Ribonucleotide reductase subunit M1 assessed by quantitative double-fluorescence immunohistochemistry predicts the efficacy of gemcitabine in biliary tract carcinoma (original) (raw)
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World Journal of Surgical Oncology, 2013
Background: Gemcitabine is a pyrimidine nucleoside analog that is a commonly used chemotherapeutic agent for unresectable or recurrent biliary tract cancer (BTC). Several molecules involved in gemcitabine metabolism, including human equilibrative nucleoside transporter (hENT1), deoxycytidine kinase (dCK), and ribonucleotide reductase subunit M1 (RRM1), have been investigated as predictive biomarkers of gemcitabine efficacy, mostly in pancreatic cancer. The aim of this study is to clarify which biomarker is the most reliable among hENT1, dCK, and RRM1 to predict survival in patients with advanced BTC treated with gemcitabine alone.
International Journal of Cancer, 2007
Pancreatic cancer is the most lethal of all solid tumors partially because of its chemoresistance. Although gemcitabine is widely used as a first selected agent for the treatment of this disease despite low response rate, molecular mechanisms of gemcitabine resistance in pancreatic cancer still remain obscure. The aim of this study is to elucidate the mechanisms of gemcitabine resistance. The 81-fold gemcitabine resistant variant MiaPaCa2-RG was selected from pancreatic cancer cell line MiaPaCa2. By microarray analysis between MiaPaCa2 and MiaPaCa2-RG, 43 genes (0.04%) were altered expression of more than 2-fold. The most upregulated gene in MiaPaCa2-RG was ribonucleotide reductase M1 subunit (RRM1) with 4.5-fold up-regulation. Transfection with RRM1-specific RNAi suppressed more than 90% of RRM1 mRNA and protein expression. After RRM1-specific RNAi transfection, gemcitabine chemoresistance of MiaPaCa2-RG was reduced to the same level of MiaPaCa2. The 18 recurrent pancreatic cancer patients treated by gemcitabine were divided into 2 groups by RRM1 levels. There was a significant association between gemcitabine response and RRM1 expression (p 5 0.018). Patients with high RRM1 levels had poor survival after gemcitabine treatment than those with low RRM1 levels (p 5 0.016). RRM1 should be a key molecule in gemcitabine resistance in human pancreatic cancer through both in vitro and clinical models. RRM1 may have the potential as predictor and modulator of gemcitabine treatment. ' 2006 Wiley-Liss, Inc.
Chemotherapy with Gemcitabine in Advanced Biliary Tract Carcinoma
Reviews on Recent Clinical Trials, 2008
Background: Biliary tract carcinoma is infrequent; usually majority of cases are detected in an advanced phase of the disease, thus surgical resection is not feasible and prognosis is poor, mean survival is 6 months and, chemotherapy is the main therapeutic option. Objective: An overall review of all clinical trials published regarding gemcitabine, alone or in combination, as a treatment in advanced biliary tract carcinoma. Results: Gemcitabine has been reported as a single drug, in 12 trials and as a combination in 21 studies. As a single agent it has been evaluated in a 30 minute infusion, biweekly administration, fixed infusion [10 mg/m 2 /min] or as a prolonged infusion [24 hours]. Objective response has been reported between 0 and 36%, stable disease 13 to 15%, time to progression 2-10.7 months, overall survival 4 to 14 months. Chemotherapy combinations based on gemcitabine have been evaluated with several agents, among them were 5-FU, mitomycin oxaliplatin, capecitabine, cisplatin, docetaxel and irinotecan; the objective response seen: 9.3% to 64%, stable disease 9.3% to 53%, time to progression 3-10 months and overall survival 4.7 to 18 months. Conclusion: Gemcitabine is an effective drug in advanced biliary tract carcinoma with a low toxicity profile. It should be considered as the standard treatment for unresectable or metastatic disease while awaiting phase III results.
Biomolecules
Biliary tract cancer (BTC) compromises a heterogenous group of tumors with poor prognoses. Curative surgery remains the first choice for localized disease; however, most BTC patients have had unresectable or metastatic disease. The gold standard therapy for these patients is chemotherapy with gemcitabine and cisplatin. There are no consensus guidelines for standard treatment in a second-line setting, although the data of the ABC-06 trial showed a slight survival benefit from oxaliplatin and 5-fluorouracil combination chemotherapy. Recent progress in comprehensive genomic profiling for advanced BTC (ABTC) has helped to clarify tumorigenesis and facilitate the coming era of precision medicine. Generally, targeted agents fail to show significant clinical benefits in unselected populations. Only fibroblast growth factor receptor 2 (FGFR2) fusion and isocitrate dehydrogenase (IDH)- and BRAF mutation-enriched populations have survival benefits from the corresponding inhibitors. Several in...
Current Cancer Drug Targets, 2011
Pancreatic cancer is one of the most lethal cancers, where curative surgical resections are rare and less than 5% of patients experience long-term survival. Despite numerous clinical trials, improvements in the systemic treatment of this disease have been limited. Gemcitabine, a nucleoside analogue, is still considered the standard of care chemotherapy for most patients in the advanced disease setting. To exert its cytotoxic effects, gemcitabine must enter cells via nucleoside transporters, most notably human equilibrative nucleoside transporter 1 (hENT1). Increasingly strong evidence suggests hENT1 is a prognostic biomarker in gemcitabine-treated pancreatic cancer, and may well be a predictive biomarker of gemcitabine efficacy. In this review, we synthesize the literature surrounding hENT1 in pancreatic cancer, identify the key outstanding questions, and suggest strategies to prospectively evaluate the clinical utility of hENT1 in future clinical studies.
A Phase II study of gemcitabine and cisplatin in advanced biliary tract cancer
Cancer, 2006
BACKGROUND. The authors performed a Phase II study of combination chemotherapy with gemcitabine and cisplatin in patients with inoperable biliary tract cancer to evaluate efficacy and toxicity of this combination. In addition, the correlation between the CA 19-9 response and clinical outcome was analyzed.
Phase II study of gemcitabine and cisplatin in advanced biliary tract cancer
Journal of Gastroenterology and Hepatology, 2006
Background: The aim of this phase II study was to determine the efficacy of gemcitabine plus cisplatin chemotherapy in patients with advanced biliary tract cancer.Methods: Eligibility criteria included histologically confirmed adenocarcinoma with measurable tumor in the biliary tract that was unresectable and either locally advanced or metastatic. Patients received a combination of gemcitabine (1000 mg/m2 intravenously [IV] on days 1, 8, and 15) and cisplatin (75 mg/m2 IV on day 1). Cycles were repeated every 28 days. Objective tumor response rates and toxicities were evaluated according to World Health Organization criteria.Results: Twenty-seven patients were enrolled in the study and a total of 120 cycles of chemotherapy were administrated. Objective partial response was observed in nine (33.3%) patients, while stable disease was found in seven (25.9%) patients. The median survival time was 10.0 months and the 1-year survival rate was 36%. Median time to disease progression was 5.6 months. The most common grade 3–4 toxicities were leukopenia (25.9%), anemia (29.6%), thrombocytopenia (22.2%), and vomiting (18.5%). Only one patient was hospitalized for chemotherapy-related complications.Conclusion: Gemcitabine and cisplatin combination chemotherapy is an effective, safe, and well-tolerated regimen for the treatment of advanced biliary tract cancer.