by fluorescence microscopy as well as flow cytometry, demonstrating increased cell membrane permeability. The 4 cell lines differed in the degree to which infrasound exposure increased calcein uptake, and these differences were predictive of the extent to which infrasound enhanced cisplatin-induced apoptosis. When exposed to specific frequencies, membrane permeabilization also appeared to be differentially responsive for each cell line, suggesting the potential for selective targeting of tissue types using isolated infrasonic frequencies. Additionally, the pressure amplitudes used in this study were several orders of magnitude less than those used in similar studies involving ultrasound and shock waves. The results of this study provide support for using infrasound to enhance the chemotherapeutic effects of cisplatin in a clinical setting. PMID:23165942

  1. 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

  2. Combined cancer photothermal-chemotherapy based on doxorubicin/gold nanorod-loaded polymersomes.

    PubMed

    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.

  3. Preliminary results of a phase I/II trial of paclitaxel in patients with relapsed or cisplatin-refractory testicular cancer.

    PubMed

    Bokemeyer, C; Schmoll, H J; Natt, F; Knoche, M; Beyer, J; Souchon, R

    1994-01-01

    Paclitaxel represents a novel antitumour agent with demonstrated activity in cisplatin-sensitive tumours, particularly ovarian cancer. In addition, responses to paclitaxel have been observed in patients with cisplatin-refractory ovarian cancer. The role of paclitaxel in the treatment of testicular cancer has not been explored so far. Despite the generally high cure rates in patients with metastatic testicular cancer, patients with relapsed disease not responding to platin-based salvage chemotherapy have an extremely poor prognosis. In a phase I/II trial 10 patients with relapsed, cisplatin-refractory malignant germ-cell tumours were treated with paclitaxel as 6-h infusions (8 patients) or 3-h infusions (2 patients) at doses from 135 mg/m2 to 310 mg/m2 at 3-week intervals. Three patients achieved a response to paclitaxel, but disease recurred shortly in two patients after two and four cycles of therapy, respectively. One patient has remained in marker-negative partial response for more than 5 months. The toxicity of paclitaxel was tolerable for a dose range from 135 mg/m2 to 225 mg/m2. Granulocytopenia, WHO grades 3 and 4, occurred in all patients but was of short duration (median 3 days; range: 2-7 days). Other toxicities such as mucositis (5 patients grade 1), neurotoxicity (1 patient grade 1, 2 patients grade 2), infection (1 patient grade 3) and diarrhoea (1 patient grade 2) were not dose-limiting. There were no hypersensitivity reactions, but 1 patient developed severe myalgias during therapy with paclitaxel. Six patients with documented cisplatin-refractory disease were retreated with cisplatin-based chemotherapy after paclitaxel treatment and, in 4 of these, tumour responses of 3, 4, 5 and more than 5 months duration were achieved. In order to explore the role of paclitaxel in relapsed and/or cisplatin-refractory testicular cancer a phase II study using a 3-h infusion of 225 mg/m2 paclitaxel every 3 weeks, conducted by the German Testicular Cancer Study Group

  4. Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas

    PubMed Central

    Bain, G H; Collie-Duguid, E; Murray, G I; Gilbert, F J; Denison, A; Mckiddie, F; Ahearn, T; Fleming, I; Leeds, J; Phull, P; Park, K; Nanthakumaran, S; Grabsch, H I; Tan, P; Welch, A; Schweiger, L; Dahle-Smith, A; Urquhart, G; Finegan, M; Petty, R D

    2014-01-01

    Background: Cytotoxic chemotherapy remains the main systemic therapy for gastro-oesophageal adenocarcinoma, but resistance to chemotherapy is common, resulting in ineffective and often toxic treatment for patients. Predictive biomarkers for chemotherapy response would increase the probability of successful therapy, but none are currently recommended for clinical use. We used global gene expression profiling of tumour biopsies to identify novel predictive biomarkers for cytotoxic chemotherapy. Methods: Tumour biopsies from patients (n=14) with TNM stage IB–IV gastro-oesophageal adenocarcinomas receiving platinum-based combination chemotherapy were used as a discovery cohort and profiled with Affymetrix ST1.0 Exon Genechips. An independent cohort of patients (n=154) treated with surgery with or without neoadjuvant platinum combination chemotherapy and gastric adenocarcinoma cell lines (n=22) were used for qualification of gene expression profiling results by immunohistochemistry. A cisplatin-resistant gastric cancer cell line, AGS Cis5, and the oesophageal adenocarcinoma cell line, OE33, were used for in vitro validation investigations. Results: We identified 520 genes with differential expression (Mann–Whitney U, P<0.020) between radiological responding and nonresponding patients. Gene enrichment analysis (DAVID v6.7) was used on this list of 520 genes to identify pathways associated with response and identified the adipocytokine signalling pathway, with higher leptin mRNA associated with lack of radiological response (P=0.011). Similarly, in the independent cohort (n=154), higher leptin protein expression by immunohistochemistry in the tumour cells was associated with lack of histopathological response (P=0.007). Higher leptin protein expression by immunohistochemistry was also associated with improved survival in the absence of neoadjuvant chemotherapy, and patients with low leptin protein-expressing tumours had improved survival when treated by neoadjuvant

  5. Carboplatin versus cisplatin: density functional approach to their molecular properties

    NASA Astrophysics Data System (ADS)

    Tornaghi, Elena; Andreoni, Wanda; Carloni, Paolo; Hutter, Jürg; Parrinello, Michele

    1995-12-01

    Carboplatin is a platinum-based drug in common clinical use. Here we present the first ab initio calculation of its molecular properties, namely structural, electronic and vibrational. Comparison of the calculated molecular structure with experimental data taken in the solid phase shows quite good agreement. Comparison of our results on its parent complex, cisplatin, is particularly instructive. Unlike the chlorine ligands in cisplatin, the substituting dicarboxylate strongly participates in the chemically active orbitals.

  6. Elemental bioimaging of Cisplatin in Caenorhabditis elegans by LA-ICP-MS

    PubMed Central

    Crone, Barbara; Aschner, Michael; Schwerdtle, Tanja; Karst, Uwe; Bornhorst, Julia

    2015-01-01

    Cis-diamminedichloroplatinum(II) (Cisplatin) is one of the most important and frequently used cytostatic drugs for the treatment of various solid tumors. Herein, a laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) method incorporating a fast and simple sample preparation protocol was developed for the elemental mapping of Cisplatin in the model organism Caenorhabditis elegans (C. elegans). The method allows imaging of the spatially-resolved elemental distribution of platinum in the whole organism with respect to the anatomic structure in L4 stage worms at a lateral resolution of 5 µm. In addition, a dose- and time-dependent Cisplatin uptake was corroborated quantitatively by a total reflection X-ray fluorescence spectroscopy (TXRF) method, and the elemental mapping indicated that Cisplatin is located in the intestine and in the head of the worms. Better understanding of the distribution of Cisplatin in this well-established model organism will be instrumental in deciphering Cisplatin toxicity and pharmacokinetics. Since the cytostatic effect of Cisplatin is based on binding the DNA by forming intra- and interstrand crosslinks, the response of poly(ADP-ribose)metabolism enzyme 1 (pme-1) deletion mutants to Cisplatin was also examined. Loss of pme-1, which is the C. elegans ortholog of human poly(ADP-ribose) polymerase 1 (PARP-1) led to disturbed DNA damage response. With respect to survival and brood size, pme-1 deletion mutants were more sensitive to Cisplatin as compared to wildtype worms, while Cisplatin uptake was indistinguishable. PMID:25996669

  7. Kinin B2 receptor deletion and blockage ameliorates cisplatin-induced acute renal injury.

    PubMed

    Estrela, Gabriel R; Wasinski, Frederick; Bacurau, Reury F; Malheiros, Denise M A C; Câmara, Niels O S; Araújo, Ronaldo C

    2014-09-01

    Cisplatin treatment has been adopted in some chemotherapies; however, this drug can induce acute kidney injury due its ability to negatively affect renal function, augment serum levels of creatinine and urea, increase the acute tubular necrosis score and up-regulate cytokines (e.g., IL-1β and TNF-α). The kinin B2 receptor has been associated with the inflammation process, as well as the regulation of cytokine expression, and its deletion resulted in an improvement in the diabetic nephropathy status. To examine the role of the kinin B2 receptor in cisplatin-induced acute kidney injury, kinin B2 receptor knockout mice were challenged with cisplatin. Additionally, WT mice were treated with a B2 receptor antagonist after cisplatin administration. B2 receptor-deficient mice were less sensitive to this drug than the WT mice, as shown by reduced weight loss, better preservation of kidney function, down regulation of inflammatory cytokines and less acute tubular necrosis. Moreover, treatment with the kinin B2 receptor antagonist effectively reduced the levels of serum creatinine and blood urea after cisplatin administration. Thus, our data suggest that the kinin B2 receptor is involved in cisplatin-induced acute kidney injury by mediating the necrotic process and the expression of inflammatory cytokines, thus resulting in declined renal function. These results highlight the kinin B2 receptor antagonist treatment in amelioration of nephrotoxicity induced by cisplatin therapy.

  8. Kinin B2 receptor deletion and blockage ameliorates cisplatin-induced acute renal injury.

    PubMed

    Estrela, Gabriel R; Wasinski, Frederick; Bacurau, Reury F; Malheiros, Denise M A C; Câmara, Niels O S; Araújo, Ronaldo C

    2014-09-01

    Cisplatin treatment has been adopted in some chemotherapies; however, this drug can induce acute kidney injury due its ability to negatively affect renal function, augment serum levels of creatinine and urea, increase the acute tubular necrosis score and up-regulate cytokines (e.g., IL-1β and TNF-α). The kinin B2 receptor has been associated with the inflammation process, as well as the regulation of cytokine expression, and its deletion resulted in an improvement in the diabetic nephropathy status. To examine the role of the kinin B2 receptor in cisplatin-induced acute kidney injury, kinin B2 receptor knockout mice were challenged with cisplatin. Additionally, WT mice were treated with a B2 receptor antagonist after cisplatin administration. B2 receptor-deficient mice were less sensitive to this drug than the WT mice, as shown by reduced weight loss, better preservation of kidney function, down regulation of inflammatory cytokines and less acute tubular necrosis. Moreover, treatment with the kinin B2 receptor antagonist effectively reduced the levels of serum creatinine and blood urea after cisplatin administration. Thus, our data suggest that the kinin B2 receptor is involved in cisplatin-induced acute kidney injury by mediating the necrotic process and the expression of inflammatory cytokines, thus resulting in declined renal function. These results highlight the kinin B2 receptor antagonist treatment in amelioration of nephrotoxicity induced by cisplatin therapy. PMID:24975837

  9. Can pharmacogenetics explain efficacy and safety of cisplatin pharmacotherapy?

    PubMed Central

    Roco, Ángela; Cayún, Juan; Contreras, Stephania; Stojanova, Jana; Quiñones, Luis

    2014-01-01

    Several recent pharmacogenetic studies have investigated the variability in both outcome and toxicity in cisplatin-based therapies. These studies have focused on the genetic variability of therapeutic targets that could affect cisplatin response and toxicity in diverse type of cancer including lung, gastric, ovarian, testicular, and esophageal cancer. In this review, we seek to update the reader in this area of investigation, focusing primarily on DNA reparation enzymes and cisplatin metabolism through Glutathione S-Transferases (GSTs). Current evidence indicates a potential application of pharmacogenetics in therapeutic schemes in which cisplatin is the cornerstone of these treatments. Therefore, a collaborative effort is required to study these molecular characteristics in order to generate a genetic panel with clinical utility. PMID:25452763

  10. Utilization of arsenic trioxide as a treatment of cisplatin-resistant non-small cell lung cancer PC-9/CDDP and PC-14/CDDP cells

    PubMed Central

    SUZUKI, TOSHIHIRO; ISHIBASHI, KENICHI; YUMOTO, ATSUSHI; NISHIO, KAZUTO; OGASAWARA, YUKI

    2015-01-01

    Cisplatin is a commonly used drug in combination chemotherapy. However, various malignant tumors frequently acquire resistance to cisplatin. Arsenic trioxide (ATO) has been approved as a chemotherapeutic drug for the treatment of acute promyelocytic leukemia, and the combination of ATO and cisplatin has been revealed to demonstrate synergistic effects in ovarian and small cell lung cancer cells. Thus, it was hypothesized that ATO may also be active against cisplatin-resistant non-small cell lung cancer (NSCLC) PC-9/CDDP and PC-14/CDDP cells. The present study also evaluated the effects of ATO on the cisplatin-sensitive NSCLC PC-9 and PC-14 cell lines. Notably, ATO demonstrated a markedly decreased IC50 in the cisplatin-resistant PC-9/CDDP and PC-14/CDDP cells compared with the IC50 in the cisplatin-sensitive parental PC-9 and PC-14 cells. Additionally, it was found that arsenite accumulation in the PC-9 cell line was affected through the downregulation of GS-X pump systems. Although it is likely that cisplatin resistance in PC-9 cells does not depend on the GS-X pump systems, ATO was effective against cisplatin-resistant NSCLC PC-9/CDDP and PC-14/CDDP cells in combination chemotherapy. PMID:26622574

  11. Natural history of postural instability in breast cancer patients treated with taxane-based chemotherapy: A pilot study.

    PubMed

    Monfort, Scott M; Pan, Xueliang; Patrick, Robyn; Singaravelu, Janani; Loprinzi, Charles L; Lustberg, Maryam B; Chaudhari, Ajit M W

    2016-07-01

    Over 230,000 new cases of breast cancer are expected to be diagnosed in the United States in 2015. Taxane-based chemotherapy is often an effective treatment, but can also cause adverse symptoms in patients due to neurotoxicity. These side effects can impair postural control in patients; however, this instability has scarcely been quantified. The purpose of this pilot study was to gain insight into the natural history of postural instability in breast cancer patients being treated with taxane-based chemotherapy. Thirty-two breast cancer patients (31 female/1 male; 47.6±11.2 year; 16 stage II/16 stage III) completed eyes open and eyes closed quiet standing trials in the oncology clinic where they were being treated. These trials were collected at five timepoints throughout their chemotherapy treatment: (1) before initiating chemotherapy to provide a baseline, (2-4) before starting subsequent chemotherapy cycles, and (5) 1-3 months after receiving their last taxane infusion. After the first chemotherapy cycle, patients demonstrated increases in 95% confidence ellipse area of center of pressure (CoP) [45.2%, p=0.01] and root mean squared CoP excursion [18%, p=0.006] compared to baseline values for the eyes closed condition. These balance deficiencies progressed with cumulative taxane exposure. Postural instability persisted 1-3 months after completing chemotherapy with increases in 95% CoP ellipse area [86.8%, p=0.002], root mean squared CoP excursion [32.6%, p=0.001], and mean CoP velocity [30.4%, p=0.024]. The balance impairments demonstrated by patients in this study appear to be clinically relevant when compared to balance impairments previously reported in other patient populations. PMID:27341530

  12. Gallic acid induces apoptosis and enhances the anticancer effects of cisplatin in human small cell lung cancer H446 cell line via the ROS-dependent mitochondrial apoptotic pathway.

    PubMed

    Wang, Ruixuan; Ma, Lijie; Weng, Dan; Yao, Jiahui; Liu, Xueying; Jin, Faguang

    2016-05-01

    Small cell lung cancer (SCLC) is the most aggressive lung cancer subtype and accounts for more than 15% of all lung cancer cases. Cisplatin [cis-diamminedichloroplatinum (CDDP)]-based combination chemotherapy is the cornerstone for all stages of SCLC. However, acquired multidrug resistance (MDR) and intolerable toxicities lead to a high mortality rate in SCLC patients. Gallic acid [3,4,5-trihydroxybenzoic acid (GA)] is a natural botanic phenolic compound which can induce cell apoptosis in several types of cancers. In the present study, we aimed to explore the anticancer effects of GA on human SCLC H446 cells and its promotive effects on the anticancer activities of cisplatin. The viability of the H446 cells was analyzed by MTT assay. Morphological changes in the H446 cells were observed under an inverted microscope. Apoptosis induction was determined by Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. The level of reactive oxygen species (ROS) was assessed by 2'7'-dichlorofluorescein diacetate (DCFH‑DA), mitochondrial membrane potential (MMP) by JC-1, and western blotting was used to examine the expression of mitochondrial apoptosis-related proteins. The results showed that both GA and cisplatin changed the morphology, inhibited the growth and induced apoptosis in the H446 cells by inducing generation of ROS, disruption of MMP, downregulation of XIAP expression, and upregulation of Bax, Apaf-1, DIABLO and p53 expression. More importantly, GA combined with cisplatin exhibited synergistic effects on inducing of these pro-apoptotic mediators and modulating the activation of apoptosis-related molecules. However, inhibition of the generation of ROS by N-acetyl-l-cysteine (NAC), a specific ROS inhibitor, reversed the cell apoptosis induced by cisplatin combined with GA. In conclusion, the results from the present study revealed that GA exhibited an anticancer effect on human SCLC H446 cells and enhanced the antitumor activities of cisplatin

  13. 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

  14. Patterns of chemotherapy, toxicity, and short-term outcomes for older women receiving adjuvant trastuzumab-based therapy.

    PubMed

    Freedman, Rachel A; Vaz-Luis, Ines; Barry, William T; Lii, Huichuan; Lin, Nancy U; Winer, Eric P; Keating, Nancy L

    2014-06-01

    Limited data are available regarding patterns of chemotherapy receipt and treatment-related toxicities for older women receiving adjuvant trastuzumab-based therapy. We used surveillance, epidemiology and end results (SEER)-Medicare data to identify patients ≥66 years with stage I-III breast cancer treated during 2005-2009, who received trastuzumab-based therapy. We examined patterns of chemotherapy receipt, and using multivariable logistic regression, we examined associations of age and comorbidity with non-standard chemotherapy. In propensity-weighted cohorts of women receiving standard and non-standard trastuzumab-based therapy, we also examined rates of (1) hospital events during the first 6 months of chemotherapy and (2) short-term survival. Among 2,106 women, 29.7 % were aged ≥76 and 66 % had a comorbidity score = 0. Overall, 31.3 % of women received non-standard chemotherapy. Compared to patients aged 66-70, older patients more often received non-standard chemotherapy [adjusted odds ratio (OR) = 4.1, 95 % confidence interval (CI) = 3.40-4.92 (ages 76-80); OR = 15.3, 95 %CI = 9.92-23.67 (age ≥ 80)]. However, comorbidity was not associated with receipt of non-standard chemotherapy. After propensity score adjustment, hospitalizations were more frequent in the standard (vs. non-standard) group (adjusted OR = 1.7, 95 % CI = 1.29-2.24). With a median follow-up of 2.8 years, 276 deaths occurred; the adjusted hazard ratio (HR) for death was lower in standard versus non-standard treated women (HR = 0.69, 95 % CI = 0.52-0.91). Among a population-based cohort of older women receiving trastuzumab, nearly one-third received non-standard chemotherapy, with the highest rates among the oldest women. Non-standard chemotherapy was associated with fewer toxicity-related hospitalizations but worse survival. Further exploration of treatment toxicities and outcomes for older women with HER2-positive breast cancer is warranted.

  15. Suppression of Rev3, the catalytic subunit of Pol{zeta}, sensitizes drug-resistant lung tumors to chemotherapy.

    PubMed

    Doles, Jason; Oliver, Trudy G; Cameron, Eleanor R; Hsu, Gerald; Jacks, Tyler; Walker, Graham C; Hemann, Michael T

    2010-11-30

    Platinum-based chemotherapeutic drugs are front-line therapies for the treatment of non-small cell lung cancer. However, intrinsic drug resistance limits the clinical efficacy of these agents. Recent evidence suggests that loss of the translesion polymerase, Polζ, can sensitize tumor cell lines to cisplatin, although the relevance of these findings to the treatment of chemoresistant tumors in vivo has remained unclear. Here, we describe a tumor transplantation approach that enables the rapid introduction of defined genetic lesions into a preclinical model of lung adenocarcinoma. Using this approach, we examined the effect of impaired translesion DNA synthesis on cisplatin response in aggressive late-stage lung cancers. In the presence of reduced levels of Rev3, an essential component of Polζ, tumors exhibited pronounced sensitivity to cisplatin, leading to a significant extension in overall survival of treated recipient mice. Additionally, treated Rev3-deficient cells exhibited reduced cisplatin-induced mutation, a process that has been implicated in the induction of secondary malignancies following chemotherapy. Taken together, our data illustrate the potential of Rev3 inhibition as an adjuvant therapy for the treatment of chemoresistant malignancies, and highlight the utility of rapid transplantation methodologies for evaluating mechanisms of chemotherapeutic resistance in preclinical settings.

  16. 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. PMID:26991853

  17. 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.

  18. Toxicity profile and clinical outcomes in locally advanced head and neck cancer patients treated with induction chemotherapy prior to concurrent chemoradiation.

