levoleucovorin and 5-fluoropyrimidine

Topics: Animals; Antineoplastic Agents; Colorectal Neoplasms; Drug Synergism; Floxuridine; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Prodrugs; Pyrimidines; Thymidylate Synthase

To evaluate the efficacy and safety of FOLFIRI regimen in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin.. The FOLFIRI regimen consisted of intravenous infusion of irinotecan 180 mg/m(2) on day 1 plus leucovorin (LV) 400 mg/m(2) on day 1 plus 5-fluorouracil (5-FU) 400 mg/m(2) bolus on day 1 plus 46-hour intravenous infusion of 5-FU 2,400 mg/m(2), every 2 weeks as one cycle. The main selection criterion for this study was the advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin.. Of the 57 evaluable patients for efficacy, 4 (7.5%) had a partial response, 36 (67.9%) had stable disease, and 13 (24.5%) had progressive disease. Median progression-free survival was 4.8 months (95% CI 3.9-5.7 months), and median overall survival was 7.8 months (95% CI 13.1-16.5 months). Safety analysis was based on the data of 57 evaluable patients. The most frequently observed grade 3 or 4 toxicities were neutropenia 16 (27.8%), nausea/vomiting 7 (12.3%), and diarrhea 1 (1.8%).. FOLFIRI regimen is effective and well tolerated in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin in Chinese population.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; China; Colorectal Neoplasms; Diarrhea; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Nausea; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Pyrimidines; Survival; Vomiting; Young Adult

To evaluate the efficacy and safety of modified FOLFIRI regimen in advanced colorectal cancer (CRC) patients refractory to fluoropyrimidine and oxaliplatin.. The modified FOLFIRI regimen consisted of intravenous infusion of irinotecan 180 mg/m2 d1 + LV 200 mg/m2 dl + 5-Fu 400 mg/m2 bolus dl plus 46-hour intravenous infusion of 5-Fu 2.4 g/m2, every 2 weeks as one cycle. The main selection criterion for this study was the advanced CRC refractory to fluoropyrimidine and oxaliplatin.. Of the 80 evaluable patients for efficacy: 10 (12.5%) had a partial response, 51 (63.7%) stable disease, and 19 (23.8%) progressive disease. The median time to progression was 96 days. Safety analysis was based on the data of 83 evaluable patients. The most frequently observed grade 3 or 4 toxicities were neutropenia (24.1%), nausea/vomiting (8.4%), and diarrhea (2.4%).. Modified FOLFIRI regimen is effective and well tolerated in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Diarrhea; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Nausea; Neoplasm Staging; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Prospective Studies; Pyrimidines; Rectal Neoplasms; Remission Induction; Treatment Failure

5-Fluorouracil (5-FU) and capecitabine are fluoropyrimidine derivatives that mainly metabolized with dihydropyrimidine dehydrogenase enzyme (DPD). The genetic polymorphism in the genes encoding this enzyme may result in a decrease or loss of enzyme activity which may lead to the accumulation of medicines, their metabolites and potential toxicity.. This cross-sectional study was conducted on 88 participants with colorectal cancer (CRC). After DNA extraction, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to determine the DPD gene (DPYD) polymorphisms including IVS 14 + 1 G > A, 2846 A > T and 2194 G > A. Chemotherapy-induced side effects were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE Version 5.0).. Data were collected from 227 chemotherapy cycles of 88 patients with CRC. In a comparison of FOLFOX and FOLFIRI regimens, there was no significant difference in the occurrence of chemotherapy-induced diarrhea, nausea, vomiting and oral mucositis. However, the peripheral neuropathy was more frequent in patients who were treated with FOLFOX (P <  0.001) and hair loss was more common in patients who received FOLFIRI regimen (P = 0.048). Incidence of the DPD IVS14 + 1 G > A polymorphism was observed in four patients (5.5%). There was no association between IVS14 + 1 G > A polymorphism and the occurrence of adverse reactions.. FOLFOX and FOLFIRI were the most common regimens in CRC patients and their toxicity profile was different in some adverse reactions. Prevalence of IVS14 + 1G > A variant was relatively higher than other similar studies.. Approval code; IR.MAZUMS.REC.95.2480.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Cross-Sectional Studies; Dihydrouracil Dehydrogenase (NADP); Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Pyrimidines

According to some guidelines for the management of gastric cancer, adjuvant chemotherapy is recommended for patients with pT3-4 or node-positive disease. The aim of this study was to define low- and high-risk groups in terms of survival, and to predict the benefit of adjuvant fluoropyrimidine plus oxaliplatin (F-OX) chemotherapy.. Patients with pT3-4 or node-positive gastric cancer after gastrectomy with D2 lymphadenectomy between 2000 and 2013 were included. The performance of a previously published nomogram was assessed by discrimination and calibration. Patients were stratified into risk groups on the basis of the nomogram-predicted overall survival probability. The efficacy of F-OX within each risk subgroup was assessed using the log rank test and Cox regression analysis weighted by inverse propensity score.. Some 1464 patients were included. The nomogram showed better discrimination than the seventh AJCC staging classification (concordance index 0·72 versus 0·68 respectively; P = 0·008) and accurate calibration. F-OX was not associated with improved survival in patients in the low-risk group, whereas it reduced the risk of death by over 20 per cent in the intermediate- and high-risk groups (P = 0·036 and P < 0·001 respectively) (P for interaction = 0·014).. A nomogram can aid in individualized decision-making regarding the administration of F-OX after gastrectomy for cancer.

