s-1-(combination) and Digestive-System-Neoplasms

S-1 is an oral antitumor agent that contains tegafur, which is converted to fluorouracil (5-FU) in the human body. Cytochrome P450 2A6 (CYP2A6) is the principal enzyme responsible for bioconversion of tegafur to 5-FU. A number of CYP2A6 polymorphisms have been associated with variations in enzyme activity in several ethnic populations. The CYP2A6*4C allele leads to deletion of the entire CYP2A6 gene, and is the main finding in patients with reduced CYP2A6 enzymatic activity. Thus, the aim of our study was to evaluate the allele frequencies of CYP2A6 polymorphisms in a population with cancer of the digestive system. We developed a simple screening method, which combined TA cloning and direct-sequencing, to detect CYP2A6 genetic polymorphisms in Chinese patients with cancers of the digestive system. A total of 77 patients with various types of digestive system cancers were screened for CYP2A6 genetic polymorphisms. The allele frequencies of CYP2A6*1A, CYP2A6*1B and CYP2A6*4C in the 77 patients screened were 62, 42 and 13%, respectively. Frequencies of the homozygous genotypes for CYP2A6*1A and CYP2A6*4C were 27 and 12%, respectively. As expected, patients that were determined to be homozygous for CYP2A6*4C exhibited the characteristic chemotherapy efficacy and toxicity profiles. The TA cloning-based direct sequencing method facilitated allele frequency and genotyping determination for CYP2A6*1A, 1B and 4C of cancer patients. The findings indicated that the population carries a high frequency of the CYP2A6*4C homozygous genotype. Thus, the reduced efficacy of standard chemotherapy dosage in Chinese cancer patients may be explained by the lack of CYP2A6-mediated S-1 bioconversion to 5-FU.

Topics: Adolescent; Adult; Aged; Antimetabolites, Antineoplastic; Aryl Hydrocarbon Hydroxylases; Base Sequence; Cytochrome P-450 CYP2A6; Digestive System Neoplasms; Drug Combinations; Female; Gene Frequency; Genotype; Humans; Male; Middle Aged; Molecular Sequence Data; Oxonic Acid; Polymorphism, Genetic; Tegafur; Treatment Outcome; Young Adult

Recently, in drug therapy for patients with advanced digestive cancer, S-1 (tegafur x gimeracil x oteracil potassium) alone or S-1 combined with other chemotherapeutic agents (S-1+alpha) is prescribed. However, many patients are often forced to give up long-term S-1 treatment owing to high incidence rates of adverse effects. The purpose of this study was to evaluate the efficacy of superfine dispersed lentinan (SDL) for the suppression of adverse effects of S-1 or S-1+alpha.. The subjects were 72 patients who had unresectable or recurrent advanced digestive cancer. The subject group consisted of 45 men and 27 women, with a median age of 64 (31-85) years; 29 gastric, 25 colorectal, 10 pancreatic and 8 other digestive cancer patients. Thirty -one patients were administered S-1 alone and 41 patients were administered S-1+alpha. SDL (15mg of lentinan/bag/day) was orally administered to all patients for 12 weeks. Adverse events and overall survival time were evaluated according to the CTCAE ver 3.0 and the Kaplan-Meier method, respectively.. Seventy-two patients were enrolled in this study. Adverse events which had an undeniable causal relationship to SDL were observed in 2 patients (2.7 %, constipation [Grade 2] and nausea [Grade 1]) out of 72 patients; all of the events were not severe and disappeared when the SDL administration was discontinued. Adverse events associated with S-1 or S-1+ alpha were observed in 9 patients (12.5% ) (11 events) out of 72 patients. Grade 3 adverse events were observed in 3 patients (4.2% ) (leukopenia, 2; thrombocytopenia, 1). Incidence rates of both hematological and nonhematological adverse events were very low. In no gastrointestinal toxicity associated with S-1 or S-1+alpha was observed, which was estimated to be an effect of SDL combination. Mean survival times in gastric cancer and colorectal cancer patients were 9. 5 months (95%confidential interval [CI], 7.0-22.4 months) and 18.4 months (95% CI, 13.2 -28.5 months), respectively.. From the results of the present study, SDL is considered completely free of anything harmful to advanced digestive cancer patients and is effective for the suppression of adverse effects of S-1 or S-1+alpha therapy. It is suggested that SDL can prolong the administration period of S-1 and, as a result, contribute to prolongation of survival in patients with advanced digestive cancer.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Colorectal Neoplasms; Digestive System Neoplasms; Drug Combinations; Drug Therapy, Combination; Female; Humans; Lentinan; Male; Middle Aged; Oxonic Acid; Pancreatic Neoplasms; Stomach Neoplasms; Tegafur