    PubMed

    Ko, Eric C; Genden, Eric M; Misiukiewicz, Krzysztof; Som, Peter M; Kostakoglu, Lale; Chen, Chien-Ting; Packer, Stuart; Kao, Johnny

    2012-02-01

    The use of induction chemotherapy prior to chemoradiation for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) remains controversial. We explored whether toxicity from induction chemotherapy influenced the delivery of concurrent chemoradiation. Among 171 consecutive previously unirradiated patients with HNSCC treated with combined chemotherapy and radiation, we identified 66 patients with stage III-IVB head and neck carcinoma who were treated with induction chemotherapy prior to planned chemoradiation. The most common induction regimen was docetaxel, cisplatin and 5-FU (TPF; 80%) for 2 to 3 cycles. Mean radiation dose was 72 Gy (range, 36-75 Gy). Concurrent chemotherapy regimens included cisplatin (26%), cetuximab (5%) and 5-fluorouracil/hydroxyurea (65%)-based regimens. At a median follow-up of 27 months (range, 9-56 months), the 2-year locoregional control and distant control rates were 85 and 86%, respectively. The 2-year disease-free survival and overall survival rates were 74 and 80%, respectively. Although there were no grade 5 toxicities during induction chemotherapy, 26% of patients required hospitalization for adverse events, including 5% needing intensive care. The most common high grade adverse events were grade 4 neutropenia (21%) and neutropenic fever (17%). Six percent of patients were unable to tolerate concurrent chemotherapy. The 2-year disease-free survival was significantly higher in patients able to complete induction and concurrent chemoradiation as planned (83 vs. 27%, p<0.001). Induction chemotherapy followed by concurrent chemoradiation results in promising survival rates in our cohort of advanced head and neck carcinoma patients. Due to severe toxicities in a subset of patients, this strategy is only recommended in selected high-risk patients who are carefully followed by an experienced multidisciplinary team. PMID:22020564

  19. 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.

  20. Heat shock protein-mediated protection against Cisplatin-induced hair cell death.

    PubMed

    Baker, Tiffany G; Roy, Soumen; Brandon, Carlene S; Kramarenko, Inga K; Francis, Shimon P; Taleb, Mona; Marshall, Keely M; Schwendener, Reto; Lee, Fu-Shing; Cunningham, Lisa L

    2015-02-01

    Cisplatin is a highly successful and widely used chemotherapy for the treatment of various solid malignancies in both adult and pediatric patients. Side effects of cisplatin treatment include nephrotoxicity and ototoxicity. Cisplatin ototoxicity results from damage to and death of cells in the inner ear, including sensory hair cells. We showed previously that heat shock inhibits cisplatin-induced hair cell death in whole-organ cultures of utricles from adult mice. Since heat shock protein 70 (HSP70) is the most upregulated HSP in response to heat shock, we investigated the role of HSP70 as a potential protectant against cisplatin-induced hair cell death. Our data using utricles from HSP70 (-/-) mice indicate that HSP70 is necessary for the protective effect of heat shock against cisplatin-induced hair cell death. In addition, constitutive expression of inducible HSP70 offered modest protection against cisplatin-induced hair cell death. We also examined a second heat-inducible protein, heme oxygenase-1 (HO-1, also called HSP32). HO-1 is an enzyme responsible for the catabolism of free heme. We previously showed that induction of HO-1 using cobalt protoporphyrin IX (CoPPIX) inhibits aminoglycoside-induced hair cell death. Here, we show that HO-1 also offers significant protection against cisplatin-induced hair cell death. HO-1 induction occurred primarily in resident macrophages, with no detectable expression in hair cells or supporting cells. Depletion of macrophages from utricles abolished the protective effect of HO-1 induction. Together, our data indicate that HSP induction protects against cisplatin-induced hair cell death, and they suggest that resident macrophages mediate the protective effect of HO-1 induction.

  1. Nrf2 induces cisplatin resistance through activation of autophagy in ovarian carcinoma

    PubMed Central

    Bao, Ling-Jie; Jaramillo, Melba C; Zhang, Zhen-Bo; Zheng, Yun-Xi; Yao, Ming; Zhang, Donna D; Yi, Xiao-Fang

    2014-01-01

    Cisplatin resistance is a major problem affecting ovarian carcinoma treatment. NF-E2-related factor 2 (Nrf2), a nuclear transcription factor, plays an important role in chemotherapy resistance. However, the underlying mechanism by which Nrf2 mediates cisplatin chemoresistance is unclear. Methods: The human ovarian carcinoma cell line, A2780, and its cisplatin-resistant variant, A2780cp were cultivated. Cell viability was determined with WST-8 assay. Western blot was applied to detect the expression of Nrf2, Nrf2 target genes, and autophagy-related proteins. RNA interference was used to knock down target genes. Annexin V and propidium iodide (PI) staining was utilized to quantify apoptosis. The ultrastructural analysis of autophagosomes was performed by transmission electron microscopy (TEM). Results: Nrf2 and its targeting genes, NQO1 and HO-1, are overexpressed in A2780cp cells compared with A2780 cells. Knocking down Nrf2 sensitized A2780cp cells to cisplatin treatment and decreased autophagy-related genes, Atg3, Atg6, Atg12 and p62 in both mRNA and protein levels. Furthermore, we demonstrated that in both cell lines cisplatin could induce the formation of autophagosomes and upregulate the expression of autophagy-related genes Atg3, Atg6 and Atg12. Treatment with an autophagy inhibitor, 3-Methyladenine (3-MA), or beclin 1 siRNA enhanced cisplatin-induced cell death in A2780cp cells, suggesting that inhibition of autophagy renders resistant cells to be more sensitive to cisplatin. Taken together, Nrf2 signaling may regulate cisplatin resistance by activating autophagy. Conclusions: Nrf2-activated autophagy may function as a novel mechanism causing cisplatin-resistance. PMID:24817946

  2. Heat shock protein-mediated protection against Cisplatin-induced hair cell death.

    PubMed

    Baker, Tiffany G; Roy, Soumen; Brandon, Carlene S; Kramarenko, Inga K; Francis, Shimon P; Taleb, Mona; Marshall, Keely M; Schwendener, Reto; Lee, Fu-Shing; Cunningham, Lisa L

    2015-02-01

    Cisplatin is a highly successful and widely used chemotherapy for the treatment of various solid malignancies in both adult and pediatric patients. Side effects of cisplatin treatment include nephrotoxicity and ototoxicity. Cisplatin ototoxicity results from damage to and death of cells in the inner ear, including sensory hair cells. We showed previously that heat shock inhibits cisplatin-induced hair cell death in whole-organ cultures of utricles from adult mice. Since heat shock protein 70 (HSP70) is the most upregulated HSP in response to heat shock, we investigated the role of HSP70 as a potential protectant against cisplatin-induced hair cell death. Our data using utricles from HSP70 (-/-) mice indicate that HSP70 is necessary for the protective effect of heat shock against cisplatin-induced hair cell death. In addition, constitutive expression of inducible HSP70 offered modest protection against cisplatin-induced hair cell death. We also examined a second heat-inducible protein, heme oxygenase-1 (HO-1, also called HSP32). HO-1 is an enzyme responsible for the catabolism of free heme. We previously showed that induction of HO-1 using cobalt protoporphyrin IX (CoPPIX) inhibits aminoglycoside-induced hair cell death. Here, we show that HO-1 also offers significant protection against cisplatin-induced hair cell death. HO-1 induction occurred primarily in resident macrophages, with no detectable expression in hair cells or supporting cells. Depletion of macrophages from utricles abolished the protective effect of HO-1 induction. Together, our data indicate that HSP induction protects against cisplatin-induced hair cell death, and they suggest that resident macrophages mediate the protective effect of HO-1 induction. PMID:25261194

  3. Efficacy of concurrent single-agent chemotherapy using radiotherapy in patients with cervical cancer: a meta-analysis.

    PubMed

    Zhang, Ying; Yang, Zhicheng; Zhou, Yijin; Pan, Jingjing; Liu, Yongyuan

    2015-01-01

    Concurrent chemoradiotherapy has proven to be more effective on patients with advanced cervical cancer than radiotherapy alone. Although cisplatin has been recommended to be the standard agent in chemotherapy, it has some limitations in clinical use because of its strong side effects. Moreover, the optimal chemotherapy regimen remains unclear. A comprehensive electronic search was conducted via the Internet retrieval system to identify eligible trials. The ending points included response, overall survival (OS), local recurrent, and distant metastasis rates. Odds ratios and 95% confidence interval were calculated to compare the effects. Fifteen trials with 1142 patients were eligible. With regard to the response rate, only nedaplatin showed a significant improvement compared with cisplatin. Docetaxel, pacitaxel, fluoropyrimidine, paclitaxel liposome, and irinotecan did not show any advantages. When targeted on OS or local recurrent rate, no significant advantage was found when these single-drug regimens were compared with cisplatin. However, when aimed at distant metastasis rate, fluoropyrimidine showed a disadvantage to cisplatin, whereas others showed equal efficacy. Nedaplatin, docetaxel, pacitaxel, and fluoropyrimidine showed a better effect on reducing chemotherapy toxicity than cisplatin. Single-drug chemotherapy concurrent with radiotherapy, except for nedaplatin, may have no advantage on clinical outcomes when compared with cisplatin but showed a better effect on reducing chemotherapy toxicity, which could be used as an alternative to patients who can not tolerate the side effects of cisplatin. Nedaplatin is also effective and safe, and may be highly valuable in clinical applications. PMID:26309518

  4. The tocotrienol-rich fraction from rice bran enhances cisplatin-induced cytotoxicity in human mesothelioma H28 cells.

    PubMed

    Nakashima, Keisuke; Virgona, Nantiga; Miyazawa, Mio; Watanabe, Takashi; Yano, Tomohiro

    2010-09-01

    Resistance to chemotherapy (chemoresistance) is a serious problem in malignant mesothelioma, a highly aggressive neoplasm. Gamma-tocotrienol (gamma-T3) can sensitize various cancerous cells to chemotherapeutic agents by inhibiting pathways that lead to treatment resistance. In this study, we investigated the modulating effect of tocotrienol-rich fraction (TRF) from rice bran, which is abundant in gamma-T3, on chemoresistance in human MM H28 cells. TRF treatment caused a marked reduction in the viability of H28 cells in a dose-dependent manner, while cisplatin treatment had no effect on the cells, indicating that H28 cells are resistant to cisplatin. A significant increase in cytotoxicity was observed in H28 cells treated with TRF, and this effect was enhanced by the combination treatment with cisplatin. The cytotoxic effect was closely related to the inhibition of phosphatidylinositol 3-kinase (PI3K)-AKT signaling. Inactivation of Akt signaling by TRF or the combination with cisplatin mitigated cisplatin-induced activation of Akt, resulting in reducing the chemoresistance H28 cells to cisplatin. Reduced cell viability and attenuated chemoresistance of the H28 cells against cisplatin were also observed following the use of a PI3K inhibitor, LY294002. These results suggest that the combination therapy of cisplatin with TRF is a plausible strategy for achieving tolerance for the chemotherapeutic agent in MM therapy.

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

    SciTech Connect

    Ko, Andrew H.; Venook, Alan P.

    2007-07-01

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

  6. Selection of a patient subgroup with advanced esophageal squamous carcinoma who could benefit from second-line chemotherapy.

    PubMed

    Kim, Seung Tae; Park, Kyong Hwa; Oh, Sang Cheul; Seo, Jae Hong; Shin, Sang Won; Kim, Jun Suk; Kim, Yeul Hong

    2010-01-01

    Despite first-line therapy, most patients with advanced esophageal squamous cell carcinoma (ESCC) experience disease progression and may become eligible for second-line chemotherapy. Although commonly used, the role of salvage chemotherapy in patients with recurrent or metastatic ESCC has not yet been established. We analyzed 53 patients who had received second-line chemotherapy after the failure of cisplatin-based combination chemotherapy with or without radiotherapy as first-line therapy in ESCC between March 2000 and June 2008. Median progression-free survival (PFS) and overall survival (OS) for second-line chemotherapy were 2.4 and 5.2 months, respectively, with an overall response rate of 18.9%. In multivariate analysis, Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 2 or more and PFS under first-line therapy <4 months were independent prognostic factors for decreased OS. OS was estimated based on the number of adverse prognostic factors: 0 = good; 1 = intermediate, and 2 = poor. The median OS for the good, intermediate, and poor prognostic groups were 11.2, 4.5 and 4.3 months, respectively (p < 0.001). The good prognostic group showed better OS than the intermediate or poor groups (p < 0.001). Second-line chemotherapy may be beneficial for OS in ESCC patients with ECOG PS 0-1 and PFS under first-line therapy ≥4 months.

  7. Pyriform sinus squamous cell carcinoma: oncological outcomes in good responders of induction chemotherapy-based larynx preservation protocols.

    PubMed

    Vourexakis, Zacharias; Le Ridant, Anne-Marie; Dulguerov, Pavel; Janot, François

    2015-07-01

    Induction chemotherapy-based larynx preservation protocols use chemotherapy to select exclusively patients with 'chemosensitive' tumors for a nonsurgical treatment with radiation therapy. This study on pyriform sinus squamous cell carcinoma (SCC) is interested in the oncological outcome of treatment based on radiation therapy when offered to patients with tumors responding to induction chemotherapy. This was a retrospective cohort study. The cohort included good responders to induction chemotherapy, subsequently treated with definite radiation therapy (with or without concomitant chemotherapy) for pyriform sinus SCC, in a tertiary referral cancer center. The primary endpoints were overall, laryngectomy-free and disease-free survival and the secondary endpoints were analysis of treatment failures and possibilities of salvage treatment. Forty-two patients fulfilled the inclusion criteria and were retained for analysis; 7% were stage II (3/42), 48% stage III (20/42) and 45% stage IV (19/42). At 1, 3 and 5 years, the overall survival was 95% (40/42), 74% (31/42), and 60% (SE ≈ 0.08), respectively. For the same intervals, the laryngectomy-free survival was 90% (38/42), 69% (29/42) and 50% (SE ≈ 0.08), respectively. The estimated 5-year disease-free survival was also 50%. Disease-free survival was significantly better for N0 patients. There was a 28% recurrence rate, mainly in the primary tumor site (9/11), with or without simultaneous nodal recurrence. Interestingly, more than one-third of all oncologic failures occurred beyond the first 3 years of follow-up. Salvage treatment was not possible or definitely inefficient in at least 2/3 of all recurrences. In candidates for larynx preservation for a pyriform sinus SCC, good response to induction chemotherapy followed by definite radiation therapy seems to be associated with a more favorable prognosis. Nevertheless, in case of locoregional recurrence the possibilities for efficient salvage treatment are limited.

  8. MRP1 expression in CTCs confers resistance to irinotecan-based chemotherapy in metastatic colorectal cancer.

    PubMed

    Abdallah, Emne Ali; Fanelli, Marcello Ferretti; Souza E Silva, Virgílio; Machado Netto, Marcelo Calil; Gasparini Junior, José Luiz; Araújo, Daniel Vilarim; Ocea, Luciana Menezes Mendonça; Buim, Marcilei Eliza Cavicchioli; Tariki, Milena Shizue; Alves, Vanessa da Silva; Piana de Andrade, Victor; Dettino, Aldo Lourenço Abbade; Abdon Lopes de Mello, Celso; Chinen, Ludmilla Thomé Domingos

    2016-08-15

    Circulating tumor cells are important markers of tumor progression and can reflect tumor behavior in metastatic colorectal cancer (mCRC). Identification of proteins that confer resistance to treatment is an important step to predict response and better selection of treatment for patients. Multidrug resistance-associated protein 1 (MRP1) and Multidrug resistance-associated protein 4 (MRP4) play a role in irinotecan-resistance, and Excision Repair Cross-Complementation group 1 (ERCC1) expression can confer resistance to platinum compounds. Here, we included 34 patients with mCRC and most of them received FOLFIRI or FOLFOX chemotherapy (91.1%). CTCs were isolated by ISET(®) Technology and identified in 30 patients (88.2%), with a median of 2.0 CTCs/mL (0-31.0). We analyzed the immunocytochemical expression of MRP1, MRP4 and ERCC1 only in patients who had previously detectable CTCs, accordingly to treatment received (n = 19, 15 and 13 patients, respectively). Among patients treated with irinotecan-based chemotherapy, 4 out of 19 cases with MRP1 positive CTCs showed a worse progression free survival (PFS) in comparison to those with MRP1 negative CTCs (2.1 months vs. 9.1 months; p = 0.003). None of the other proteins studied in CTCs had significant association with PFS. We analyzed also histological sections of primary tumors and metastases by immunohistochemistry, and found no association with clinicopathological characteristics or with PFS. Our results show MRP1 as a potential biomarker of resistance to treatment with irinotecan when found in CTCs from mCRC patients. This is a small proof-of-principle study and these early findings need to be validated in a larger cohort of patients. PMID:26950035

  9. Metallomics in drug development: characterization of a liposomal cisplatin drug formulation in human plasma by CE-ICP-MS.

    PubMed

    Nguyen, Tam T T N; Østergaard, Jesper; Stürup, Stefan; Gammelgaard, Bente

    2013-02-01

    A capillary electrophoresis inductively coupled plasma mass spectrometry method for separation of free cisplatin from liposome-encapsulated cisplatin and protein-bound cisplatin was developed. A liposomal formulation of cisplatin based on PEGylated liposomes was used as model drug formulation. The effect of human plasma matrix on the analysis of liposome-encapsulated cisplatin and intact cisplatin was studied. The presence of 1 % of dextran and 4 mM of sodium dodecyl sulfate in HEPES buffer was demonstrated to be effective in improving the separation of liposomes and cisplatin bound to proteins in plasma. A detection limit of 41 ng/mL of platinum and a precision of 2.1 % (for 10 μg/mL of cisplatin standard) were obtained. Simultaneous measurements of phosphorous and platinum allows the simultaneous monitoring of the liposomes, liposome-encapsulated cisplatin, free cisplatin and cisplatin bound to plasma constituents in plasma samples. It was demonstrated that this approach is suitable for studies of the stability of liposome formulations as leakage of active drug from the liposomes and subsequent binding to biomolecules in plasma can be monitored. This methodology has not been reported before and will improve characterization of liposomal drugs during drug development and in studies on kinetics.

  10. 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.

  11. 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

  12. 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.

  13. Predictive effects of bilirubin on response of colorectal cancer to irinotecan-based chemotherapy

    PubMed Central

    Yu, Qian-Qian; Qiu, Hong; Zhang, Ming-Sheng; Hu, Guang-Yuan; Liu, Bo; Huang, Liu; Liao, Xin; Li, Qian-Xia; Li, Zhi-Huan; Yuan, Xiang-Lin

    2016-01-01

    AIM: To examine the predictive effects of baseline serum bilirubin levels and UDP-glucuronosyltransferase (UGT) 1A1*28 polymorphism on response of colorectal cancer to irinotecan-based chemotherapy. METHODS: The present study was based on a prospective multicenter longitudinal trial of Chinese metastatic colorectal cancer (mCRC) patients treated with irinotecan-based chemotherapy (NCT01282658). Baseline serum bilirubin levels, including total bilirubin (TBil) and unconjugated bilirubin (UBil), were measured, and genotyping of UGT1A1*28 polymorphism was performed. Receiver operating characteristic curve (ROC) analysis was used to determine cutoff values of TBil and UBil. The TBil values were categorized into > 13.0 or ≤ 13.0 groups; the UBil values were categorized into > 4.1 or ≤ 4.1 groups. Combining the cutoff values of TBil and UBil, which was recorded as CoBil, patients were classified into three groups. The classifier’s performance of UGT1A1*28 and CoBil for predicting treatment response was evaluated by ROC analysis. Associations between response and CoBil or UGT1A1*28 polymorphism were estimated using simple and multiple logistic regression models. RESULTS: Among the 120 mCRC patients, the serum bilirubin level was significantly different between the UGT1A1*28 wild-type and mutant genotypes. Patients with the mutant genotype had an increased likelihood of a higher TBil (P = 0.018) and a higher UBil (P = 0.014) level compared with the wild-type genotype. Patients were stratified into three groups based on CoBil. Group 1 was patients with TBil > 13.0 and UBil > 4.1; Group 2 was patients with TBil ≤ 13.0 and UBil > 4.1; and Group 3 was patients with TBil ≤ 13.0 and UBil ≤ 4.1. Patients in Group 3 had more than a 10-fold higher likelihood of having a response in the simple (OR = 11.250; 95%CI: 2.286-55.367; P = 0.003) and multiple (OR = 16.001; 95%CI: 2.802 -91.371; P = 0.002) analyses compared with the Group 1 individuals. Patients carrying the UGT1

  14. [A case of secondary myelodysplastic syndrome following chemotherapy for lung cancer].

    PubMed

    Uemura, M; Kasamatsu, Y; Sawada, M; Takemura, S; Sugino, S; Kondou, M

    1992-10-01

    A case of secondary myelodysplastic syndrome (MDS) following chemotherapy for lung cancer is reported. A 78-year-old man, with a smoking history of 20 cigarettes/day for 55 years, was incidentally, diagnosed as having stage IV squamous cell carcinoma of the lung in 1987 during admission for transurethral resection of bladder cancer. He received combination chemotherapy of mitomycin C, vincristin, and cisplatin for his lung cancer between July and September 1988. His clinical course remained almost stable until October 1989, when his blood count showed severe anemia and thrombocytopenia. He was diagnosed as having secondary MDS induced by cytotoxic agents used for the treatment of lung cancer, based on the dysplastic findings of precursor cells in the bone marrow and the chromosome abnormality of 51XY, +8, +9, +21, 3p-, 5q-, +2mar. He died of infection with the progression of MDS in March 1990.

