gimeracil and Colorectal-Neoplasms

Colorectal carcinoma is an important cause of cancer morbidity and mortality. 5-fluorouracil has been the major chemotherapeutic agent for the treatment of colorectal carcinoma for the past four decades. This regimen is noncurative, and its impact on survival is unclear. Attempts at identifying more effective chemotherapeutic agents for colorectal cancer have yielded oral formulations and prodrugs of 5-fluorouracil with apparently equivalent efficacy. Specific thymidylate synthase inhibitors are now available. Platinum analogues with activity in colorectal carcinoma, and no cross-resistance to the antimetabolites have also been developed. The topoisomerase I inhibitors represent a new class of agents with a novel mechanism of action. These agents are in phase II and Phase III clinical trials, others have been approved for clinical use within the last 3 years.

Topics: Antineoplastic Agents; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Fluorouracil; Glutamates; Guanine; Humans; Pemetrexed; Platinum Compounds; Pyridines; Quinazolines; Tegafur; Thiophenes; Uracil

5-Fluorouracil (5-FU) has been the mainstay of systemic therapy for colorectal cancer since its initial development 40 years ago. Efforts to improve the therapeutic index of 5-FU have included alteration of schedule and addition of biochemical modulators. An understanding of 5-FU mechanisms of action has resulted in major therapeutic advances in the past 10 years; however, a plateau has been reached in the efficacy of 5-FU, mandating a paradigm shift for those involved in colorectal cancer drug development. One direction vigorously pursued is the development of orally administered fluoropyrimidines that maintain or improve upon the effectiveness of intravenous 5-FU. In this paper the preclinical and clinical development of oral fluoropyrimidines and their modulators is reviewed, including UFT, capecitabine, ethynyluracil and S-1.

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Enzyme Inhibitors; Fluorouracil; Humans; Oxidoreductases; Pyridines; Tegafur; Uracil

To analyze the therapeutic actions of tegafur gimeracil oteracil combined with oxaliplatin for treating patients with advanced colorectal cancer, and its effects on the K-ras gene mutation and the CK20 mRNA.. Forty-one patients with advanced colorectal cancer from our hospital, from October 2013 to October 2014, were enrolled in this study. After obtaining consent from the hospital Ethics Committee and the patients as well as their relatives, all 41 patients were divided into two groups. The control group, which consisted of 20 cases, were treated with capecitabine combined with oxaliplatin. The study group, which comprised of 21 cases, were treated with tegafur gimeracil oteracil combined with oxaliplatin. Both groups were followed-up after six months to evaluate the treatment outcomes.. The survival rate in the observation group was higher than that in the control group. The progression-free survival time (PFS) in the observation group was longer than that in the control group. The objective response rate (ORR) and disease control rate (DCR) were higher for the observation group. The differences had statistical significance (p < 0.05). The proportion of K-ras gene mutation in the observation group was substantially superior to that in the control group. The positive expression rate of CK 20 mRNA in the observation group was significantly lower than that in the control group. The differences had statistical significance (p < 0.05). The incidence of adverse reaction in the observation group was lower than that of the control group, and the differences had statistical significance (p < 0.05).. Tegafur/gimeracil/oteracil combined with oxaliplatin therapy had better treatment outcomes than capecitabine combined oxaliplatin for advanced colorectal cancer. This maybe related to K-ras gene mutation and the reduction of CK20 mRNA expression.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Female; Humans; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pyridines; Tegafur

Acquired resistance to 5-fluorouracil (5-FU) is one of the important reasons for failure in 5-FU-based chemotherapy. The upregulation of dihydropyrimidine dehydrogenase (DPD) in tumours was reported as an important factor for acquired 5-FU resistance. The aim of this study is to examine whether intra-hepatic DPD was involved in acquired 5-FU resistance.. HT-29 human colorectal xenograft tumours were established in nude mice. After long-term exposure to 5-FU, some of the tumour became "resistant" and the others remained "sensitive" to 5-FU. DPD expression levels in the livers and tumours of "resistant", "sensitive" or untreated mice were examined, and pharmacokinetics of 5-FU in rats' plasma were investigated. Gimeracil, a DPD inhibitor, was checked whether it could reverse the reduced bioavailability of 5-FU.. DPD expression was upregulated obviously in tumours of "resistant" mice as reported previously. Importantly, DPD expression was also upregulated significantly in livers of "resistant" mice, compared with those of "sensitive" or untreated mice. Furthermore, the upregulation of DPD expression in livers led to accelerated metabolism of 5-FU. Gimeracil was found to reverse the reduced serum 5-FU concentration. The cultured tumour cells from 5-FU treated mice showed relative sensitivity to higher concentration of 5-FU, even the "resistant" tumour cells.. Our study suggested that the upregulation of DPD in liver may be involved in acquired resistance to 5-FU, and DPD inhibitors or increasing 5-FU dosage may have potential application in overcoming 5-FU acquired resistance.

Topics: Animals; Antimetabolites, Antineoplastic; Blotting, Western; Cell Proliferation; Colorectal Neoplasms; Dihydrouracil Dehydrogenase (NADP); Drug Resistance, Neoplasm; Female; Fluorouracil; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Liver; Mice; Mice, Inbred BALB C; Mice, Nude; Pyridines; Rats; Reverse Transcriptase Polymerase Chain Reaction; Tumor Burden; Up-Regulation; Xenograft Model Antitumor Assays