Topics: Aftercare; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; China; Clinical Decision-Making; Deoxycytidine; Female; Fluorouracil; Gastrectomy; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Nomograms; Organoplatinum Compounds; Oxaloacetates; Patient Selection; Postoperative Care; Pyrimidines; Stomach Neoplasms

CCRF-CEM human leukemia sublines resistant to short-term methotrexate (MTX) exposure as a result of decreased folylpolyglutamate synthetase (FPGS) activity were examined for their response to other cytotoxic agents. The R3/7 and R30dm sublines display 25 and 1%, respectively, of the FPGS activity of CCRF-CEM cells as measured with MTX in vitro. Response to agents in outgrowth experiments was examined under both continuous exposure (120 h, where MTX resistance is not observed) and short-term (6-14.5 h) exposure. During continuous exposure to various classes of agents, cross-resistance of R3/7 and R30dm that correlated with FPGS level was not observed, although some minor (< or = 3-fold) stochastic variations in sensitivity were noted. These agents included actinomycin D, Adriamycin, etoposide, vincristine, cisplatin, cytosine arabinoside, 5-fluorouracil, and some other antifolates. Cross-resistance during continuous exposure that did correlate with FPGS level was noted, however, to glutamate-containing thymidylate synthase inhibitors (including ICI D1694) and, to a minor extent, to 6-mercaptopurine and 5-fluorodeoxyuridine. Slight collateral sensitivity during continuous exposure that apparently correlated with FPGS level was noted to the lipid-soluble antifolate trimetrexate and to 5,8-dideazapteroyl-L-ornithine, an FPGS-specific inhibitor. In short-term exposures (where MTX resistance of the sublines is observed), the resistant sublines displayed sensitivity or cross-resistance to each agent that was qualitatively similar to that observed for the same agent in continuous exposure. Because of the requirement for reduced folates in the anti-DNA mechanism of action of fluoropyrimidines and the current clinical use of leucovorin (LV) to enhance their effects, the interaction of LV and fluoropyrimidines was examined. The results suggest that even highly FPGS-deficient cells are as sensitive to the effects of LV modulation as are wild-type cells even at fluoropyrimidine exposure times as short as 4 h.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Cell Division; Drug Resistance; Folic Acid Antagonists; Humans; Leucovorin; Methotrexate; Peptide Synthases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; Quinazolines; Tetrahydrofolates; Thiophenes; Tumor Cells, Cultured

The biomodulators leucovorin and dipyridamole potentiate the cytotoxicity of 5-fluorodeoxyuridine (FdUrd) and 5-fluorouracil (5-FU), respectively. It was hypothesized that these biomodulators would increase fluoropyrimidine-mediated radiosensitization. This hypothesis was tested using cultured HT29 human colon cancer cells. As was predicted, leucovorin increased both FdUrd-mediated cytotoxicity and radiosensitization. The increase in radiation sensitivity was associated with a decrease in the repair of radiation-induced DNA double strand breaks (DSB's). Dipyridamole potentiated the cytotoxicity produced by 5-FU. However, dipyridamole appeared to confer slight protection from irradiation, thus decreasing 5-FU-mediated radiosensitization. This demonstrates that the simple fact that a biomodulator can increase fluoropyrimidine-induced cytotoxicity does not guarantee a corresponding increase in radiation sensitivity. Clinical trials combining fluoropyrimidines and their biomodulators will need to take these potentially complex interactions into account.

Topics: Adenocarcinoma; Colonic Neoplasms; Combined Modality Therapy; Dipyridamole; DNA Repair; DNA, Neoplasm; Drug Synergism; Humans; Leucovorin; Pyrimidines; Radiation Tolerance; Radiation-Sensitizing Agents; Tumor Cells, Cultured

Leucovorin augments the growth inhibitory effect of 5-fluoropyrimidines on neoplastic cells. The effect is paralleled by much higher levels of DNA fragmentation than in cells treated with 5-fluoropyrimidines alone at the same concentration. The lesions are induced by a mechanism independent of incorporation of the drug into DNA, in all probability due to reduced repair of DNA lesions induced independently of the drug treatment. Thymidine added after the treatment with fluoropyrimidines partly rescues the cells and reduces the level of DNA fragmentation.

Topics: Adenocarcinoma; Aphidicolin; Cell Line; Cell Survival; Colonic Neoplasms; Diterpenes; DNA; DNA Damage; Drug Synergism; Floxuridine; Fluorouracil; Humans; Leucovorin; Pyrimidines; Thymidine