  15. Behavioral and electrophysiological studies in rats with cisplatin-induced chemoneuropathy.

    PubMed

    Cata, Juan P; Weng, Han-Rong; Dougherty, Patrick M

    2008-09-16

    Neuropathy is the chief dose-limiting side effect associated with the major classes of frontline cancer therapy drugs. Here the changes in behavioral responses of rats to cutaneous mechanical and thermal stimuli occurring following treatment with cisplatin and the changes in spinal neurophysiology accompanying the development of chemotherapy-induced hyperalgesia were explored. Systemic treatment with cisplatin induced changes in both mechanical and thermal cutaneous sensory withdrawal thresholds of Sprague-Dawley rats. High doses of chemotherapy produced hypoalgesia whereas lower doses produced hyperalgesia. Follow-up neurophysiological studies in rats with chemotherapy-induced hyperalgesia revealed that deep spinal lamina wide dynamic range neurons had significantly higher spontaneous activity and longer afterdischarges to noxious mechanical stimuli than wide dynamic range neurons in control rats; cisplatin administration was also associated with longer afterdischarges and abnormal wind-up to transcutaneous electrical stimuli. The hyperexcitability observed during cisplatin-induced hyperalgesia is very similar to that observed in rats with hyperalgesia produced following treatment with other very diverse types of chemotherapeutic agents and similar to that observed following specific types of direct nerve injury. PMID:18657527

  16. Comprehensive identification of the binding sites of cisplatin in hen egg white lysozyme.

    PubMed

    Zhang, Ningbo; Du, Yonggang; Cui, Meng; Liu, Zhiqiang; Liu, Shuying

    2014-06-01

    Platinum drugs have become one of the most important kinds of chemotherapy agents, and the interactions of these drugs with proteins play very important roles in their side effects and drug resistance. However, it is still a challenge to determine the binding sites of platinum drugs in proteins with multiple disulfide bonds and stable three-dimensional structures using mass spectrometry. Here, the interaction between cisplatin and hen egg white lysozyme (HEWL), a multi-disulfide-bond-containing protein with a stable three-dimensional structure, was investigated using Fourier transform ion cyclotron resonance mass spectrometry. Typical disulfide bond reduction with dithiothreitol/tris(2-carboxyethyl)phosphine before trypsin digestion destroyed the binding of cisplatin to HEWL, and no platination sites were found. Efficient trypsin digestion methods for HEWL-cisplatin adducts were developed to avoid the loss of platinum binding to protein. At 55 °C, platinated HEWL was digested directly by trypsin in 6 h, and multiple platinated peptides were observed. In 60% acetonitrile, the digestion time of platinated HEWL was shortened to 2 h, and most of the platinated peptides were observed. In addition, the reduction of the disulfide bonds of HEWL greatly accelerated the reaction between HEWL and cisplatin, and the potential binding sites of cisplatin in reduced HEWL could be easily recognized. On the basis of the above-mentioned methods, multiple binding sites of cisplatin in HEWL were first identified by mass spectrometry. PMID:24748452

  17. 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.

  18. 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

  19. Nicotinamide adenine dinucleotide: An essential factor in preserving hearing in cisplatin-induced ototoxicity.

    PubMed

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

    2015-08-01

    Ototoxicity is an important issue in patients receiving cisplatin chemotherapy. Numerous studies have demonstrated that several mechanisms, including oxidative stress, DNA damage, and inflammatory responses, are closely associated with cisplatin-induced ototoxicity. Although much attention has been directed at identifying ways to protect the inner ear from cisplatin-induced damage, the precise underlying mechanisms have not yet been elucidated. The cofactor nicotinamide adenine dinucleotide (NAD(+)) has emerged as an important regulator of cellular energy metabolism and homeostasis. NAD(+) acts as a cofactor for various enzymes including sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs), and therefore, maintaining adequate NAD(+) levels has therapeutic benefits because of its effect on NAD(+)-dependent enzymes. Recent studies demonstrated that disturbance in intracellular NAD(+) levels is critically involved in cisplatin-induced cochlear damage associated with oxidative stress, DNA damage, and inflammatory responses. In this review, we describe the importance of NAD(+) in cisplatin-induced ototoxicity and discuss potential strategies for the prevention or treatment of cisplatin-induced ototoxicity with a particular focus on NAD(+)-dependent cellular pathways. PMID:25891352

  20. 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

  1. Chemotherapy-Related Neurotoxicity.

    PubMed

    Taillibert, Sophie; Le Rhun, Emilie; Chamberlain, Marc C

    2016-09-01

    Chemotherapy may have detrimental effects on either the central or peripheral nervous system. Central nervous system neurotoxicity resulting from chemotherapy manifests as a wide range of clinical syndromes including acute, subacute, and chronic encephalopathies, posterior reversible encephalopathy, acute cerebellar dysfunction, chronic cognitive impairment, myelopathy, meningitis, and neurovascular syndromes. These clinical entities vary by causative agent, degree of severity, evolution, and timing of occurrence. In the peripheral nervous system, chemotherapy-induced peripheral neuropathy (CIPN) and myopathy are the two main complications of chemotherapy. CIPN is the most common complication, and the majority manifest as a dose-dependent length-dependent sensory axonopathy. In severe cases of CIPN, the dose of chemotherapy is reduced, the administration delayed, or the treatment discontinued. Few treatments are available for CIPN and based on meta-analysis, duloxetine is the preferred symptomatic treatment. Myopathy due to corticosteroid use is the most frequent cause of muscle disorders in patients with cancer. PMID:27443648

  2. 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

  3. 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

  4. Evaluation of Platinum Chemotherapy in Combination with HER2-Targeted α-Particle Radiation

    PubMed Central

    Baidoo, Kwamena E.; Shih, Joanna H.; Wong, Karen J.; Brechbiel, Martin W.

    2013-01-01

    Abstract 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 213Bi-trastuzumab in the LS-174T i.p. xenograft model. This initial study determined the administration sequence of cisplatin and 213Bi-trastuzumab. Cisplatin coinjected with 213Bi-trastuzumab increased the median survival (MS) to 90 days versus 65 days for 213Bi-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 213Bi-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 213Bi-trastuzumab alone. The combination of carboplatin with 212Pb radioimmunotherapy was also evaluated. The therapeutic efficacy of 212Pb-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. PMID:23758610

  5. Astragalosides reduce cisplatin ototoxicity in guinea pigs.

    PubMed

    Xiong, Min; He, Qinglian; Wang, Jian; Lai, Huangwen

    2011-01-01

    Cisplatin is known to cause high-frequency neurosensory hearing loss. While reactive oxygen species have been shown to play a role, reactive nitrogen species have been implicated, but not proven to be involved, in cisplatin ototoxicity. The purpose of the present study was to investigate the role of nitric oxide (NO) in cisplatin ototoxicity by administering astragalosides, a natural antioxidant, in conjunction with cisplatin. Guinea pigs were injected with cisplatin, astragalosides or both. Auditory brainstem-evoked responses (ABRs) were measured before and 3 days after cisplatin administration. The cochlear tissue was then assayed for NO and malondialdehyde (MDA), and cochleae were also examined by scanning electron microscopy. Cisplatin alone caused significant ABR threshold shifts at all stimuli tested, whereas astragalosides alone caused no shifts. There was a significant reduction in threshold shift for clicks, 8-kHz and 16-kHz tone bursts (but not 32 kHz) when astragalosides was given with cisplatin. Both the MDA concentration and the NO concentration in the astragalosides/cisplatin group were significantly lower than those of the cisplatin group. Correspondingly, the loss of outer hair cells in the astragalosides/cisplatin group was much less than that in the cisplatin group. This suggests that astragalosides reduces cisplatin ototoxicity by its antioxidant property. PMID:21494054

  6. Chemotherapy-induced peripheral neurotoxicity and ototoxicity: new paradigms for translational genomics.

    PubMed

    Travis, Lois B; 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

    2014-03-12

    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.

  7. 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

  8. Clinical Implications of iNOS Levels in Triple-Negative Breast Cancer Responding to Neoadjuvant Chemotherapy

    PubMed Central

    Jiang, Nan; Zhang, Lei; Li, Yiming; Xu, Xiaoyin; Cai, Shouliang; Wei, Liang; Liu, Xuhong; Chen, Guanglei; Zhou, Yizhen; Liu, Cheng; Li, Zhan; Jin, Feng; Chen, Bo

    2015-01-01

    Triple-negative breast cancer is a high-risk breast cancer with poor survival rate. To date, there is a lack of targeted therapy for this type of cancer. One unique phenomenon is that inflammatory breast cancer is frequently triple negative. However, it is still ambiguous how inflammation influences triple-negative breast cancer growth and responding to chemotherapy. Herein, we investigated the levels of inflammation-associated enzyme, iNOS, in 20 triple-negative breast cancer patients’ tumors, and examined its correlation with patients’ responses to platinum-based neoadjuvant chemotherapy. Our studies showed that triple-negative breast cancer patients with attenuated iNOS levels in tumor cells after treatment showed better responses to platinum-based neoadjuvant chemotherapy than other triple-negative breast cancer patients. Our further in vitro studies confirmed that induction of proper levels of NO increased the resistance to cisplatin in triple-negative MDA-MB-231 cells. Our data suggest that aberrant high level of iNOS/NO are associated with less effectiveness of platinum-based neoadjuvant chemotherapy in triple-negative breast cancer. Therefore, we propose to monitor iNOS levels as a new predictor for triple-negative breast cancer patient’s response to platinum-based neoadjuvant chemotherapy. Moreover, iNOS/NO is considered as a potential target for combination therapy with platinum drugs for triple-negative breast cancer. PMID:26196284

  9. 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

  10. Cisplatin selects for stem-like cells in osteosarcoma by activating Notch signaling

    PubMed Central

    Yang, Jian; Gao, Tian; Simões, Bruno M.; Eyre, Rachel; Guo, Weichun; Clarke, Robert B.

    2016-01-01

    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. PMID:27102300

  11. Antitumor effects of different administration sequences of cisplatin and Endostar on Lewis lung carcinoma

    PubMed Central

    FAN, JUAN; DU, JIANGRONG; WU, JINGBO; FU, SHAOZHI; HU, DEFENG; WAN, QIANG

    2015-01-01

    Angiogenesis plays an essential role in the growth and metastasis of a number of tumors. Anti-angiogenic drugs are able to normalize tumor vasculature and inhibit tumor growth. Therefore, it has been hypothesized that the combination of cytotoxic chemotherapy drugs and angiogenesis inhibitors may exert complementary therapeutic benefits in the treatment of cancer. In the present study, the effect of the angiogenesis inhibitor, recombinant human endostatin (Endostar), in combination with cisplatin, was evaluated in C57/BL/6 mouse xenografts under different administration sequences. The drug combinations and sequences of administration were analyzed within the cancer xenografts for any inhibitory effects. Changes in the cell cycle distribution of the cells were monitored using flow cytometry. The effects of Endostar, particularly a reduction in the density of microvessels, were assessed using a method that employed anti-cluster of differentiation 31 antibodies. The concentration of cisplatin in the blood and tumor tissue at various time-points following administration was detected by high-performance liquid chromatography. The tumor tissues that received simultaneous Endostar and cisplatin exhibited increased inhibition of tumor growth and improved cell cycle distribution compared with those that received cisplatin alone, or those in which Endostar was administered prior to cisplatin. The simultaneous administration of the drugs resulted in the lowest microvessel density in the xenografts. Under these conditions, the concentration of cisplatin was revealed to be the highest in the grafted tumor tissue. The results of the present study suggest that the co-administration of Endostar and cisplatin may aid in the optimization of the antitumor activity of cisplatin. PMID:25624906

  12. Multicenter phase II trial of adjuvant therapy for resected pancreatic cancer using cisplatin, 5-fluorouracil, and interferon-alfa-2b–based chemoradiation: ACOSOG Trial Z05031

    PubMed Central

    Picozzi, V. J.; Abrams, R. A.; Decker, P. A.; Traverso, W.; O'Reilly, E. M.; Greeno, E.; Martin, R. C.; Wilfong, L. S.; Rothenberg, M. L.; Posner, M. C.

    2011-01-01

    Background: The American College of Surgeons Oncology Group sought to confirm the efficacy of a novel interferon-based chemoradiation regimen in a multicenter phase II trial. Patients and methods: Patients with resected (R0/R1) adenocarcinoma of the pancreatic head were treated with adjuvant interferon-alfa-2b (3 million units s.c. on days 1, 3, and 5 of each week for 5.5 weeks), cisplatin (30 mg/m2 i.v. weekly for 6 weeks), and continuous infusion 5-fluorouracil (5-FU; 175 mg·m2/day for 38 days) concurrently with external-beam radiation (50.4 Gy). Chemoradiation was followed by two 6-week courses of continuous infusion 5-FU (200 mg·m2/day). The primary study end point was 18-month overall survival from protocol enrollment (OS18); an OS18 ≥65% was considered a positive study outcome. Results: Eighty-nine patients were enrolled. Eighty-four patients were assessable for toxicity. The all-cause grade ≥3 toxicity rate was 95% (80 patients) during therapy. No long-term toxicity or toxicity-related deaths were noted. At 36-month median follow-up, the OS18 was 69% [95% confidence interval (CI) 60% to 80%]; the median disease-free survival and overall survival were 14.1 months (95% CI 11.0–20.1 months) and 25.4 months (95% CI 23.4–34.1 months), respectively. Conclusions: Notwithstanding promising multi-institutional efficacy results, further development of this regimen will require additional modifications to mitigate toxic effects. PMID:20670978

  13. Correlation of UGT1A1 and ERCC1 gene polymorphisms with the outcome of combined irinotecan plus cisplatin treatment in recurrent ovarian cancer.

    PubMed

    Xu, Q; Ding, Y Y; Song, L X; Xu, J F

    2015-01-01

    The aim of this study was to define the genotypes of UGT1A1 and ERCC1 and to examine their relationship with the efficacy and toxicity of a combination therapy of irinotecan and cisplatin in patients with advanced ovarian cancer. The allelic frequencies of the UGT1A1 and ERCC1 variants in a group of 89 patients with advanced ovarian cancer were determined. The relationship between the adverse events of irinotecan-based chemotherapy and the efficacy of cisplatin in patients with advanced ovarian cancer were analyzed. For patients who carried the UGT1A1*28 wild-type (WW) or the UGT1A1*28 heterozygous and homozygous mutant (WM+MM) genotypes, the incidences of grade 2 or 3 tardive diarrhea were 52.2 and 72.7% respectively, and the difference was statistically significant (P = 0.031, OR = 2.1, 95%CI = 1.6-9.2). For grade 3 or 4 tardive diarrhea, the incidence rates were 7.5 and 36.4% respectively; this difference was also statistically significant (P = 0.000, OR = 4.9, 95%CI = 3.3-15.8). The response rates of ERCC1 WW and ERCC1 WM+MM carriers were 30.3 and 20.2% respectively; this difference was significant (P = 0.032, OR = 3.2, 95%CI = 1.4-9.1). Together, the results from this study suggest that UGT1A1 is a target gene for tardive diarrhea, and that the UGT1A1*28 gene mutation might increase the risk of diarrhea with irinotecan-based chemotherapy. Furthermore, the results suggest that ERCC1 WW carriers might obtain a better rate of clinical response from a combined irinotecan and cisplatin regimen than ERCC1 WM+MM carriers. PMID:26125934

  14. Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration.

    PubMed

    Kenward, Hannah; Pelligand, Ludovic; Elliott, Jonathan

    2014-08-01

    Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies.

  15. Upregulation of miR-21 in Cisplatin Resistant Ovarian Cancer via JNK-1/c-Jun Pathway

    PubMed Central

    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. PMID:24865582

  16. Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without detriment to quality of life

    PubMed Central

    Spiro, S; Rudd, R; Souhami, R; Brown, J; Fairlamb, D; Gower, N; Maslove, L; Milroy, R; Napp, V; Parmar, M; Peake, M; Stephens, R; Thorpe, H; Waller, D; West, P

    2004-01-01

    Background: In 1995 a meta-analysis of randomised trials investigating the value of adding chemotherapy to primary treatment for non-small cell lung cancer (NSCLC) suggested a small survival benefit for cisplatin-based chemotherapy in each of the primary treatment settings. However, the meta-analysis included many small trials and trials with differing eligibility criteria and chemotherapy regimens. Methods: The aim of the Big Lung Trial was to confirm the survival benefits seen in the meta-analysis and to assess quality of life and cost in the supportive care setting. A total of 725 patients were randomised to receive supportive care alone (n = 361) or supportive care plus cisplatin-based chemotherapy (n = 364). Results: 65% of patients allocated chemotherapy (C) received all three cycles of treatment and a further 27% received one or two cycles. 74% of patients allocated no chemotherapy (NoC) received thoracic radiotherapy compared with 47% of the C group. Patients allocated C had a significantly better survival than those allocated NoC: HR 0.77 (95% CI 0.66 to 0.89, p = 0.0006), median survival 8.0 months for the C group v 5.7 months for the NoC group, a difference of 9 weeks. There were 19 (5%) treatment related deaths in the C group. There was no evidence that any subgroup benefited more or less from chemotherapy. No significant differences were observed between the two groups in terms of the pre-defined primary and secondary quality of life end points, although large negative effects of chemotherapy were ruled out. The regimens used proved to be cost effective, the extra cost of chemotherapy being offset by longer survival. Conclusions: The survival benefit seen in this trial was entirely consistent with the NSCLC meta-analysis and subsequent similarly designed large trials. The information on quality of life and cost should enable patients and their clinicians to make more informed treatment choices. PMID:15454647

  17. 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.

  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. PMID:26003673

  19. 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.

  20. Neoadjuvant chemotherapy improves survival of patients with upper tract urothelial carcinoma

    PubMed Central

    Porten, Sima; Siefker-Radtke, Arlene O.; Xiao, Lianchun; Margulis, Vitaly; Kamat, Ashish M.; Wood, Christopher G.; Jonasch, Eric; Dinney, Colin P. N.; Matin, Surena F.

    2015-01-01

    Background High-grade upper tract urothelial carcinoma (UTUC) is frequently upstaged after surgery and is associated with uniformly poor survival. Neoadjuvant chemotherapy may offer a way to improve clinical outcomes. We compare the survival rates of UTUC patients who received neoadjuvant chemotherapy prior to surgery with patients who did not. Methods Retrospective review of patients with high-risk UTUC who received neoadjuvant chemotherapy followed by surgery in 2004–2008 (study group), compared to a matched cohort who underwent initial surgery in 1993–2003 (control group). The Fisher exact, Wilcoxon rank-sum, and Kaplan-Meier methods were used. The log-rank test and Cox proportional hazards model were used to evaluate association of these two outcomes with patient, treatment, and tumor characteristics in univariate and multivariate models. Results Of 112 patients, 31 were in the study group and 81 in the control group. Patients who received neoadjuvant chemotherapy had improved OS and DSS with a 5-year DSS of 90.1% and 5-year OS rate 80.2%, versus a 5-year DSS and OS of 57.6% for those treated with initial surgery (p = 0.0204 and p = 0.0015, respectively). In multivariate analyses the neoadjuvant group had a lower risk of mortality (OS hazard ratio 0.42 [p = 0.035]; DSS hazard ratio 0.19 [p = 0.006]). Conclusions Neoadjuvant chemotherapy improves survival in patients with UTUC compared with a matched historical cohort of patients treated with initial surgery. Patients with high-risk UTUC should be considered for neoadjuvant chemotherapy, in view of the limited opportunity to administer effective cisplatin-based chemotherapy after nephroureterectomy. PMID:24633966

  1. 5-Aminolevulinic Acid Protects against Cisplatin-Induced Nephrotoxicity without Compromising the Anticancer Efficiency of Cisplatin in Rats In Vitro and In Vivo

    PubMed Central

    Matsumoto, Tatsuki; Ishihara, Masayuki; Hamada, Kazu; Shimamura, Yoshiko; Ogata, Koji; Inoue, Kosuke; Taniguchi, Yoshinori; Horino, Taro; Karashima, Takashi; Tamura, Kenji; Fukuhara, Hideo; Fujimoto, Shimpei; Tsuda, Masayuki; Shuin, Taro

    2013-01-01

    Background/Aims Nephrotoxicity is a frequent and major limitation in cisplatin (CDDP)-based chemotherapy. 5-Aminolevulinic acid (ALA) is widely distributed in animal cells, and it is a precursor of tetrapyrole compounds such as heme that is fundamentally important in aerobic energy metabolism. The aim of this study is to evaluate the protective role of ALA in CDDP-induced acute kidney injury (AKI). Method We used CDDP-induced AKI rat model and cultured renal tubular cells (NRK-52E). We divided four groups of rats: control, CDDP only, CDDP + ALA(post);(ALA 10 mg/kg + Fe in drinking water) after CDDP, CDDP + ALA(pre & post). Result CDDP increased Cr up to 6.5 mg/dl, BUN up to 230 mg/dl, and ALA significantly reduced these changes. ALA ameliorates CDDP-induced morphological renal damages, and reduced tubular apoptosis evaluated by TUNEL staining and cleaved caspase 3. Protein and mRNA levels of ATP5α, complex(COX) IV, UCP2, PGC-1α in renal tissue were significantly decreased by CDDP, and ALA ameliorates reduction of these enzymes. In contrast, Heme Oxigenase (HO)-1 level is induced by CDDP treatment, and ALA treatment further up-regulates HO-1 levels. In NRK-52E cells, the CDDP-induced reduction of protein and mRNA levels of mitochondrial enzymes was significantly recovered by ALA + Fe. CDDP-induced apoptosis were ameliorated by ALA + Fe treatment. Furthermore, we evaluated the size of transplantated bladder carcinoma to the rat skin, and ALA did not change the anti cancer effects of CDDP. Conclusion These data suggested that the protective role of ALA in cisplatin-induced AKI is via protection of mitochondrial viability and prevents tubular apoptosis. Also there are no significant effects of ALA on anticancer efficiency of CDDP in rats. Thus, ALA has the potential to prevent CDDP nephrotoxicity without compromising its anticancer efficacy. PMID:24324635

  2. Genetic Variations in ABCG2 Gene Predict Breast Carcinoma Susceptibility and Clinical Outcomes after Treatment with Anthracycline-Based Chemotherapy

    PubMed Central

    Wu, Huizhe; Liu, Yong; Kang, Hui; Xiao, Qinghuan; Yao, Weifan; Zhao, Haishan; Wang, Enhua; Wei, Minjie

    2015-01-01

    The genetic variants of the ATP-binding cassette, subfamily G, member 2 (ABCG2) are known to be involved in developing cancer risk and interindividual differences in chemotherapeutic response. The polymorphisms in ABCG2 gene were genotyped by using PCR-RFLP assays. We found that ABCG2 G34A GA/AA genotype, C421A AA genotype, and haplotypes 34A-421C and 34G-421A were significantly associated with increased risk for developing breast carcinoma. Furthermore, ABCG2 C421A AA homozygote had a significant enhanced therapeutic response in patients with neoadjuvant anthracycline-based chemotherapy. Moreover, ABCG2 G34A AA genotype carriers displayed a longer OS in ER positive patients or PR positive patients after postoperative anthracycline-based chemotherapy. These results suggested that the ABCG2 polymorphisms might be a candidate pharmacogenomic factor to assess susceptibility and prognosis for breast carcinoma patients. PMID:26634205

  3. Pemetrexed Maintenance Therapy Following Bevacizumab-Containing First-Line Chemotherapy in Advanced Malignant Pleural Mesothelioma

    PubMed Central

    Jing, Xu-Quan; Zhou, Lei; Sun, Xin-Dong; Yu, Jin-Ming; Meng, Xue

    2016-01-01

    Abstract Malignant pleural mesothelioma (MPM) is a lethal disease with poor prognosis. The combination of cisplatin and pemetrexed has been confirmed as the standard of care for nonoperable MPM. Data have shown that the adoption of pemetrexed maintenance therapy (PMT) following first-line treatment appears extremely promising. We describe a 57-year-old man diagnosed as advanced MPM. We treated this patient with PMT after first-line cisplatin-based bevacizumab-containing chemotherapy and residual tumor disappeared after 6 course of PMT. A perfect response and a long progression-free survival (PFS) were reached with tumor mass disappearing and 14 months duration of PFS. This case suggests that adding bevacizumab to standard first-line chemotherapy is feasible and that PMT could be promising and useful for treating advanced MPM. We further entail a review of the literature on the first-line treatment, continuation maintenance therapy, switch maintenance therapy, and second-line treatment of patients with advanced MPM. PMID:27057918

  4. 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

  5. Cisplatin enhances NK cells immunotherapy efficacy to suppress HCC progression via altering the androgen receptor (AR)-ULBP2 signals.

    PubMed

    Shi, Liang; Lin, Hui; Li, Gonghui; Sun, Yin; Shen, Jiliang; Xu, Junjie; Lin, Changyi; Yeh, Shuyuan; Cai, Xiujun; Chang, Chawnshang

    2016-04-01

    The aim of this study is to investigate the influence of cisplatin on the efficacy of natural killer (NK) cells immunotherapy to suppress HCC progression, and provide valuable information on better application of cisplatin in clinical settings. By using in vitro cell cytotoxicity test and in vivo liver orthotopic xenograft mice model, we identified the role of cisplatin in modulating NK cells cytotoxicity. Luciferase report assay and chromatin immunoprecipitation assay were applied for mechanism dissection. Immunohistochemistry is performed for sample staining. We found cisplatin could enhance the efficacy of NK cells immunotherapy to better suppress HCC progression via altering the androgen receptor (AR)-UL16-binding protein 2 (ULBP2) signals both in vitro and in vivo. Mechanism dissection revealed that cisplatin could suppress AR expression via two distinct ways: increasing miR-34a-5p to suppress AR expression and altering the ubiquitination to accelerate the AR protein degradation. The suppressed AR might then function through up-regulating ULBP2, a natural-killer group 2 member D ligand, to enhance the cytotoxicity of NK cells. Together, these results indicated an unrecognized favoring effect of cisplatin in HCC treatment. By suppressing AR in HCC, cisplatin could up-regulate cytotoxicity of NK cells to better target HCC. This finding may provide a potential new approach to control HCC by combining traditional chemotherapy with immunotherapy. PMID:26805759

  6. Fisetin, a dietary bioflavonoid, reverses acquired Cisplatin-resistance of lung adenocarcinoma cells through MAPK/Survivin/Caspase pathway

    PubMed Central

    Zhuo, Wenlei; Zhang, Liang; Zhu, Yi; Zhu, Bo; Chen, Zhengtang

    2015-01-01

    Cisplatin has been a key chemotherapy drug for treatment of non-small cell lung cancer (NSCLC) for decades. However, the efficacy of Cisplatin is usually reduced by the occurrence of drug-resistance of cancer cells. Fisetin is a flavonol naturally found in many fruits and vegetables, which has been reported to suppress cell proliferation and induce apoptosis in various cancers. In this study, we aimed to investigate whether Fisetin was capable of enhancing cytotoxicity of Cisplatin in Cisplatin-resistant NSCLC cells, and explore the possible signaling pathways involved. Cisplatin-resistant NSCLC cells, A549-CR, was established by repeated subculturing of A549 cells with increasing Cisplatin. Proliferation ability was assessed by MTT analysis and apoptosis was detected by flow cytometry. The results showed that Fisetin effectively increased sensitivity of A549-CR cells to Cisplatin, possibly mediated by inhibiting aberrant activation of MAPK signaling pathways. This increases the possibility of Fisetin as a promising agent for lung cancer therapy. PMID:26692948

  7. Cisplatin enhances NK cells immunotherapy efficacy to suppress HCC progression via altering the androgen receptor (AR)-ULBP2 signals.

    PubMed

    Shi, Liang; Lin, Hui; Li, Gonghui; Sun, Yin; Shen, Jiliang; Xu, Junjie; Lin, Changyi; Yeh, Shuyuan; Cai, Xiujun; Chang, Chawnshang

    2016-04-01

    The aim of this study is to investigate the influence of cisplatin on the efficacy of natural killer (NK) cells immunotherapy to suppress HCC progression, and provide valuable information on better application of cisplatin in clinical settings. By using in vitro cell cytotoxicity test and in vivo liver orthotopic xenograft mice model, we identified the role of cisplatin in modulating NK cells cytotoxicity. Luciferase report assay and chromatin immunoprecipitation assay were applied for mechanism dissection. Immunohistochemistry is performed for sample staining. We found cisplatin could enhance the efficacy of NK cells immunotherapy to better suppress HCC progression via altering the androgen receptor (AR)-UL16-binding protein 2 (ULBP2) signals both in vitro and in vivo. Mechanism dissection revealed that cisplatin could suppress AR expression via two distinct ways: increasing miR-34a-5p to suppress AR expression and altering the ubiquitination to accelerate the AR protein degradation. The suppressed AR might then function through up-regulating ULBP2, a natural-killer group 2 member D ligand, to enhance the cytotoxicity of NK cells. Together, these results indicated an unrecognized favoring effect of cisplatin in HCC treatment. By suppressing AR in HCC, cisplatin could up-regulate cytotoxicity of NK cells to better target HCC. This finding may provide a potential new approach to control HCC by combining traditional chemotherapy with immunotherapy.

  8. 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.

  9. Anticancer chemotherapy

    SciTech Connect

    Weller, R.E.

    1988-10-01

    Despite troubled beginnings, anticancer chemotherapy has made significant contribution to the control of cancer in man, particularly within the last two decades. Early conceptual observations awakened the scientific community to the potentials of cancer chemotherapy. There are now more than 50 agents that are active in causing regression of clinical cancer. Chemotherapy's major conceptual contributions are two-fold. First, there is now proof that patients with overt metastatic disease can be cured, and second, to provide a strategy for control of occult metastases. In man, chemotherapy has resulted in normal life expectancy for some patients who have several types of metastatic cancers, including choriocarcinoma, Burkitt's lymphomas, Wilm's tumor, acute lymphocytic leukemia, Hodgkins disease, diffuse histiocytic lymphoma and others. Anticancer chemotherapy in Veterinary medicine has evolved from the use of single agents, which produce only limited remissions, to the concept of combination chemotherapy. Three basic principles underline the design of combination chemotherapy protocols; the fraction of tumor cell killed by one drug is independent of the fraction killed by another drug; drugs with different mechanisms of action should be chosen so that the antitumor effects will be additive; and since different classes of drugs have different toxicities the toxic effects will not be additive.

  10. 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

  11. 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

  12. Magnetic nanoparticle-based therapeutic agents for thermo-chemotherapy treatment of cancer.

    PubMed

    Hervault, Aziliz; Thanh, Nguyen Th Kim

    2014-10-21

    Magnetic nanoparticles have been widely investigated for their great potential as mediators of heat for localised hyperthermia therapy. Nanocarriers have also attracted increasing attention due to the possibility of delivering drugs at specific locations, therefore limiting systematic effects. The enhancement of the anti-cancer effect of chemotherapy with application of concurrent hyperthermia was noticed more than thirty years ago. However, combining magnetic nanoparticles with molecules of drugs in the same nanoformulation has only recently emerged as a promising tool for the application of hyperthermia with combined chemotherapy in the treatment of cancer. The main feature of this review is to present the recent advances in the development of multifunctional therapeutic nanosystems incorporating both magnetic nanoparticles and drugs, and their superior efficacy in treating cancer compared to either hyperthermia or chemotherapy as standalone therapies. The principle of magnetic fluid hyperthermia is also presented. PMID:25212238

  13. Chemotherapy and Your Mouth

    MedlinePlus

    ... Health > Chemotherapy and Your Mouth Chemotherapy and Your Mouth Main Content Are You Being Treated With Chemotherapy ... Back to Top How Does Chemotherapy Affect the Mouth? Chemotherapy is the use of drugs to treat ...

  14. Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression.

    PubMed

    Li, Dan; Williams, Jon I; Pietras, Richard J

    2002-04-25

    Angiogenesis is important for growth and progression of ovarian cancers. Squalamine is a natural antiangiogenic sterol, and its potential role in treatment of ovarian cancers with or without standard cisplatin chemotherapy was assessed. Since HER-2 gene overexpression is associated with cisplatin resistance in vitro and promotion of tumor angiogenesis in vivo, the response of ovarian cancer cells with or without HER-2 gene overexpression to squalamine and cisplatin was evaluated both in tumor xenograft models and in tissue culture. Ovarian cancer cells with or without HER-2 overexpression were grown as subcutaneous xenografts in nude mice. Animals were treated by intraperitoneal injection with control vehicle, cisplatin, squalamine or cisplatin combined with squalamine. At the end of the experiment, tumors were assessed for tumor growth inhibition and for changes in microvessel density and apoptosis. Additional in vitro studies evaluated effects of squalamine on tumor and endothelial cell growth and on signaling pathways in human endothelial cells. Profound growth inhibition was elicited by squalamine alone and by combined treatment with squalamine and cisplatin for both parental and HER-2-overexpressing ovarian tumor xenografts. Immunohistochemical evaluation of tumors revealed decreased microvessel density and increased apoptosis. Although HER-2-overexpressing tumors had more angiogenic and less apoptotic activity than parental cancers, growth of both tumor types was similarly suppressed by treatment with squalamine combined with cisplatin. In in vitro studies, we found that squalamine does not directly affect proliferation of ovarian cells. However, squalamine significantly blocked VEGF-induced activation of MAP kinase and cell proliferation in human vascular endothelial cells. The results suggest that squalamine is anti-angiogenic for ovarian cancer xenografts and appears to enhance cytotoxic effects of cisplatin chemotherapy independent of HER-2 tumor status

  15. Say No to DMSO: Dimethylsulfoxide Inactivates Cisplatin, Carboplatin and Other Platinum Complexes

    PubMed Central

    Hall, Matthew D.; Telma, Katherine A.; Chang, Ki-Eun; Lee, Tobie D.; Madigan, James P.; Lloyd, John R.; Goldlust, Ian S.; Hoeschele, James D.; Gottesman, Michael M.

    2014-01-01

    The platinum drugs cisplatin, carboplatin and oxaliplatin are highly utilized in the clinic and as a consequence are extensively studied in the laboratory setting. In this study, we examined the literature and found a significant number of studies (11 - 34%) in prominent cancer journals utilizing cisplatin dissolved in dimethylsulfoxide (DMSO). However, dissolving cisplatin in DMSO for laboratory-based studies results in ligand displacement and changes the structure of the complex. We examined the effect of DMSO on platinum complexes, including cisplatin, carboplatin and oxaliplatin, finding that DMSO reacted with the complexes, inhibited their cytotoxicity and their ability to initiate cell death. These results render a substantial portion of the literature on cisplatin uninterpretable. Raising awareness of this significant issue in the cancer biology community is critical, and we make recommendations on appropriate solvation of platinum drugs for research. PMID:24812268

  16. Prevention and Restoration of Hearing Loss Associated with the Use of Cisplatin

    PubMed Central

    Chirtes, Felician; Albu, Silviu

    2014-01-01

    Background. Cisplatin is a well known platinum-based chemotherapeutic agent used for the treatment of various malignant tumours. A frequent side effect of cisplatin therapy is ototoxicity. Unfortunately, currently there are no available treatments. Material and Methods. Experimental, clinical studies and reviews published between 2004 and 2014 in the English medical literature concerning ototoxicity were selected using Medline, PubMed, and Google Scholar databases. Inclusion criteria were cisplatin-induced ototoxicity and therapy aimed at preventing or curing this disorder. Molecular mechanisms and clinical, audiological, and histological markers of cisplatin-induced ototoxicity are described. Moreover, experimental and clinical strategies for prevention or treatment of hearing loss were also reviewed. Results and Discussion. Experimental studies demonstrate a wide range of otoprotective molecules and strategies efficient against cisplatin-induced hearing loss. However, only dexamethasone proved a slight otoprotective effect in a clinical study. Conclusion. Further research must be completed to bring future therapeutic options into clinical setting. PMID:25140325

  17. Documentation of chemotherapy infusion preparation costs in academic- and community-based oncology practices.

    PubMed

    Brixner, Diana I; Oderda, Gary M; Nickman, Nancy A; Beveridge, Roy; Jorgenson, James A

    2006-03-01

    Significant changes in Medicare reimbursement for outpatient oncology services were proposed as part of the Medicare Modernization Act of 2003. The purpose of this study was to identify the "true cost" associated with drug-related handling for the preparation and delivery of chemotherapy doses to estimate the impact of changing reimbursement schema by Medicare. Two academic medical outpatient infusion centers and 2 community cancer centers provided data used to estimate all costs (excluding drug cost) associated with the preparation of chemotherapy doses. The data included both fixed costs (drug storage, space, equipment, and information resources) and variable costs (insurance management, inventory, waste management, pharmacy staff payroll, supplies, and shipping). The average cost for the preparation of chemotherapy doses across all sites was dollar 34.27 (range, dollar 32.08-dollar 41.23). A time-and-motion study was also performed to determine what tasks were conducted by pharmacy staff and how much time was spent in the preparation of the top 15 chemotherapeutic drugs and regimens used in the 4 sites. Data from the 4 centers was projected to show that if 3,990,495 million chemotherapy infusions were administered to a national Medicare population in 2003, when multiplied by the average cost of preparation for infusions determined by the current study (dollar 34.27), the estimated total annual cost to Medicare for chemotherapy preparation by pharmacists is dollar 136,754,263.65. The pharmacists spent most of their days (90% or more) performing tasks directly related to the preparation of these agents. These data provide scientific support for the consideration of appropriate reimbursement for chemotherapy services provided by pharmacists to Medicare beneficiaries. PMID:16507268

  18. Putting evidence into practice: evidence-based interventions for chemotherapy-induced peripheral neuropathy.

    PubMed

    Visovsky, Constance; Collins, Mary; Abbott, Linda; Aschenbrenner, Julie; Hart, Connie

    2007-12-01

    Chemotherapy-induced peripheral neuropathy (CIPN) continues to be a significant, debilitating symptom resulting from the administration of neurotoxic chemotherapy for the treatment of cancer. CIPN is an important consequence of cancer treatment because of its potential impact on physical functioning and quality of life. Oncology nurses play an important role in assessing, monitoring, and educating clients about CIPN. Despite investigations concerning pharmacologic and nonpharmacologic approaches to either preventing or minimizing the neurotoxicity resulting from certain chemotherapeutic agents, evidence to support the interventions is lacking. This article presents information concerning CIPN and summarizes the evidence for pharmacologic and nonpharmacologic approaches to the prevention and treatment of CIPN. PMID:18063548

  19. Conjugation of Cisplatin Analogues and Cyclooxygenase Inhibitors to Overcome Cisplatin Resistance

    PubMed Central

    Neumann, Wilma; Crews, Brenda C.; Sárosi, Menyhárt B.; Daniel, Cristina M.; Ghebreselasie, Kebreab; Scholz, Matthias S.; Marnett, Lawrence J.

    2015-01-01

    Cyclooxygenase (COX) is an enzyme involved in tumorigenesis and is associated with tumor cell resistance against platinum-based antitumor drugs. Cisplatin analogues were conjugated with COX inhibitors (indomethacin, ibuprofen) to study the synergistic effects that were previously observed in combination treatments. The conjugates ensure concerted transport of both drugs into cells, and subsequent intracellular cleavage enables a dual-action mode. Whereas the platinum(II) complexes showed cytotoxicities similar to those of cisplatin, the platinum(IV) conjugates revealed highly increased cytotoxic activities and were able to completely overcome cisplatin-related resistance. Although some of the complexes are potent COX inhibitors, the conjugates appear to execute their cytotoxic action via COX-independent mechanisms. Instead, the increased lipophilicity and kinetic inertness of the conjugates seem to facilitate cellular accumulation of the platinum drugs and thus improve the efficacy of the antitumor agents. These conjugates are important tools for the elucidation of the direct influence of COX inhibitors on platinum-based anticancer drugs in tumor cells. PMID:25318459

  20. Targeting human 8-oxoguanine DNA glycosylase (hOGG1) to mitochondria enhances cisplatin cytotoxicity in hepatoma cells.

    PubMed

    Zhang, Haihong; Mizumachi, Takatsugu; Carcel-Trullols, Jaime; Li, Liwen; Naito, Akihiro; Spencer, Horace J; Spring, Paul M; Smoller, Bruce R; Watson, Amanda J; Margison, Geoffrey P; Higuchi, Masahiro; Fan, Chun-Yang

    2007-08-01

    Many chemoradiation therapies cause DNA damage through oxidative stress. An important cellular mechanism that protects cells against oxidative stress involves DNA repair. One of the primary DNA repair mechanisms for oxidative DNA damage is base excision repair (BER). BER involves the tightly coordinated function of four enzymes (glycosylase, apurinic/apyrimidinic endonuclease, polymerase and ligase), in which 8-oxoguanine DNA glycosylase 1 initiates the cycle. An imbalance in the production of any one of these enzymes may result in the generation of more DNA damage and increased cell killing. In this study, we targeted mitochondrial DNA to enhance cancer chemotherapy by over-expressing a human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene in the mitochondria of human hepatoma cells. Increased hOGG1 transgene expression was achieved at RNA, protein and enzyme activity levels. In parallel, we observed enhanced mitochondrial DNA damage, increased mitochondrial respiration rate, increased membrane potential and elevated free radical production. A greater proportion of the hOGG1-over-expressing hepatoma cells experienced apoptosis. Following exposure to a commonly used chemotherapeutic agent, cisplatin, cancer cells over-expressing hOGG1 displayed much shortened long-term survival when compared with control cells. Our results suggest that over-expression of hOGG1 in mitochondria may promote mitochondrial DNA damage by creating an imbalance in the BER pathway and sensitize cancer cells to cisplatin. These findings support further evaluation of hOGG1 over-expression strategies for cancer therapy.

  1. Mitomycin-based hepatic arterial infusion chemotherapy for solitary ampullary cancer liver metastasis: an unusual treatment for an uncommon disease.

    PubMed

    Vitale, Felice V; Romeo, Placido; Luciani, Bruno; Raffaele, Mario; Colina, Paolo; Ferraù, Francesco

    2015-10-01

    Ampullary carcinoma is an uncommon gastrointestinal disease. Its natural history is often characterized by the occurrence of liver metastases. Among patients who undergo pancreatoduodenectomy, those presenting with lymph nodes involvement are more prone to early distant disease relapse. In this report, a patient previously diagnosed with ampullary carcinoma had been treated with curative surgery. After subsequent adjuvant gemcitabine, the patient developed significant myelotoxicity and suffered from a single liver metastasis a few months later. A hepatic intra-arterial mitomycin plus fluorouracil-based chemotherapy was administered in order to avoid any serious systemic toxicity. The treatment was well tolerated and no serious side effects occurred. Extra-hepatic cancer relapse, involving intra-thoracic and abdominal lymph nodes, was observed not long after the initial intra-hepatic almost complete response. In conclusion, the locoregional chemotherapy administration was effective in overcoming any systemic toxicities and showed activity against the liver metastasis but it did not prevent extra-hepatic cancer dissemination.

  2. Cisplatin stimulates protein tyrosine phosphorylation in macrophages.

    PubMed

    Kumar, R; Shrivastava, A; Sodhi, A

    1995-03-01

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

  3. The expression of ERCC1 and BRCA1 predicts prognosis of platinum-based chemotherapy in urothelial cancer

    PubMed Central

    Song, Wenhui; Ma, Hongshun

    2016-01-01

    Objective To investigate the expression and clinical significance of ERCC1 and BRCA1 genes in urothelial cancer patients. Methods Forty-two urothelial cancer patients who did not receive platinum-based chemotherapy during January 2009 to May 2013 were enrolled. The expression levels of ERCC1 and BRCA1 were determined by immunohistochemistry and the median survival time (MST) for these patients was calculated. Results ERCC1-positive patients who received oxaliplatin-based chemotherapy had a shorter MST than ERCC1-negative patients (P<0.05), whereas there is no difference of MST between BRCA1-positive and -negative patients. Furthermore, MST in ERCC1 and BRCA1 double-positive patients was shorter than ERCC1 and BRCA1 double-negative patients (P<0.05). The positive expression of ERCC1 had a significant positive correlation with BRCA1 (r=0.313, P=0.044). Conclusion The expression level of ERCC1 may be used as a prognostic marker for urothelial cancer patients who received postoperative adjuvant chemotherapy. PMID:27366083

  4. Epirubicin-based compared with docetaxel-based chemotherapy for advanced gastric carcinoma: A systematic review and meta-analysis.

    PubMed

    Petrioli, Roberto; Roviello, Giandomenico; Zanotti, Laura; Roviello, Franco; Polom, Karol; Bottini, Alberto; Marano, Luigi; Francini, Edoardo; Marrelli, Daniele; Generali, Daniele

    2016-06-01

    Docetaxel or Epirubicin-based regimens are both approved for the treatment of metastatic gastric cancer. We perform a systemic review with metanalysis to evaluate the efficacy and toxicities of docetaxel-based chemotherapy compared with epirubicin-containing regimens. A metaanalysis of randomized studies in accordance with the preference guidelines for reported items in systematic reviews and meta-analyses is performed in which the databases of PubMed, the Cochrane Library, and the ASCO University Meeting were searched for relevant publications. The primary outcome was efficacy, the secondary toxicities. A total of 553 cases were included in the meta-analysis; 278 received epirubicin-based treatment and 313 received docetaxel. The pooled risk ratio to achieve an objective response and a disease control rate were 1.08 (95% CI 0.85-1.37; P=0.52) and 0.90 (95% CI 0.75-1.08; P=0.27) respectively. EPI arm showed a decrease in the risk of neutropenia, anemia, fatigue, asthenia and diarrhea, paraesthesia; docetaxel arm showed a decrease in the risk of leucopenia, thrombocytopenia, anorexia, nausea, nausea-vomiting, stomatitis and neutropenic fever. The results of our study suggest a similar activity of docetaxel and epirubicin-based chemotherapeutic regimens in metastatic gastric cancer. Other parameters as, comorbidity, concomitant diseases and prior therapies should be taken into account to address the clinician's choice in selecting the best therapeutical approach for any single patient. PMID:27083592

  5. Efficacy and safety of the oxaliplatin-based chemotherapy in the treatment of advanced primary hepatocellular carcinoma

    PubMed Central

    Liu, Lin; Zheng, Ying-hui; Han, Li; Qin, Shu-Kui

    2016-01-01

    Abstract Background: Many clinical studies have demonstrated the survival benefits of oxaliplatin-based chemotherapy for advanced hepatocellular carcinoma patients. Therefore, we aim to evaluate the efficacy and safety of oxaliplatin-based chemotherapy in patients with advanced hepatocellular carcinoma by conducting a meta-analysis of prospective studies. Methods: A comprehensive literature search was performed using the PubMed, Cochrane Library, EMBASE, and Web of Science databases from their inception to June 2016. Only prospective studies evaluating oxaliplatin-based chemotherapy in patients with advanced hepatocellular carcinoma were selected. The main outcomes included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and main adverse events. Results: Ten prospective studies involving 525 patients were included. The pooled ORR, 1-year PFS, and OS were 14.4% (95% confidence interval [CI] 9.2–19.6%), 9.3% (95%CI 10–28%), and 35.7% (95%CI 27–44%), respectively, for oxaliplatin-based chemotherapy. The median PFS and OS were 4.7 and 9.4 months, respectively. The incidences of grade 3/4 toxicities of neutropenia, thrombopenia, anemia, neurotoxicity, diarrhea, and nausea/vomiting were 17.2%, 9.2%, 6.0%, 4.8%, 3.1%, and 1.8%, respectively. Subgroup analysis revealed that the pooled ORR was 13.9% (95%CI 6.8–21%) in Asian patients and 12.8% (95%CI 6.8–18.7%) in Western patients. For Asian patients, the median PFS and OS were 4.2 and 9.2 months, and the 1-year PFS and OS were 12.5% and 30.5%, respectively. For Western patients, the median PFS and OS were 4.7 and 9.5 months, and the 1-year PFS and OS were 19.6% and 42.4%, respectively. There were no significant differences in the ORR, 1-year PFS, and OS (P > 0.05) between Asian and Western patients. Conclusions: Oxaliplatin-based chemotherapy appears to be effective and safe for the treatment of advanced hepatocellular carcinoma. PMID:27749557

  6. Ambient noise levels in the chemotherapy clinic

    PubMed Central

    Gladd, Dana K.; Saunders, Gabrielle H.

    2016-01-01

    Many of the drugs used for chemotherapy treatments are known to be ototoxic, and can result in permanent hearing threshold shifts. The degree of ototoxic damage can be influenced by many factors including dosage, duration of exposure, genetics, and coadministration with other ototoxic agents. Cisplatin is known for its ototoxic effects on hearing thresholds, particularly in the high frequencies. Recent studies have indicated a synergistic relationship between Cisplatin administration and moderate to high noise level exposure starting between 70–85 dB SPL. This study measured the noise levels in the Portland Veteran’s Affairs Medical Center’s outpatient chemotherapy clinic. Average (LAeq) and peak (LCpeak) noise measures were recorded every minute from 7 am until 6 pm on the two busiest clinic days. Patients, visitors, and staff members filled out anonymous surveys regarding their reactions to noise levels. Cumulative noise levels were not at levels known to interact with Cisplatin for a significant period of time. Noise measurement analysis indicated that levels were at or above 70 dB SPL for less than ten minutes during the 11-hour recording window. The patient and visitor surveys indicated that both groups were unbothered by noise in the clinic. However, most staff members were bothered by or concerned about noise levels, and many felt that it caused stress and difficulty communicating on the phone. PMID:22122961

  7. Psychoneuroimmunology-Based Stress Management during Adjuvant Chemotherapy for Early Breast Cancer.

    PubMed

    Robins, Jo Lynne W; McCain, Nancy L; Elswick, R K; Walter, Jeanne M; Gray, D Patricia; Tuck, Inez

    2013-01-01

    Objective. In a randomized trial of women with early stage breast cancer undergoing adjuvant chemotherapy, two stress management interventions, tai chi training and spiritual growth groups, were compared to a usual care control group, to evaluate psychosocial functioning, quality of life (QOL), and biological markers thought to reflect cancer- and treatment-specific mechanisms. Method. The sample consisted of 145 women aged 27-75 years; 75% were Caucasian and 25% African American. A total of 109 participants completed the study, yielding a 75% retention rate. Grounded in a psychoneuroimmunology framework, the overarching hypothesis was that both interventions would reduce perceived stress, enhance QOL and psychosocial functioning, normalize levels of stress-related neuroendocrine mediators, and attenuate immunosuppression. Results. While interesting patterns were seen across the sample and over time, the interventions had no appreciable effects when delivered during the period of chemotherapy. Conclusions. Findings highlight the complex nature of biobehavioral interventions in relation to treatment trajectories and potential outcomes. Psychosocial interventions like these may lack sufficient power to overcome the psychosocial or physiological stress experienced during the chemotherapy treatment period. It may be that interventions requiring less activity and/or group attendance would have enhanced therapeutic effects, and more active interventions need to be tested prior to and following recovery from chemotherapy.

  8. Solid Matrix Based Lipidic Nanoparticles in Oral Cancer Chemotherapy: Applications and Pharmacokinetics.

    PubMed

    Ahmad, Javed; Amin, Saima; Rahman, Mahfoozur; Rub, Rehan Abdur; Singhal, Madhur; Ahmad, Mohammad Zaki; Rahman, Ziyaur; Addo, Richard T; Ahmad, Farhan Jalees; Mushtaq, Gohar; Kamal, Mohammad Amjad; Akhter, Sohail

    2015-01-01

    Chemotherapeutic delivery by oral route in cancer patients has the potential to create "hospitalization free chemotherapy" which is a vision of oncologists, formulation scientists and patients. Such a therapeutic approach will improve patients' compliance, ease the burden of the patients' caregivers and significantly reduce the cost of treatment. In current clinical practice, chemotherapy carried out by intravenous injection or infusion leads to undesired side-effects such as plasma concentrations crossing the maximum safe concentration, rapid body clearance and lower bioavailability. Despite the presence of challenges such as poor aqueous solubility and stability of drugs and the presence of biological barriers like multidrug efflux transporter in the GI tract, oral cancer chemotherapy has the potential to surmount those obstacles. Lipid nanoparticles (LNPs) such as solid lipid nanoparticle, nanostructured lipid carriers, nano lipid-drug conjugates, mixed micelles, liposomes and nanoemulsions have shown some promising results for use in oral anticancer drug delivery through nanotechnological approach. LNPs demonstrate enhanced oral bioavailability owing to their ability to inhibit first pass metabolism via lymphatic absorption by chylomicron-linked and/or M-cell uptake. LNPs reduce the inter- and intrasubject pharmacokinetics variability of administrated drugs. Moreover, certain classes of phospholipids and surfactants used in the formulations of LNPs can suppress the P-glycoprotein efflux system. Here, we shall be discussing the biopharmaceutical challenges in oral cancer chemotherapy and how the LNPs may provide solutions to such challenges. The effect of GI tract environment on LNPs and pharmacokinetics shall also be discussed. PMID:26264206

  9. Prevention of chemotherapy-induced nausea and vomiting: focus on fosaprepitant

    PubMed Central

    Olver, Ian N

    2008-01-01

    Fosaprepitant is a prodrug of aprepitant, a neurokinin1 (NK1) receptor antagonist used in prophylactic antiemetic regimens used prior to cytotoxic chemotherapy. Fosaprepitant is being developed to provide a parenterally administered alternative to the orally administered aprepitant. Fosaprepitant is rapidly converted to aprepitant and an intravenous dose of 115 mg is bioequivalent to 125 mg orally, with similar plasma concentrations at 24 hours. In phase I and II trials fosaprepitant shows efficacy, but the large randomized efficacy studies have utilized aprepitant. When it is added to dexamethasone and a 5HT3 receptor antagonist on day 1 prior to chemotherapy aprepitant improves the control of acute post chemotherapy emesis and when continued on days 2 and 3 with dexamethasone it demonstrated even greater improvement in the control of delayed emesis. This has been shown with both cisplatin-containing regimens and those based upon cyclophosphamide and an anthracycline. Fosaprepitant is well tolerated with mild to moderate venous irritation being the only additional toxicity to those seen with oral aprepitant, and that is a function of dose, concentration, and infusion rate. Headaches are the other toxicity most commonly reported. Fosaprepitant can be used as a parenteral alternative to aprepitant in regimens to control chemotherapy-induced emesis. PMID:18728837

  10. Downregulation of SWI/SNF chromatin remodeling factor subunits modulates cisplatin cytotoxicity

    SciTech Connect

    Kothandapani, Anbarasi; Gopalakrishnan, Kathirvel; Kahali, Bhaskar; Reisman, David; Patrick, Steve M.

    2012-10-01

    Chromatin remodeling complex SWI/SNF plays important roles in many cellular processes including transcription, proliferation, differentiation and DNA repair. In this report, we investigated the role of SWI/SNF catalytic subunits Brg1 and Brm in the cellular response to cisplatin in lung cancer and head/neck cancer cells. Stable knockdown of Brg1 and Brm enhanced cellular sensitivity to cisplatin. Repair kinetics of cisplatin DNA adducts revealed that downregulation of Brg1 and Brm impeded the repair of both intrastrand adducts and interstrand crosslinks (ICLs). Cisplatin ICL-induced DNA double strand break repair was also decreased in Brg1 and Brm depleted cells. Altered checkpoint activation with enhanced apoptosis as well as impaired chromatin relaxation was observed in Brg1 and Brm deficient cells. Downregulation of Brg1 and Brm did not affect the recruitment of DNA damage recognition factor XPC to cisplatin DNA lesions, but affected ERCC1 recruitment, which is involved in the later stages of DNA repair. Based on these results, we propose that SWI/SNF chromatin remodeling complex modulates cisplatin cytotoxicity by facilitating efficient repair of the cisplatin DNA lesions. -- Highlights: Black-Right-Pointing-Pointer Stable knockdown of Brg1 and Brm enhances cellular sensitivity to cisplatin. Black-Right-Pointing-Pointer Downregulation of Brg1 and Brm impedes the repair of cisplatin intrastrand adducts and interstrand crosslinks. Black-Right-Pointing-Pointer Brg1 and Brm deficiency results in impaired chromatin relaxation, altered checkpoint activation as well as enhanced apoptosis. Black-Right-Pointing-Pointer Downregulation of Brg1 and Brm affects recruitment of ERCC1, but not XPC to cisplatin DNA lesions.

  11. Adult medulloblastoma: multiagent chemotherapy.

    PubMed Central

    Greenberg, H. S.; Chamberlain, M. C.; Glantz, M. J.; Wang, S.

    2001-01-01

    In this study, the records of 17 adult patients with medulloblastoma treated with craniospinal radiation and 1 of 2 multiagent chemotherapy protocols were reviewed for progression-free survival, overall survival, and toxicity, and the patients were compared with each other and with similarly treated children and adults. Records of patients treated at 3 institutions were reviewed. Seventeen medulloblastoma patients (11 female, 6 male) with a median age of 23 years (range, 18-47 years) were treated with surgery, craniospinal radiation (CSRT) plus local boost, and 1 of 2 adjuvant chemotherapy regimens. All tumors were infratentorial (10 in 4th ventricle and 7 in left or right hemisphere). Ten patients presented with hydrocephalus, and 7 of them were shunted. Eight patients had gross total resection, 7 had subtotal resection (>50% removed), and 2 had partial resection (<50% removed). Postoperatively, 3 patients had positive cytology and 3 had positive spinal MRI. Five patients were classified as good risk and 12 were classified as poor risk (Chang staging system). Ten patients were treated with the "Packer protocol," consisting of CSRT plus weekly vincristine followed by 8 cycles of cisplatin, lomustine, and vincristine. Seven patients were treated with the Pediatric Oncology Group (POG) protocol, consisting of alternating courses of cisplatin/etoposide and cyclophosphamide/vincristine, followed by CSRT. Eight of 17 patients relapsed, with all 8 relapsing at the primary site. Other relapse sites included the leptomeninges (5), bone (1), and brain (1). The estimated median relapse-free survival (Kaplan-Meier) for all patients was 48 months (95% confidence interval, >26 months to infinity). Median relapse-free survival for patients on the Packer protocol was 26 months, and for those on the POG regimen was 48 months (P = 0.410). Five of 10 on the Packer protocol were relapse-free, while 4 of 7 were relapse-free on the POG regimen. Two patients relapsed during chemotherapy

  12. FTIR Biospectroscopy Investigation on Cisplatin Cytotoxicity in Three Pairs of Sensitive and Resistant Cell Line.

    PubMed

    Farhadi, Ensieh; Kobarfard, Farzad; H Shirazi, Farshad

    2016-01-01

    Fourier Transformed Infrared Spectroscopy (FTIR) has extensively been used for biological applications. Cisplatin is one the most useful antineoplastic chemotherapy drugs for a variety of different human cancers. One of the clinical problems in its application, which would consequently affect the therapeutic outcome of its application, is the occurrence of resistance to this agent. In this project three different pairs of sensitive and resistant cell lines of human ovarian A2780 and its resistant pair of A2780-CP, human ovarian OV2008 and its resistant pair of C13, and finally human lung carcinoma of HTB56 and its resistant pair of HTB56-CP were grown in the laboratory under the standard procedure. Saline was exposed to control cells, whereas 1, 5 and 10 µg/mL of cisplatin was exposed to experimental cells, for 1 h. Cells were then collected and lyophilized from which spectra were taken. According to our results, we could not trigger a well-recognized cells biomolecular band at 1015 cm(-1), being modified after exposure to cisplatin in all cell lines. On the other hand, there was a clear dose-dependent increase in protein β-sheet structure related peaks shift in resistant cell lines after exposure to cisplatin. This would probably indicate an easier protein interaction site for cisplatin in the resistant cell lines, which would probably inhibit cisplatin from binding to DNA, as the cytotoxic target. As a conclusion, FTIR biospectroscopy has proven its potency to identify the interactions, as well as the false engagement cellular sites for cisplatin in sensitive and resistant cell lines. PMID:27610161

  13. FTIR Biospectroscopy Investigation on Cisplatin Cytotoxicity in Three Pairs of Sensitive and Resistant Cell Line

    PubMed Central

    Farhadi, Ensieh; Kobarfard, Farzad; H. Shirazi, Farshad

    2016-01-01

    Fourier Transformed Infrared Spectroscopy (FTIR) has extensively been used for biological applications. Cisplatin is one the most useful antineoplastic chemotherapy drugs for a variety of different human cancers. One of the clinical problems in its application, which would consequently affect the therapeutic outcome of its application, is the occurrence of resistance to this agent. In this project three different pairs of sensitive and resistant cell lines of human ovarian A2780 and its resistant pair of A2780-CP, human ovarian OV2008 and its resistant pair of C13, and finally human lung carcinoma of HTB56 and its resistant pair of HTB56-CP were grown in the laboratory under the standard procedure. Saline was exposed to control cells, whereas 1, 5 and 10 µg/mL of cisplatin was exposed to experimental cells, for 1 h. Cells were then collected and lyophilized from which spectra were taken. According to our results, we could not trigger a well-recognized cells biomolecular band at 1015 cm-1, being modified after exposure to cisplatin in all cell lines. On the other hand, there was a clear dose-dependent increase in protein β-sheet structure related peaks shift in resistant cell lines after exposure to cisplatin. This would probably indicate an easier protein interaction site for cisplatin in the resistant cell lines, which would probably inhibit cisplatin from binding to DNA, as the cytotoxic target. As a conclusion, FTIR biospectroscopy has proven its potency to identify the interactions, as well as the false engagement cellular sites for cisplatin in sensitive and resistant cell lines. PMID:27610161

  14. Cisplatin dose rate as a risk factor for nephrotoxicity in children.

    PubMed Central

    Skinner, R.; Pearson, A. D.; English, M. W.; Price, L.; Wyllie, R. A.; Coulthard, M. G.; Craft, A. W.

    1998-01-01

    The purpose of the study was to evaluate the incidence, risk factors and changes in severity with time of cisplatin nephrotoxicity in children. A total of 35 children underwent measurement of glomerular filtration rate (GFR) and tubular function after completion of cisplatin chemotherapy. No child received ifosfamide. A clinically relevant 'nephrotoxicity score' was derived from GFR and serum magnesium. Follow-up studies were performed in 16 children at 1 year and in 15 at 2 years after cisplatin. Considerable interpatient variability in nephrotoxicity was observed. Treatment was modified in three patients because of nephrotoxicity. GFR was low in 18 out of 31 patients. Proximal nephron toxicity caused hypomagnesaemia in ten patients and hypocalcaemia in five patients. Elevated urinary N-acetylglucosaminidase excretion was seen in 22 out of 30 children, indicating subclinical tubular toxicity. Nephrotoxicity was less severe in children who received cisplatin courses at a dose rate of 40 mg m(-2) day(-1) than in those who received higher dose rates (P < 0.005), but there was no correlation with total dose received. Follow-up studies revealed partial recovery of GFR (P < 0.05). Glomerular and proximal nephron toxicity are common in children treated with cisplatin, and more severe at higher dose rates. Despite partial recovery of GFR, the long-term outcome of nephrotoxicity remains unknown and careful monitoring of chronic toxicity is necessary. PMID:9635848

  15. Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy.

    PubMed

    Paraskar, Abhimanyu S; Soni, Shivani; Chin, Kenneth T; Chaudhuri, Padmaparna; Muto, Katherine W; Berkowitz, Julia; Handlogten, Michael W; Alves, Nathan J; Bilgicer, Basar; Dinulescu, Daniela M; Mashelkar, Raghunath A; Sengupta, Shiladitya

    2010-07-13

    Cisplatin is a first line chemotherapy for most types of cancer. However, its use is dose-limited due to severe nephrotoxicity. Here we report the rational engineering of a novel nanoplatinate inspired by the mechanisms underlying cisplatin bioactivation. We engineered a novel polymer, glucosamine-functionalized polyisobutylene-maleic acid, where platinum (Pt) can be complexed to the monomeric units using a monocarboxylato and an O --> Pt coordinate bond. We show that at a unique platinum to polymer ratio, this complex self-assembles into a nanoparticle, which releases cisplatin in a pH-dependent manner. The nanoparticles are rapidly internalized into the endolysosomal compartment of cancer cells, and exhibit an IC50 (4.25 +/- 0.16 microM) comparable to that of free cisplatin (3.87 +/- 0.37 microM), and superior to carboplatin (14.75 +/- 0.38 microM). The nanoparticles exhibited significantly improved antitumor efficacy in terms of tumor growth delay in breast and lung cancers and tumor regression in a K-ras(LSL/+)/Pten(fl/fl) ovarian cancer model. Furthermore, the nanoparticle treatment resulted in reduced systemic and nephrotoxicity, validated by decreased biodistribution of platinum to the kidney as quantified using inductively coupled plasma spectroscopy. Given the universal need for a better platinate, we anticipate this coupling of nanotechnology and structure-activity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer. PMID:20616005

  16. Overexpression of β-Catenin Induces Cisplatin Resistance in Oral Squamous Cell Carcinoma.

    PubMed

    Li, Long; Liu, Hai-Chao; Wang, Cheng; Liu, Xiqiang; Hu, Feng-Chun; Xie, Nan; Lü, Lanhai; Chen, Xiaohua; Huang, Hong-Zhang

    2016-01-01

    Abnormal expression of β-catenin contributes to tumor development, progression, and metastasis in various cancers. However, little is known about the relationship between abnormal expression of β-catenin and cisplatin chemotherapy in oral squamous cell carcinoma (OSCC). The present study aimed to investigate the effect of β-catenin on OSCC cisplatin resistance and evaluated the drug susceptibility of stable cell lines with β-catenin knockin and knockdown. In this study, we found that higher expression level of β-catenin can be observed in CDDP-treated cell lines as compared with the control group. Furthermore, the expression levels of β-catenin increased in both a concentration- and time-dependent manner with the cisplatin treatment. More importantly, the nuclear translocation of β-catenin could also be observed by confocal microscope analysis. Stable cell lines with CTNNB1 knockin and knockdown were established to further investigate the potential role and mechanism of β-catenin in the chemoresistance of OSCC in vitro and in vivo. Our findings indicated that overexpression of β-catenin promoted cisplatin resistance in OSCC in vitro and in vivo. We confirmed that GSK-3β, C-myc, Bcl-2, P-gp, and MRP-1 were involved in β-catenin-mediated drug resistance. Our findings indicate that the Wnt/β-catenin signaling pathway may play important roles in cisplatin resistance in OSCC. PMID:27529071

  17. Overexpression of β-Catenin Induces Cisplatin Resistance in Oral Squamous Cell Carcinoma

    PubMed Central

    Li, Long; Liu, Hai-Chao; Wang, Cheng; Liu, Xiqiang; Hu, Feng-Chun; Xie, Nan; Lü, Lanhai

    2016-01-01

    Abnormal expression of β-catenin contributes to tumor development, progression, and metastasis in various cancers. However, little is known about the relationship between abnormal expression of β-catenin and cisplatin chemotherapy in oral squamous cell carcinoma (OSCC). The present study aimed to investigate the effect of β-catenin on OSCC cisplatin resistance and evaluated the drug susceptibility of stable cell lines with β-catenin knockin and knockdown. In this study, we found that higher expression level of β-catenin can be observed in CDDP-treated cell lines as compared with the control group. Furthermore, the expression levels of β-catenin increased in both a concentration- and time-dependent manner with the cisplatin treatment. More importantly, the nuclear translocation of β-catenin could also be observed by confocal microscope analysis. Stable cell lines with CTNNB1 knockin and knockdown were established to further investigate the potential role and mechanism of β-catenin in the chemoresistance of OSCC in vitro and in vivo. Our findings indicated that overexpression of β-catenin promoted cisplatin resistance in OSCC in vitro and in vivo. We confirmed that GSK-3β, C-myc, Bcl-2, P-gp, and MRP-1 were involved in β-catenin-mediated drug resistance. Our findings indicate that the Wnt/β-catenin signaling pathway may play important roles in cisplatin resistance in OSCC. PMID:27529071

  18. Impact of age on efficacy of postoperative oxaliplatin-based chemotherapy in patients with rectal cancer after neoadjuvant chemoradiotherapy

    PubMed Central

    Song, Yong-xi; Sun, Jing-xu; Chen, Xiao-wan; Zhao, Jun-hua; Ma, Bin; Wang, Jun; Wang, Zhen-ning

    2016-01-01

    Background Clinical practice guidelines focusing on age-related adjuvant chemotherapy for rectal cancer are currently limited. The present study aimed to explore the impact of age on the efficacy of adjuvant oxaliplatin-based chemotherapy in patients with rectal cancer after neoadjuvant chemoradiotherapy. Methods We performed a retrospective cohort analysis using data from the Surveillance, Epidemiology, and End Results-Medicare-linked database from 1992–2009. We enrolled patients with yp stages I–III rectal cancer who received neoadjuvant chemoradiotherapy and underwent curative resection. The age-related survival benefit of adding oxaliplatin to adjuvant 5-fluorouracil (5-FU) chemotherapy was evaluated using Kaplan–Meier survival analysis with propensity score-matching and Cox proportional hazards models. Results Comparing the oxaliplatin group with the 5-FU group, there were significant interactions between age and chemotherapy efficacy in terms of overall survival (OS) (p for interaction = 0.017) among patients with positive lymph nodes (ypN+). Adding oxaliplatin to 5-FU could prolong survival in patients aged < 73 years and ypN+ category, and but did not translate into survival benefits in patients aged ≥ 73 years and ypN+ category. No significant interactions were observed among ypN− patients, and oxaliplatin did not significantly improve OS, regardless of age. Conclusions In patients with rectal cancer who have already received neoadjuvant chemoradiotherapy and undergone curative resection, adding oxaliplatin to 5-FU could prolong OS in patients aged < 73 years and ypN+ category. However, adding oxaliplatin did not translate into survival benefits in patients age ≥ 73 years and ypN+ category, or in ypN− patients. PMID:26910371

  19. Prognostic value of ERCC1 and ERCC2 gene polymorphisms in patients with gastric cancer receiving platinum-based chemotherapy

    PubMed Central

    Mo, Juanmei; Luo, Min; Cui, Jiandong; Zhou, Shaozhang

    2015-01-01

    We conducted a prospective study to analyze whether ERCC1 rs11615 and rs3212986 and ERCC2 rs13181 and rs1799793 gene polymorphisms could serve as potential biomarkers for the prognosis of gastric cancer. A total of 228 patients with pathologically proven gastric cancer and receiving platinum-based chemotherapy were recruited from our hospital between October 2009 and October 2011. The ERCC1 rs11615 and rs3212986 and ERCC2 rs13181 and rs1799793 polymorphisms were genotyped using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. Conditional logistic regression analysis revealed that patients carrying the CA and AA genotypes of ERCC1 rs3212986 polymorphism showed a poorer response to chemotherapy compared to the CC genotype (CA vs. CC: OR = 0.28, 95% CI = 0.06-0.98, P = 0.04; AA vs. CC: OR = 0.49, 95% CI = 0.06-0.98, P = 0.01). Moreover, the CA+AA genotype of ERCC1 rs3212986 polymorphism showed a significantly poorer response to chemotherapy (CA+AA vs. CC: OR = 0.49, 95% CI = 0.27-0.90). Patients with the AA genotype of ERCC1 rs3212986 polymorphism had a longer overall survival time when compared with the CC genotype (34.91 months vs. 51.19 months, log-rank P = 0.003). The AA genotype of ERCC1 rs3212986 polymorphism in gastric cancer patients was correlated with a higher risk of death from varying causes by the Cox proportional hazards model, compared to the CC genotype (HR = 6.19, 95% CI = 1.42-30.60). In conclusion, the ERCC1 rs3212986 polymorphism was found to influence the response to chemotherapy and overall survival of gastric cancer patients. PMID:26823845

  20. Therapy related myelodysplasia/myeloproliferative neoplasia-unclassified with acute leukemic transformation following Paclitaxel and Carboplatin based chemotherapy in an ovarian cancer patient.

    PubMed

    Vanajakshi, S; Prasad, S V S S; Amina, S S; Kavitha, E; Iravathy Goud, K; Kshitija, K

    2014-09-01

    Alkylating agents used in chemotherapy are mutagenic and have strong leukemogenic potential. The most serious long term complication of chemotherapy is the development of secondary disease, particularly hematological malignancy; they have rarely been reported in the context of ovarian cancer treatment. We describe quite a rare occurrence of a myelodyplastic/myeloproliferative neoplasm, unclassified (MDS/MPN-U) with acute leukemic transformation and multiple cytogenetic abnormalities not usually found together as JAK2 V617F mutation, 5q- and 7q-deletion, after exposure to paclitaxel and carboplatin based chemotherapy in a patient treated for ovarian cancer. We should be aware of such complication whose prognosis is really poor. PMID:25332593

  1. Phase II study of preoperative paclitaxel/cisplatin with radiotherapy in locally advanced esophageal cancer

    SciTech Connect

    Kim, Dong W.; Blanke, Charles D.; Wu, Huiyun; Shyr, Yu; Berlin, Jordan; Beauchamp, R. Daniel; Chakravarthy, Bapsi . E-mail: bapsi.chak@vanderbilt.edu

    2007-02-01

    Purpose: Preoperative paclitaxel-based chemoradiotherapy may improve the response rates and survival in patients with localized esophageal cancer. We evaluated paclitaxel-based induction chemoradiotherapy in patients with localized esophageal cancer to determine its feasibility, clinical response, pathologic response, and overall survival. Methods and Materials: Between 1995 and 1998, 50 patients were enrolled in this study. At study entry, patients were categorized as either resectable or unresectable according to evaluation by an experienced thoracic surgeon. All patients were treated with paclitaxel 175 mg/m{sup 2} and cisplatin 75 mg/m{sup 2} on Day 1, 29 with radiotherapy to 3,000 cGy in 15 fractions. Resectable patients underwent esophagectomy 4 weeks later. Postoperatively, patients received two cycles of paclitaxel 175 mg/m{sup 2} on Day 1 and 5-fluorouracil 350 mg/m{sup 2} and leucovorin 300 mg on Days 1-3, given every 28 days. Patients who were deemed unsuitable for resection from the outset continued radiotherapy to a total dose of 6,000 cGy. Results: Of the 50 patients, all began neoadjuvant chemoradiotherapy, 40 patients underwent surgery, and 25 patients completed postoperative chemotherapy. A pathologic complete response was seen in 7 patients (17.5%). Patients with a pathologic response had a median survival of 32.4 months vs. 14.4 months for nonresponders (p <0.001). Patients with a clinical response had a median survival of 25.2 months compared with 15.6 months for nonresponders (p = 0.002). At a median follow up of 19.8 months (range 2.4-100.8), the median survival was 20.4 months and the 3-year overall survival rate was 23.2%. Conclusion: Although preoperative cisplatin/paclitaxel with 3,000 cGy was tolerable, this multimodality regimen did not appear to be superior to standard cisplatin/5-fluorouracil-containing regimens and its use is not recommended.

  2. 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

  3. Efficacy of cisplatin, 5-fluorouracil, and paclitaxel regimen for carcinoma of the esophagus.

    PubMed

    Belani, C P; Luketich, J D; Landreaneau, R J; Kim, R; Ramanathan, R K; Day, R; Ferson, P F; Keenan, R J; Posner, M; Seeger, J; Lembersky, B

    1997-12-01

    Eighteen patients with esophageal carcinoma (16 adenocarcinoma, two squamous cell carcinoma) were treated with two cycles of induction chemotherapy consisting of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 175 mg/m2 (3-hour infusion), cisplatin 20 mg/m2/d x 4 days, and 5-fluorouracil 1 g/m2/d (continuous infusion x 4 days) separated by a 28-day interval before surgical resection. After resection, patients received two more cycles of the same regimen. A thorough staging evaluation was performed before patients were enrolled in the study. The salient chemotherapy toxicities included grade 3 nausea (two patients), grade 3 vomiting (two patients), grades 3 and 4 diarrhea (one patient each), and grades 3 and 4 neutropenia (two and 10 patients, respectively). No deaths occurred due to toxicity. Surgical resection was attempted in all 18 patients (100%) after two cycles of induction chemotherapy. Esophageal resection was successfully completed in 17 patients. Liver metastases were noted at laparotomy in the one patient who subsequently did not undergo esophageal resection. Surgical complications were minor, and no postoperative deaths occurred. Fifteen patients received two additional cycles of the paclitaxel/5-fluorouracil/cisplatin regimen postoperatively, two received only one cycle, and one refused further therapy. Of 15 patients alive, 14 show no evidence of disease. The 1-year actuarial survival rate of this group of patients is 82%. In conclusion, the paclitaxel/5-fluorouracil/cisplatin combination is well tolerated and is an active regimen in esophageal carcinoma. PMID:9427275

  4. Cannabinoid type-1 receptor reduces pain and neurotoxicity produced by chemotherapy

    PubMed Central

    Khasabova, Iryna A.; Khasabov, Sergey; Paz, Justin; Harding-Rose, Catherine; Simone, Donald A.; Seybold, Virginia S.

    2012-01-01

    Painful peripheral neuropathy is a dose-limiting complication of chemotherapy. Cisplatin produces a cumulative toxic effect on peripheral nerves, and 30%–40% of cancer patients receiving this agent experience pain. By modeling cisplatin-induced hyperalgesia in mice with daily injections of cisplatin (1 mg/kg, i.p.) for 7 days, we investigated the antihyperalgesic effects of anandamide (AEA) and URB597, an inhibitor of AEA hydrolysis. Cisplatin-induced mechanical and heat hyperalgesia were accompanied by a decrease in the level of AEA in plantar paw skin. No changes in motor activity were observed after 7 injections of cisplatin. Intraplantar injection of AEA (10 μg/10 μl) or URB597 (9 μg/10 μl) transiently attenuated hyperalgesia through activation of peripheral CB1 receptors. Co-injections of URB597 (0.3 mg/kg daily, i.p.) with cisplatin decreased and delayed the development of mechanical and heat hyperalgesia. The effect of URB597 was mediated by CB1 receptors since AM281 (0.33 mg/kg daily, i.p) blocked the effect of URB597. Co-injection of URB597 also normalized the cisplatin-induced decrease in conduction velocity of Aα/Aβ fibers and reduced the increase of ATF-3 and TRPV-1 immunoreactivity in dorsal root ganglion (DRG) neurons. Since DRGs are a primary site of toxicity by cisplatin, effects of cisplatin were studied on cultured DRG neurons. Incubation of DRG neurons with cisplatin (4 μg/ml) for 24 h decreased the total length of neurites. URB597 (100 nM) attenuated these changes through activation of CB1 receptors. Collectively, these results suggest that pharmacological facilitation of AEA signaling is a promising strategy for attenuating cisplatin-associated sensory neuropathy. PMID:22593077

  5. 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.

  6. Endocrinological late effects after chemotherapy for testicular cancer.

    PubMed Central

    Berger, C. C.; Bokemeyer, C.; Schuppert, F.; Schmoll, H. J.

    1996-01-01

    Type and extent of endocrinological alterations were studied in long-term disease-free survivors after cisplatin-based chemotherapy for testicular cancer. A total of 63 patients with a median age of 30 (19-53) years, and median follow-up of 42 (16-128) months were included. Elevated serum follicle-stimulating hormone (FSH) levels were found in 63% of patients, 24% showed pathologically elevated luteinising hormone (LH) levels with normal and 10% with subnormal testosterone levels. The degree of gonadotropin elevation was highly significantly correlated with the cumulative platinum (P) dose. Patients treated with platinum-vinblastine-bleomycin regimens showed higher gonadotropin levels than those treated with platinum-etoposide-bleomycin. The adrenal androgen dehydroepiandrosterone (DHEA), pathologically elevated in 68% of patients, was significantly correlated with the cumulative doses of chemotherapy (ctx) used and to the gonadotropin levels. Treatment variables, such as type and dose of cytotoxic agents used, as well as degree of gonadotropin elevation were further correlated with changes in oestron, testosterone and 17 alpha-OH-progesterone levels. Cholesterol levels were elevated in 32% of patients and significant interactions between the steroid hormone levels and cardiovascular risk factors could be shown. PMID:8624272

  7. Hydroxyl radical mediates cisplatin-induced apoptosis in human hair follicle dermal papilla cells and keratinocytes through Bcl-2-dependent mechanism

    PubMed Central

    Luanpitpong, Sudjit; Chanvorachote, Pithi; Leonard, Stephen S.; Pongrakhananon, Varisa; Wang, Liying

    2016-01-01

    Induction of massive apoptosis of hair follicle cells by chemotherapy has been implicated in the pathogenesis of chemotherapy-induced alopecia (CIA), but the underlying mechanisms of regulation are not well understood. The present study investigated the apoptotic effect of cisplatin in human hair follicle dermal papilla cells and HaCaT keratinocytes, and determined the identity and role of specific reactive oxygen species (ROS) involved in the process. Treatment of the cells with cisplatin induced ROS generation and a parallel increase in caspase activation and apoptotic cell death. Inhibition of ROS generation by antioxidants inhibited the apoptotic effect of cisplatin, indicating the role of ROS in the process. Studies using specific ROS scavengers further showed that hydroxyl radical, but not hydrogen peroxide or superoxide anion, is the primary oxidative species responsible for the apoptotic effect of cisplatin. Electron spin resonance studies confirmed the formation of hydroxyl radicals induced by cisplatin. The mechanism by which hydroxyl radical mediates the apoptotic effect of cisplatin was shown to involve down-regulation of the anti-apoptotic protein Bcl-2 through ubiquitin-proteasomal degradation. Bcl-2 was also shown to have a negative regulatory role on hydroxyl radical. Together, our results indicate an essential role of hydroxyl radical in cisplatin-induced cell death of hair follicle cells through Bcl-2 regulation. Since CIA is a major side effect of cisplatin and many other chemotherapeutic agents with no known effective treatments, the knowledge gained from this study could be useful in the design of preventive treatment strategies for CIA through localized therapy without compromising the chemotherapy efficacy. PMID:21573972

  8. Hydroxyl radical mediates cisplatin-induced apoptosis in human hair follicle dermal papilla cells and keratinocytes through Bcl-2-dependent mechanism.

    PubMed

    Luanpitpong, Sudjit; Nimmannit, Ubonthip; Chanvorachote, Pithi; Leonard, Stephen S; Pongrakhananon, Varisa; Wang, Liying; Rojanasakul, Yon

    2011-08-01

    Induction of massive apoptosis of hair follicle cells by chemotherapy has been implicated in the pathogenesis of chemotherapy-induced alopecia (CIA), but the underlying mechanisms of regulation are not well understood. The present study investigated the apoptotic effect of cisplatin in human hair follicle dermal papilla cells and HaCaT keratinocytes, and determined the identity and role of specific reactive oxygen species (ROS) involved in the process. Treatment of the cells with cisplatin induced ROS generation and a parallel increase in caspase activation and apoptotic cell death. Inhibition of ROS generation by antioxidants inhibited the apoptotic effect of cisplatin, indicating the role of ROS in the process. Studies using specific ROS scavengers further showed that hydroxyl radical, but not hydrogen peroxide or superoxide anion, is the primary oxidative species responsible for the apoptotic effect of cisplatin. Electron spin resonance studies confirmed the formation of hydroxyl radicals induced by cisplatin. The mechanism by which hydroxyl radical mediates the apoptotic effect of cisplatin was shown to involve down-regulation of the anti-apoptotic protein Bcl-2 through ubiquitin-proteasomal degradation. Bcl-2 was also shown to have a negative regulatory role on hydroxyl radical. Together, our results indicate an essential role of hydroxyl radical in cisplatin-induced cell death of hair follicle cells through Bcl-2 regulation. Since CIA is a major side effect of cisplatin and many other chemotherapeutic agents with no known effective treatments, the knowledge gained from this study could be useful in the design of preventive treatment strategies for CIA through localized therapy without compromising the chemotherapy efficacy.

  9. 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.

  10. Computed Tomography (CT) Perfusion as an Early Predictive Marker for Treatment Response to Neoadjuvant Chemotherapy in Gastroesophageal Junction Cancer and Gastric Cancer - A Prospective Study

    PubMed Central

    Hansen, Martin Lundsgaard; Fallentin, Eva; Lauridsen, Carsten; Law, Ian; Federspiel, Birgitte; Bæksgaard, Lene; Svendsen, Lars Bo; Nielsen, Michael Bachmann

    2014-01-01

    Objectives To evaluate whether early reductions in CT perfusion parameters predict response to pre-operative chemotherapy prior to surgery for gastroesophageal junction (GEJ) and gastric cancer. Materials and Methods Twenty-eight patients with adenocarcinoma of the gastro-esophageal junction (GEJ) and stomach were included. Patients received three series of chemotherapy before surgery, each consisting of a 3-week cycle of intravenous epirubicin, cisplatin or oxaliplatin, concomitant with capecitabine peroral. The patients were evaluated with a CT perfusion scan prior to, after the first series of, and after three series of chemotherapy. The CT perfusion scans were performed using a 320-detector row scanner. Tumour volume and perfusion parameters (arterial flow, blood volume and permeability) were computed on a dedicated workstation with a consensus between two radiologists. Response to chemotherapy was evaluated by two measures. Clinical response was defined as a tumour size reduction of more than 50%. Histological response was evaluated based on residual tumour cells in the surgical specimen using the standardized Mandard Score 1 to 5, in which values of 1 and 2 were classified as responders, and 3 to 5 were classified as nonresponders. Results A decrease in tumour permeability after one series of chemotherapy was positively correlated with clinical response after three series of chemotherapy. Significant changes in permeability and tumour volume were apparent after three series of chemotherapy in both clinical and histological responders. A cut-off value of more than 25% reduction in tumour permeability yielded a sensitivity of 69% and a specificity of 58% for predicting clinical response. Conclusion Early decrease in permeability is correlated with the likelihood of clinical response to pre-operative chemotherapy in GEJ and gastric cancer. As a single diagnostic test, CT Perfusion only has moderate sensitivity and specificity in response assessment of pre

  11. New drugs in the palliative chemotherapy of advanced non-small-cell lung cancer.

    PubMed

    Malayeri, R; Pirker, R; Huber, H

    2001-10-01

    In inoperable advanced non-small-cell lung cancer (NSCLC), palliative chemotherapy is established and aims at palliation of symptoms, improvement of quality of life and prolongation of survival. In the last years, several new drugs with enhanced activity towards NSCLC and improved toxicity profile have been characterised, for example vinorelbine, gemcitabine, paclitaxel and docetaxel. Data from randomised trials suggest that regimens containing new drugs are more active than older combinations. Platin-based combinations of either vinorelbine, gemcitabine or paclitaxel have resulted in better outcome than cisplatin alone and new drugs in combination with platins are more active than the corresponding single agent. Non-platin-based combinations must be considered investigational until their non-inferiority to platin-based protocols has been proven in randomised trials on large patient populations. Patients with good performance status and adequate organ function should receive platin-based chemotherapy that includes the new drugs (vinorelbine, gemcitabine, paclitaxel or docetaxel). New drugs without platins are suitable for elderly patients and patients with poor performance status. Second-line chemotherapy prolongs survival in selected patients and should be particularly offered to patients with good performance status. PMID:11694767

  12. [Effect of plant biocomposites based on Georgian tea "per se" and in combination with cisplatin on Walker carcinosarcoma W-256 and Guerin's carcinoma growth rate in rats].

    PubMed

    Zalietok, S P; Orlovs'kyĭ, O A; Hohol', S V; Samoĭlenko, O A; Hulua, L; Kvesitadze, H I

    2006-12-01

    Green tea biocomposite had effectivey hampered the growth of rat Walker W-256 carcinoma and in less extent rat Guerin's carcinoma. Black tea biocomposite had not practically influenced on Guerin's carcinoma growth. The biocomposite from green tea and extract from red vine rind and lemon suppressed at the level of tendency the growth of rat Walker W-256 carcinoma. The biocomposite from green tea and extract from red vine rind had hampered only Guerin's carcinoma growth and at the tendency had increased the growth of W-256 carcinosarcoma growth. This biocomposite increased also considerably the therapeutic efficiency of cisplatin on Guerin's carcinoma. Studed vegetable biocomposites posesses antiinflammatory and antioxidant properties.

  13. First-line cetuximab-based chemotherapies for patients with advanced or metastatic KRAS wild-type colorectal cancer

    PubMed Central

    Uemura, Mamoru; Kim, Ho Min; Hata, Tsuyoshi; Sakata, Kazuya; Okuyama, Masaki; Takemoto, Hiroyoshi; Fujii, Hitoshi; Fukuzaki, Takayuki; Morita, Tetsushi; Hata, Taishi; Takemasa, Ichiro; Satoh, Taroh; Mizushima, Tsunekazu; Doki, Yuichiro; Mori, Maski

    2016-01-01

    Colorectal cancer (CRC) is one of the most commonly occurring cancers worldwide. A burgeoning number of studies have demonstrated that the addition of cetuximab to another standard first-line regimen markedly improves the outcome of CRC treatment. However, at present, the efficacy and safety of cetuximab-based combination chemotherapy has not been well described in Japan. The aim of the present study was to evaluate the efficacy and safety of first-line chemotherapies that included cetuximab for patients with advanced or metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type CRC in Japan. This prospective multicenter observational study was conducted at 13 affiliated medical institutions. A total of 64 patients were enrolled between 2010 and 2013. The patients met the following criteria for eligibility: i) histologically confirmed, advanced or metastatic KRAS wild-type CRC; and ii) cetuximab-based chemotherapies administered as a first-line treatment. First-line cetuximab-based treatments were administered as follows: 29 patients (45.3%) received a combination of infusional fluorouracil, leucovorin and oxaliplatin; 14 patients (21.9%) received a combination of capecitabine and oxaliplatin; and 10 patients (15.6%) received a combination of infusional fluorouracil, leucovorin and irinotecan. The overall response rate (including complete plus partial responses) was 50% (32/64 patients). Initially, 48 lesions were diagnosed as unresectable. Among those, 13 lesions (27.1%) were converted to a resectable status following cetuximab-based combination chemotherapy treatments. The median overall survival time and the progression-free survival time were 1,189 and 359 days, respectively. The most frequent grade 3/4 adverse event was neutropenia, which occurred in 20.3% of the patients. The incidence of grade 3/4 skin toxicity was 17.2% (11/64 patients). Cetuximab-based therapies may represent a promising first-line regimen for patients with advanced or

  14. Spectrum of cisplatin-induced mutations in Escherichia coli

    SciTech Connect

    Burnouf, D.; Duane, M.; Fuchs, R.P.

    1987-06-01

    Using a forward-mutation assay based on the inactivation of the tetracycline-resistance gene located on plasmid pBR322, we have determined the mutation spectrum induced in Escherichia coli by cisplatin (cis-diamminedichloroplatinum(II)), a widely used antitumor drug. Cisplatin is known to form mainly intrastrand diadducts at ApG and GpG sites. We found that cisplatin efficiently induces mutations in an SOS-dependent way (i.e., dependent upon UV irradiation of the host bacteria). More than 90% of the mutations are single-base-pair substitutions occurring at the potential sites of cisplatin adducts (ApG and GpG). Taking into account the relative proportions of ApG and GpG adducts, we found that the ApG adducts are at least 5 times more mutagenic than the GpG adducts. Moreover, a strong mutation specificity was seen at the 5' side of the ApG adducts (A X T----T X A transversions). The observation that most mutations occur at the 5' end of the adduct at both ApG and GpG sites is discussed in relation to recent structural data.

  15. High Intra-abdominal Pressure Enhances the Penetration and Antitumor Effect of Intraperitoneal Cisplatin on Experimental Peritoneal Carcinomatosis

    PubMed Central

    Esquis, Philippe; Consolo, David; Magnin, Guy; Pointaire, Philippe; Moretto, Philippe; Ynsa, Maria Dolores; Beltramo, Jean-Luc; Drogoul, Carole; Simonet, Michel; Benoit, Laurent; Rat, Patrick; Chauffert, Bruno

    2006-01-01

    Objective: To investigate the role of increased intra-abdominal pressure (IAP) on the intratumoral accumulation and the antitumor effect of intraperitoneal cisplatin in rats with advanced peritoneal carcinomatosis. To evaluate the tolerance of IAP in pigs, as it is a large animal with a body size equivalent to humans. Summary Background Data: To investigate if an active convection, driven by a positive IAP, increases cisplatin penetration and antitumor effectiveness in a model of advanced peritoneal carcinomatosis in rats. Experimental Design: BDIX rats with macroscopic peritoneal tumors received cisplatin administered as intravenous injection (IV), conventional intraperitoneal injection (IP), or sustained intraperitoneal injection of cisplatin given in a large volume of solvent for maintaining IAP for 1 hour. Platinum tissue concentration was measured by atomic absorption spectroscopy (AAS), and platinum distribution into the tumor nodules was assessed by the particular-induced x-ray emission (PIXE) method. The antitumor effect was assessed in a survival experiment. The hemodynamic, local, and systemic tolerance of IAP, with or without cisplatin, was evaluated in Large White pigs. Results: The maximum tolerated IAP was 22 mm Hg for 1 hour in nonventilated rats. IAP, in comparison with IV or conventional IP injections, resulted in the increased concentration and depth of diffusion of platinum into diaphragm and peritoneal tumor nodules. Consequently, IAP treatment induced an extended survival of rats treated at an advanced stage of carcinomatosis. In 7 50- to 70-kg ventilated pigs, a 40-mm Hg IAP was well tolerated when maintained stable for 2 hours. Renal failure occurred in pigs receiving a total dose of 200 and 400 mg of cisplatin with IAP, but a dose of 100 mg was well tolerated. Conclusions: Intraperitoneal chemotherapy with increased IAP, in comparison with conventional IP or IV chemotherapy, improved the tumor accumulation and the antitumor effect of

  16. Anti-tumor Efficiency of Lipid-coated Cisplatin Nanoparticles Co-loaded with MicroRNA-375.

    PubMed

    Yang, Tan; Zhao, Pengxuan; Rong, Zhao; Li, Bin; Xue, Huiying; You, Jia; He, Chuanchuan; Li, Weijie; He, Xingxing; Lee, Robert J; Ma, Xiang; Xiang, Guangya

    2016-01-01

    One of the major challenges in the hepatocellular carcinoma (HCC) treatment is its insensitivity to chemotherapeutic drugs. Here, we report the development of novel lipid-coated cisplatin nanoparticles co-loaded with microRNA-375 (NPC/miR-375) as a potential treatment for chemotherapy insensitive HCC. The NPC/miR-375 was fabricated by mixing two reverse microemulsions containing KCl solution and a highly soluble cis-diaminedihydroplatinum (II) coated with a cationic lipid layer. Subsequently, the miR-375 was incorporated into the lipid-coated cisplatin nanoparticles. The NPC/miR375 nanoparticles were expected to further decrease cell proliferation and to enhance the anti-tumor effect of cisplatin in chemotherapy resistant HCC cells. In vitro analysis of intracellular trafficking revealed that NPC/miR-375 were able to escape from the late endosomes instead of lysosomes thus avoiding degradation of the miR-375 in lysosomes. Importantly, NPC/miR-375 enhanced apoptosis and induced cell cycle arrest in HCC cells in vitro. In the double oncogenes Akt/Ras-induced primary HCC mouse model, multiple doses of NPC/miR-375 significantly inhibited tumor growth and delayed the tumor relapse. Our results indicate that cisplatin nanoparticles co-loaded with miR-375 represent a potential therapeutic agent for chemotherapy-insensitive HCC.

  17. Anti-tumor Efficiency of Lipid-coated Cisplatin Nanoparticles Co-loaded with MicroRNA-375

    PubMed Central

    Yang, Tan; Zhao, Pengxuan; Rong, Zhao; Li, Bin; Xue, Huiying; You, Jia; He, Chuanchuan; Li, Weijie; He, Xingxing; Lee, Robert J.; Ma, Xiang; Xiang, Guangya

    2016-01-01

    One of the major challenges in the hepatocellular carcinoma (HCC) treatment is its insensitivity to chemotherapeutic drugs. Here, we report the development of novel lipid-coated cisplatin nanoparticles co-loaded with microRNA-375 (NPC/miR-375) as a potential treatment for chemotherapy insensitive HCC. The NPC/miR-375 was fabricated by mixing two reverse microemulsions containing KCl solution and a highly soluble cis-diaminedihydroplatinum (II) coated with a cationic lipid layer. Subsequently, the miR-375 was incorporated into the lipid-coated cisplatin nanoparticles. The NPC/miR375 nanoparticles were expected to further decrease cell proliferation and to enhance the anti-tumor effect of cisplatin in chemotherapy resistant HCC cells. In vitro analysis of intracellular trafficking revealed that NPC/miR-375 were able to escape from the late endosomes instead of lysosomes thus avoiding degradation of the miR-375 in lysosomes. Importantly, NPC/miR-375 enhanced apoptosis and induced cell cycle arrest in HCC cells in vitro. In the double oncogenes Akt/Ras-induced primary HCC mouse model, multiple doses of NPC/miR-375 significantly inhibited tumor growth and delayed the tumor relapse. Our results indicate that cisplatin nanoparticles co-loaded with miR-375 represent a potential therapeutic agent for chemotherapy-insensitive HCC. PMID:26722380

  18. Anti-tumor Efficiency of Lipid-coated Cisplatin Nanoparticles Co-loaded with MicroRNA-375.

    PubMed

    Yang, Tan; Zhao, Pengxuan; Rong, Zhao; Li, Bin; Xue, Huiying; You, Jia; He, Chuanchuan; Li, Weijie; He, Xingxing; Lee, Robert J; Ma, Xiang; Xiang, Guangya

    2016-01-01

    One of the major challenges in the hepatocellular carcinoma (HCC) treatment is its insensitivity to chemotherapeutic drugs. Here, we report the development of novel lipid-coated cisplatin nanoparticles co-loaded with microRNA-375 (NPC/miR-375) as a potential treatment for chemotherapy insensitive HCC. The NPC/miR-375 was fabricated by mixing two reverse microemulsions containing KCl solution and a highly soluble cis-diaminedihydroplatinum (II) coated with a cationic lipid layer. Subsequently, the miR-375 was incorporated into the lipid-coated cisplatin nanoparticles. The NPC/miR375 nanoparticles were expected to further decrease cell proliferation and to enhance the anti-tumor effect of cisplatin in chemotherapy resistant HCC cells. In vitro analysis of intracellular trafficking revealed that NPC/miR-375 were able to escape from the late endosomes instead of lysosomes thus avoiding degradation of the miR-375 in lysosomes. Importantly, NPC/miR-375 enhanced apoptosis and induced cell cycle arrest in HCC cells in vitro. In the double oncogenes Akt/Ras-induced primary HCC mouse model, multiple doses of NPC/miR-375 significantly inhibited tumor growth and delayed the tumor relapse. Our results indicate that cisplatin nanoparticles co-loaded with miR-375 represent a potential therapeutic agent for chemotherapy-insensitive HCC. PMID:26722380

  19. Putting evidence into practice: evidence-based interventions to prevent, manage, and treat chemotherapy-induced nausea and vomiting.

    PubMed

    Tipton, Janelle M; McDaniel, Roxanne W; Barbour, Laurel; Johnston, Mary Pat; Kayne, Marilyn; LeRoy, Patricia; Ripple, Marita L

    2007-02-01

    Chemotherapy-induced nausea and vomiting (CINV) continues to have a considerable effect on the physical and psychological well-being of patients with cancer, despite significant advances in antiemetic drugs since the 1990s. This article reviews and summarizes past and current empirical evidence related to interventions for CINV. A resource that summarizes evidence-based interventions for CINV is critical for effective management of this distressing symptom. Pharmacologic and nonpharmacologic interventions are appraised. Finally, gaps in the literature and opportunities for research, education, and practice changes are discussed.

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

    PubMed

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

    2016-01-01

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

  1. Cisplatin and Paclitaxel Alter the Expression Pattern of miR-143/145 and miR-183/96/182 Clusters in T24 Bladder Cancer Cells.

    PubMed

    Papadopoulos, Emmanuel I; Scorilas, Andreas

    2015-12-01

    Although cisplatin-based chemotherapy is considered to be the treatment of choice for metastatic bladder cancer, its efficacy and tolerability has proven to be limited. MicroRNAs are small noncoding RNAs, whose genes are frequently organized in clusters. These molecules constitute posttranscriptional regulators of mRNA expression and are claimed to be deregulated in cancer. miR-143/145 and miR-183/96/182 clusters have been extensively studied in bladder cancer cells. Herein, we tried to add up to this knowledge by assessing the expression levels of the five mature microRNAs derived from the aforementioned clusters in T24 bladder cancer cells exposed to either cisplatin or paclitaxel. For both compounds, the viability of treated T24 cells was estimated via the MTT colorimetric assay and the Trypan Blue exclusion method, while a fraction of the cells was left to recover. The expression levels of all mature microRNAs were finally quantified both in treated and in recovered cells by performing real-time PCR. According to our data, cisplatin and paclitaxel strongly decreased T24 cells' viability, showing in parallel the ability to significantly down-regulate miR-143 levels, and up-regulate the expression levels of miR-145, miR-183, miR-96, and miR-182, which, in their total, demonstrated case-specific variations after recovery period.

  2. Cleavage enhancement of specific chemical bonds in DNA by cisplatin radiosensitization.

    PubMed

    Xiao, Fangxing; Luo, Xinglan; Fu, Xianzhi; Zheng, Yi

    2013-05-01

    X-ray photoelectron spectroscopy (XPS) is harnessed as an in situ efficient characterization technique for monitoring chemical bond transformation in DNA and cisplatin-DNA complexes under synergic X-ray irradiation. By analyzing the variation of relative peak area of core elements of DNA as a function of irradiation time, we find that the most vulnerable scission sites in DNA are those containing phosphate and glycosidic bonds. Compared to DNA, the effective rate constants of the corresponding phosphodiester and glycosidic bond cleavages for cisplatin-DNA complexes are 1.8 and 1.9 folds larger. These damages and their enhancements are similar to those induced by low energy electrons (LEE). Consistently, the magnitude of the secondary electron distribution produced by the X-rays on the cisplatin-DNA complexes is considerably increased compared to that of pristine DNA. The data suggest that DNA radiosensization by cisplatin results not only from the sensitization of DNA to the action of LEE, but also from an increase the production of LEE at the site of binding of the cisplatin. The results provide new insights into the mechanisms of cisplatin-induced sensitization of DNA under X-ray irradiation, which could be helpful in the design of new cisplatin-based antitumor drugs.

  3. [Neoadjuvant chemotherapy followed by radical surgery in pregnant patient with invasive cervical cancer: case report and literature review].

    PubMed

    da Fonseca, Allex Jardim; Dalla-Benetta, Anderson Cesar; Ferreira, Leonardo Pires; Martins, Cibelli Roldan Navarro; Lins, Cynthia Dantas Macedo

    2011-01-01

    The treatment options for pregnant patients with invasive cervical cancer (ICC) depend on gestational age, clinical stage and the patient's wishes. Some authors have reported cases of neoadjuvant chemotherapy followed by radical surgery in these patients. The aim of this paper was to revisit this subject and to add a new case and review the literature. We report the case of a 30 year-old woman in the 24th week of gestation. She was diagnosed with ICC (squamous cell carcinoma grade 2), stage IIB (International Federation of Gynecology and Obstetrics - FIGO). Nulliparous, the patient refused to interrupt the pregnancy. After meticulous counseling, the patient accepted treatment with neoadjuvant chemotherapy (cisplatin 75 mg/m² and vincristine 1 mg/m²) and subsequent evaluation of radical surgery concomitant to a cesarean section. Four complete cycles of chemotherapy were administered without delays or significant adverse effects. A few days before the date scheduled for surgery, the patient was admitted in advanced labor (37th week of gestation). Due to tumor clinical response, the obstetric team decided to monitor the labor, and the patient gave birth to a male newborn (2,450 g) uneventfully. Radical surgery was performed three days after birth, and histopathology analysis revealed carcinoma confined to the cervix without lymphatic involvement. Mother and son are in good general condition 12 months after delivery. Cisplatin-based chemotherapy during the second or third trimester of pregnancy appears to be a safe option for patients who do not wish to interrupt a pregnancy while awaiting fetal maturity. However, additional studies are needed to confirm the prognosis and assure the safety of newborns and patients.

  4. Outcome of Neoadjuvant Chemotherapy on Local Recurrence and Distant Metastasis of Oral Squamous Cell Carcinoma: A Retrospective Study

    PubMed Central

    Tabrizi, Reza; Garajei, Ata; Shafie, Ehsan; Jamshidi, Samira

    2016-01-01

    Statement of the Problem Neoadjuvant chemotherapy (NCH) is controversial in the treatment of oral squamous cell carcinoma (OSCC). Purpose The aim of this study was to evaluate the efficacy of NCH on OSCC prognosis. Materials and Method In this retrospective cohort study, 94 patients were studied in two groups. The patients in group 1 received NCH before the surgery, and those in group 2 underwent resection without any chemotherapy prior to surgery. The employed NCH agents consisted of cisplatin in combination with 5-fluorouracil in two treatment courses. Tumor size, lymph node involvement, age, and follow-up time were considered as variable factors of the study. Local recurrence (LR) and distant metastasis (DM) were outcomes of the study. Results Comparison of LR and DM in various tumor sizes demonstrated no significant difference between the two groups (p> 0.05). Analysis of the data did not show any statistically significant difference between the groups for LR in subjects with N0, N1 and N2. Each one-year increase in age was associated with 10% increase in the hazard ratio (HR) (HR distance metastasis Y/N = 1.10, p= 0.05). In the same analysis, when considering LR as a dependent factor, LR risk in N2 was 3 times more than in N1 (p= 0.02). LR risk in N3 was 5 times more than in N1 [HR local recurrence (p= 0.006). Conclusion Based on our results, neoadjuvant chemotherapy with combination of cisplatin and 5-fluorouracil may not improve prognosis of OSCC. However, further studies are suggested to assess other neoadjuvant chemotherapy protocols in OSCC patients.

  5. Outcome of Neoadjuvant Chemotherapy on Local Recurrence and Distant Metastasis of Oral Squamous Cell Carcinoma: A Retrospective Study

    PubMed Central

    Tabrizi, Reza; Garajei, Ata; Shafie, Ehsan; Jamshidi, Samira

    2016-01-01

    Statement of the Problem Neoadjuvant chemotherapy (NCH) is controversial in the treatment of oral squamous cell carcinoma (OSCC). Purpose The aim of this study was to evaluate the efficacy of NCH on OSCC prognosis. Materials and Method In this retrospective cohort study, 94 patients were studied in two groups. The patients in group 1 received NCH before the surgery, and those in group 2 underwent resection without any chemotherapy prior to surgery. The employed NCH agents consisted of cisplatin in combination with 5-fluorouracil in two treatment courses. Tumor size, lymph node involvement, age, and follow-up time were considered as variable factors of the study. Local recurrence (LR) and distant metastasis (DM) were outcomes of the study. Results Comparison of LR and DM in various tumor sizes demonstrated no significant difference between the two groups (p> 0.05). Analysis of the data did not show any statistically significant difference between the groups for LR in subjects with N0, N1 and N2. Each one-year increase in age was associated with 10% increase in the hazard ratio (HR) (HR distance metastasis Y/N = 1.10, p= 0.05). In the same analysis, when considering LR as a dependent factor, LR risk in N2 was 3 times more than in N1 (p= 0.02). LR risk in N3 was 5 times more than in N1 [HR local recurrence (p= 0.006). Conclusion Based on our results, neoadjuvant chemotherapy with combination of cisplatin and 5-fluorouracil may not improve prognosis of OSCC. However, further studies are suggested to assess other neoadjuvant chemotherapy protocols in OSCC patients. PMID:27602396

  6. Oxidative Stress Induced by Pt(IV) Pro-drugs Based on the Cisplatin Scaffold and Indole Carboxylic Acids in Axial Position

    PubMed Central

    Tolan, Dina; Gandin, Valentina; Morrison, Liam; El-Nahas, Ahmed; Marzano, Cristina; Montagner, Diego; Erxleben, Andrea

    2016-01-01

    The use of Pt(IV) complexes as pro-drugs that are activated by intracellular reduction is a widely investigated approach to overcome the limitations of Pt(II) anticancer agents. A series of ten mono- and bis-carboxylated Pt(IV) complexes with axial indole-3-acetic acid (IAA) and indole-3-propionic acid (IPA) ligands were synthesized and characterized by elemental analysis, ESI-MS, FT-IR, 1H and 195Pt NMR spectroscopy. Cellular uptake, DNA platination and cytotoxicity against a panel of human tumor cell lines were evaluated. All the complexes are able to overcome cisplatin-resistance and the most potent complex, cis,cis,trans-[Pt(NH3)2Cl2(IPA)(OH)] was on average three times more active than cisplatin. Mechanistic studies revealed that the trend in cytotoxicity of the Pt(IV) complexes is primarily consistent with their ability to accumulate into cancer cells and to increase intracellular basal reactive oxygen species levels, which in turn results in the loss of mitochondrial membrane potential and apoptosis induction. The role of the indole acid ligand as a redox modulator is discussed. PMID:27404565

  7. Oxidative Stress Induced by Pt(IV) Pro-drugs Based on the Cisplatin Scaffold and Indole Carboxylic Acids in Axial Position.

    PubMed

    Tolan, Dina; Gandin, Valentina; Morrison, Liam; El-Nahas, Ahmed; Marzano, Cristina; Montagner, Diego; Erxleben, Andrea

    2016-01-01

    The use of Pt(IV) complexes as pro-drugs that are activated by intracellular reduction is a widely investigated approach to overcome the limitations of Pt(II) anticancer agents. A series of ten mono- and bis-carboxylated Pt(IV) complexes with axial indole-3-acetic acid (IAA) and indole-3-propionic acid (IPA) ligands were synthesized and characterized by elemental analysis, ESI-MS, FT-IR, (1)H and (195)Pt NMR spectroscopy. Cellular uptake, DNA platination and cytotoxicity against a panel of human tumor cell lines were evaluated. All the complexes are able to overcome cisplatin-resistance and the most potent complex, cis,cis,trans-[Pt(NH3)2Cl2(IPA)(OH)] was on average three times more active than cisplatin. Mechanistic studies revealed that the trend in cytotoxicity of the Pt(IV) complexes is primarily consistent with their ability to accumulate into cancer cells and to increase intracellular basal reactive oxygen species levels, which in turn results in the loss of mitochondrial membrane potential and apoptosis induction. The role of the indole acid ligand as a redox modulator is discussed. PMID:27404565

  8. Oxidative Stress Induced by Pt(IV) Pro-drugs Based on the Cisplatin Scaffold and Indole Carboxylic Acids in Axial Position

    NASA Astrophysics Data System (ADS)

    Tolan, Dina; Gandin, Valentina; Morrison, Liam; El-Nahas, Ahmed; Marzano, Cristina; Montagner, Diego; Erxleben, Andrea

    2016-07-01

    The use of Pt(IV) complexes as pro-drugs that are activated by intracellular reduction is a widely investigated approach to overcome the limitations of Pt(II) anticancer agents. A series of ten mono- and bis-carboxylated Pt(IV) complexes with axial indole-3-acetic acid (IAA) and indole-3-propionic acid (IPA) ligands were synthesized and characterized by elemental analysis, ESI-MS, FT-IR, 1H and 195Pt NMR spectroscopy. Cellular uptake, DNA platination and cytotoxicity against a panel of human tumor cell lines were evaluated. All the complexes are able to overcome cisplatin-resistance and the most potent complex, cis,cis,trans-[Pt(NH3)2Cl2(IPA)(OH)] was on average three times more active than cisplatin. Mechanistic studies revealed that the trend in cytotoxicity of the Pt(IV) complexes is primarily consistent with their ability to accumulate into cancer cells and to increase intracellular basal reactive oxygen species levels, which in turn results in the loss of mitochondrial membrane potential and apoptosis induction. The role of the indole acid ligand as a redox modulator is discussed.

  9. 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.

  10. Understanding Chemotherapy

    MedlinePlus

    ... you may get chemotherapy before a peripheral blood stem cell transplant. Fill this section in with your doctor or nurse. I am getting chemo ... can be given in these forms: An IV (intravenously) A shot (injection) into a muscle or other part of your body A pill ...

  11. Anti-platelet agents augment cisplatin nanoparticle cytotoxicity by enhancing tumor vasculature permeability and drug delivery

    NASA Astrophysics Data System (ADS)

    Pandey, Ambarish; Sarangi, Sasmit; Chien, Kelly; Sengupta, Poulomi; Papa, Anne-Laure; Basu, Sudipta; Sengupta, Shiladitya

    2014-11-01

    Tumor vasculature is critically dependent on platelet mediated hemostasis and disruption of the same can augment delivery of nano-formulation based chemotherapeutic agents which depend on enhanced permeability and retention for tumor penetration. Here, we evaluated the role of Clopidogrel, a well-known inhibitor of platelet aggregation, in potentiating the tumor cytotoxicity of cisplatin nano-formulation in a murine breast cancer model. In vivo studies in murine syngeneic 4T1 breast cancer model showed a significant greater penetration of macromolecular fluorescent nanoparticles after clopidogrel pretreatment. Compared to self-assembling cisplatin nanoparticles (SACNs), combination therapy with clopidogrel and SACN was associated with a 4 fold greater delivery of cisplatin to tumor tissue and a greater reduction in tumor growth as well as higher survival rate. Clopidogrel enhances therapeutic efficiency of novel cisplatin based nano-formulations agents by increasing tumor drug delivery and can be used as a potential targeting agent for novel nano-formulation based chemotherapeutics.

  12. Eradication of CD44-variant positive population in head and neck tumors through controlled intracellular navigation of cisplatin-loaded nanomedicines.

    PubMed

    Wang, Ming; Miura, Yutaka; Tsuchihashi, Kenji; Miyano, Kazuki; Nagano, Osamu; Yoshikawa, Momoko; Tanabe, Ami; Makino, Jun; Mochida, Yuki; Nishiyama, Nobuhiro; Saya, Hideyuki; Cabral, Horacio; Kataoka, Kazunori

    2016-05-28

    Eventual relapse of tumor growth is commonly observed in head and neck cancer patients, following treatment with platinum-based chemotherapies. This occurrence is believed to be related to the failure to eradicate drug resistant, cancer stem cell (CSC) niches, thereby enriching their population in tumors after treatment. In this study, we show that in contrast to free cisplatin (CDDP), the polymer micelle-based nanomedicine incorporating cisplatin (CDDP/m), can eradicate both the undifferentiated cell and the differentiated cancer cell populations within a head and neck tumor model. Immunohistochemistry of treated tumors showed that opposing to CDDP treatment, CDDP/m could reduce tumor growth without concentrating the CSC-like population. We further showed that CDDP/m, but not CDDP, can localize into hypoxic regions, possibly CSC-rich areas, in the tumors, and can overcome their detoxification mechanism based-on high cellular expression of glutathione to successfully deliver Pt to nuclear DNA. Our data suggests CDDP/m to be a replacement for current platinum therapies, for its ability to eradicate both bulk and CSC-like populations, and in turn to prevent recurrence of tumor growth. PMID:27040816

  13. Alteration of Topoisomerase II–Alpha Gene in Human Breast Cancer: Association With Responsiveness to Anthracycline-Based Chemotherapy

    PubMed Central

    Press, Michael F.; Sauter, Guido; Buyse, Marc; Bernstein, Leslie; Guzman, Roberta; Santiago, Angela; Villalobos, Ivonne E.; Eiermann, Wolfgang; Pienkowski, Tadeusz; Martin, Miguel; Robert, Nicholas; Crown, John; Bee, Valerie; Taupin, Henry; Flom, Kerry J.; Tabah-Fisch, Isabelle; Pauletti, Giovanni; Lindsay, Mary-Ann; Riva, Alessandro; Slamon, Dennis J.

    2011-01-01

    Purpose Approximately 35% of HER2-amplified breast cancers have coamplification of the topoisomerase II-alpha (TOP2A) gene encoding an enzyme that is a major target of anthracyclines. This study was designed to evaluate whether TOP2A gene alterations may predict incremental responsiveness to anthracyclines in some breast cancers. Methods A total of 4,943 breast cancers were analyzed for alterations in TOP2A and HER2. Primary tumor tissues from patients with metastatic breast cancer treated in a trial of chemotherapy plus/minus trastuzumab were studied for amplification/deletion of TOP2A and HER2 as a test set followed by evaluation of malignancies from two separate, large trials for changes in these same genes as a validation set. Association between these alterations and clinical outcomes was determined. Results Test set cases containing HER2 amplification treated with doxorubicin and cyclophosphamide (AC) plus trastuzumab, demonstrated longer progression-free survival compared to those treated with AC alone (P = .0002). However, patients treated with AC alone whose tumors contain HER2/TOP2A coamplification experienced a similar improvement in survival (P = .004). Conversely, for patients treated with paclitaxel, HER2/TOP2A coamplification was not associated with improved outcomes. These observations were confirmed in a larger validation set, where HER2/TOP2A coamplification was again associated with longer survival when only anthracycline-containing chemotherapy was used for treatment compared with outcome in HER2-positive cancers lacking TOP2A coamplification. Conclusion In a study involving nearly 5,000 breast malignancies, both test set and validation set demonstrate that TOP2A coamplification, not HER2 amplification, is the clinically useful predictive marker of an incremental response to anthracycline-based chemotherapy. Absence of HER2/TOP2A coamplification may indicate a more restricted efficacy advantage for breast cancers than previously thought. PMID

  14. Impact of involved field radiotherapy in partial response after doxorubicin-based chemotherapy for advanced aggressive non-Hodgkin's lymphoma

    SciTech Connect

    Moser, Elizabeth C. . E-mail: e.c.moser@lumc.nl; Kluin-Nelemans, Hanneke C.; Carde, Patrice; Meerwaldt, Jacobus H.; Tirelli, Umberto; Aleman, Berthe M.P.; Baars, Joke; Thomas, Jose; Glabbeke, Martine van; Noordijk, Evert M.

    2006-11-15

    Purpose: Whether salvage therapy in patients with advanced aggressive non-Hodgkin's lymphoma (NHL) in partial remission (PR) should consist of radiotherapy or autologous stem-cell transplantation (ASCT) is debatable. We evaluated the impact of radiotherapy on outcome in PR patients treated in four successive European Organization for Research and Treatment of Cancer trials for aggressive NHL. Patients and Methods: Records of 974 patients (1980-1999) were reviewed regarding initial response, final outcome, and type and timing of salvage treatment. After 8 cycles of doxorubicin-based chemotherapy, 227 NHL patients were in PR and treated: 114 received involved field radiotherapy, 16 ASCT, 93 second-line chemotherapy, and 4 were operated. Overall survival (OS) and progression-free survival (PFS) after radiotherapy were estimated (Kaplan-Meier method) and compared with other treatments (log-rank). Impact on survival was evaluated by multivariate analysis (Cox proportional hazards model). Results: The median PFS in PR patients was 4.2 years and 48% remained progression-free at 5 years. Half of the PR patients converted to a complete remission. After conversion, survival was comparable to patients directly in complete remission. Radiotherapy resulted in better OS and PFS compared with other treatments, especially in patients with low to intermediate International Prognostic Index score, bulky disease, or nodal disease only. Correction by multivariate analysis for prognostic factors such as stage, bulky disease, and number of extranodal locations showed that radiotherapy was clearly the most significant factor affecting both OS and PFS. Conclusion: This retrospective analysis demonstrates that radiotherapy can be effective for patients in PR after fully dosed chemotherapy; assessment in a randomized trial (radiotherapy vs. ASCT) is justified.

  15. Sodium Arsenite ± Hyperthermia Sensitizes p53-Expressing Human Ovarian Cancer Cells to Cisplatin by Modulating Platinum-DNA Damage Responses

    PubMed Central

    Muenyi, Clarisse S.; Pinhas, Allan R.; Fan, Teresa W.; Brock, Guy N.; Helm, C. William; States, J. Christopher

    2012-01-01

    Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer death in the United States. Cisplatin is a DNA damaging agent initially effective against EOC but limited by resistance. P53 plays a critical role in cellular response to DNA damage and has been implicated in EOC response to platinum chemotherapy. In this study, we examined the role of p53 status in EOC response to a novel combination of cisplatin, sodium arsenite, and hyperthermia. Human EOC cells were treated with cisplatin ± 20μM sodium arsenite at 37°C or 39°C for 1 h. Sodium arsenite ± hyperthermia sensitized wild-type p53-expressing (A2780, A2780/CP70, OVCA 420, OVCA 429, and OVCA 433) EOC cells to cisplatin. Hyperthermia sensitized p53-null SKOV-3 and p53-mutant (OVCA 432 and OVCAR-3) cells to cisplatin. P53 small interfering RNA (siRNA) transfection abrogated sodium arsenite sensitization effect. XPC, a critical DNA damage recognition protein in global genome repair pathway, was induced by cisplatin only in wild-type p53-expressing cells. Cotreatment with sodium arsenite ± hyperthermia attenuated cisplatin-induced XPC in wild-type p53-expressing cells. XPC siRNA transfection sensitized wild-type p53-expressing cells to cisplatin, suggesting that sodium arsenite ± hyperthermia attenuation of XPC is a mechanism by which wild-type p53-expressing cells are sensitized to cisplatin. Hyperthermia ± sodium arsenite enhanced cellular and DNA accumulation of platinum in wild-type p53-expressing cells. Only hyperthermia enhanced platinum accumulation in p53-null cells. In conclusion, sodium arsenite ± hyperthermia sensitizes wild-type p53-expressing EOC cells to cisplatin by suppressing DNA repair protein XPC and increasing cellular and DNA platinum accumulation. PMID:22331493

  16. 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. PMID:27214593

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

    PubMed Central

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

    1999-01-01

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

  18. SIRT1 overexpression decreases cisplatin-induced acetylation of NF-{kappa}B p65 subunit and cytotoxicity in renal proximal tubule cells

    SciTech Connect

    Jung, Yu Jin; Lee, Jung Eun; Lee, Ae Sin; Kang, Kyung Pyo; Lee, Sik; Park, Sung Kwang; Lee, Sang Yong; Han, Myung Kwan; Kim, Duk Hoon; Kim, Won

    2012-03-09

    Highlights: Black-Right-Pointing-Pointer Cisplatin increases acetylation of NF-{kappa}B p65 subunit in HK2 cells. Black-Right-Pointing-Pointer SIRT1 overexpression decreases cisplatin-induced p65 acetylation and -cytotoxicity. Black-Right-Pointing-Pointer Resveratrol decreased cisplatin-induced cell viability through deacetylation of p65. -- Abstract: As the increased acetylation of p65 is linked to nuclear factor-{kappa}B (NF-{kappa}B) activation, the regulation of p65 acetylation can be a potential target for the treatment of inflammatory injury. Cisplatin-induced nephrotoxicity is an important issue in chemotherapy of cancer patients. SIRT1, nicotinamide adenine dinucleotide (NAD{sup +})-dependent protein deacetylase, has been implicated in a variety of cellular processes such as inflammatory injury and the control of multidrug resistance in cancer. However, there is no report on the effect of SIRT1 overexpression on cisplatin-induced acetylation of p65 subunit of NF-{kappa}B and cell injury. To investigate the effect of SIRT1 in on cisplatin-induced acetylation of p65 subunit of NF-{kappa}B and cell injury, HK2 cells were exposed with SIRT1 overexpression, LacZ adenovirus or dominant negative adenovirus after treatment with cisplatin. While protein expression of SIRT1 was decreased by cisplatin treatment compared with control buffer treatment, acetylation of NF-{kappa}B p65 subunit was significantly increased after treatment with cisplatin. Overexpression of SIRT1 ameliorated the increased acetylation of p65 of NF-{kappa}B during cisplatin treatment and cisplatin-induced cytotoxicity. Further, treatment of cisplatin-treated HK2 cells with resveratrol, a SIRT1 activator, also decreased acetylation of NF-{kappa}B p65 subunit and cisplatin-induced increase of the cell viability in HK2 cells. Our findings suggests that the regulation of acetylation of p65 of NF-{kappa}B through SIRT1 can be a possible target to attenuate cisplatin-induced renal cell damage.

  19. Inhibition of anandamide hydrolysis attenuates nociceptor sensitization in a murine model of chemotherapy-induced peripheral neuropathy

    PubMed Central

    Uhelski, Megan L.; Khasabova, Iryna A.

    2014-01-01

    Painful neuropathy frequently develops as a consequence of commonly used chemotherapy agents for cancer treatment and is often a dose-limiting side effect. Currently available analgesic treatments are often ineffective on pain induced by neurotoxicity. Although peripheral administration of cannabinoids, endocannabinoids, and inhibitors of endocannabinoid hydrolysis has been effective in reducing hyperalgesia in models of peripheral neuropathy, including chemotherapy-induced peripheral neuropathy (CIPN), few studies have examined cannabinoid effects on responses of nociceptors in vivo. In this study we determined whether inhibition of fatty acid amide hydrolase (FAAH), which slows the breakdown of the endocannabinoid anandamide (AEA), reduced sensitization of nociceptors produced by chemotherapy. Over the course of a week of daily treatments, mice treated with the platinum-based chemotherapy agent cisplatin developed robust mechanical allodynia that coincided with sensitization of cutaneous C-fiber nociceptors as indicated by the development of spontaneous activity and increased responses to mechanical stimulation. Administration of the FAAH inhibitor URB597 into the receptive field of sensitized C-fiber nociceptors decreased spontaneous activity, increased mechanical response thresholds, and decreased evoked responses to mechanical stimuli. Cotreatment with CB1 (AM281) or CB2 (AM630) receptor antagonists showed that the effect of URB597 was mediated primarily by CB1 receptors. These changes following URB597 were associated with an increase in the endocannabinoid anandamide in the skin. Our results suggest that enhanced signaling in the peripheral endocannabinoid system could be utilized to reduce nociceptor sensitization and pain associated with CIPN. PMID:25505113

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

    PubMed

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

    2016-05-01

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

  1. Computational metallomics of the anticancer drug cisplatin.

    PubMed

    Calandrini, Vania; Rossetti, Giulia; Arnesano, Fabio; Natile, Giovanni; Carloni, Paolo

    2015-12-01

    Cisplatin, cis-diamminedichlorido-platinum(II), is an important therapeutic tool in the struggle against different tumors, yet it is plagued with the emergence of resistance mechanisms after repeated administrations. This hampers greatly its efficacy. Overcoming resistance problems requires first and foremost an integrated and systematic understanding of the structural determinants and molecular recognition processes involving the drug and its cellular targets. Here we review a strategy that we have followed for the last few years, based on the combination of modern tools from computational chemistry with experimental biophysical methods. Using hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) simulations, validated by spectroscopic experiments (including NMR, and CD), we have worked out for the first time at atomic level the structural determinants in solution of platinated cellular substrates. These include the copper homeostasis proteins Ctr1, Atox1, and ATP7A. All of these proteins have been suggested to influence the pre-target resistance mechanisms. Furthermore, coupling hybrid QM/MM simulations with classical Molecular Dynamics (MD) and free energy calculations, based on force field parameters refined by the so-called "Force Matching" procedure, we ha