s-1-(combination) and Sarcoma-180

The combination of S-1, consisting of 1 mol/l tegafur, 0.4 mol/l 5-chloro-2,4-dihydroxypyridine and 1 mol/l potassium oxonate, plus low-dose cisplatin has showed promising anti-tumor activities in experimental and clinical studies. The aim of this study was to investigate the mechanism of this combination chemotherapy. Mice bearing sarcoma-180 cells were divided into groups of seven animals each - Group A: no treatment; Group B: 5-fluorouracil (5-FU) 10 mg/kg continuous i.p. infusion; Group C: S-1 10 mg/kg p.o.; Group D: cisplatin 0.2 mg/kg i.p.; Group E: B+D; Group F: C+D. Treatments were given for 5 consecutive days, and then anti-tumor activity, the concentration of 5-FU, the thymidylate synthase inhibition rate (TSIR) and the level of 5-FU incorporated into RNA (F-RNA) in tumor tissue were evaluated. Anti-tumor activity in Group F was higher than in any other group. A significantly higher concentration of 5-FU in tumor was detected in the S-1-treated groups (C and F) than in the 5-FU-treated groups (B and E). No differences in TSIR were observed between the groups treated with 5-FU or S-1 with or without cisplatin; however, the F-RNA level in Group F was about 1.24 times significantly higher than that in Group C. Group F showed the highest anti-tumor activity, with increasing intratumoral levels of 5-FU and F-RNA, but not that of TSIR. These results suggested that the superior anti-tumor activity obtained by S-1+cisplatin might be associated with an incorporation of 5-FU into RNA.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cisplatin; Drug Combinations; Fluorouracil; Male; Mice; Mice, Inbred Strains; Oxonic Acid; Pyridines; RNA, Neoplasm; Sarcoma 180; Tegafur; Thymidine Kinase; Uridine Triphosphate

TS-1 contains tegaful (FT), 5-chloro-2,4-dihydroxypyridine (CDHP; an inhibitor of 5-fluorouracil (5-FU) degradation) and potassium oxonate (Oxo; an inhibitor of 5-FU assimilation mainly in the digestive tract) in a molar ratio of 1:0.4:1. We evaluated the combination of TS-1 and low-dose cisplatin on mouse sarcoma. Male ddy strain mice at 6 weeks of age were s.c. transplanted with 5 x 106 sarcoma-180 (S-1800) cells and divided into groups of seven animals each: Group A, no treatment; Group B, 5-FU alone by continuous i.p. infusion of 10 mg/kg with a minipump (Alzet); Group C, TS-1 10 mg/kg p.o. alone; Group D, cisplatin 0.2 mg/kg i.p. alone; Group E, B+D; Group F, C+D. Treatment was given for 5 days. Antitumor activity was evaluated on the basis of the tumor weight on day 8, and white blood cell count, red blood cell count, platelet count, BUN, GOT and GPT were determined to detect adverse effects. Tumor weights (g, mean+/-SD) were 0.54+/-0.15 in Group A, 0.52+/-0.17 in Group B, 0.34+/-0.05 in Group C, 0.46+/-0.12 in Group D, 0.34+/-0.07 in Group E and 0.16+/-0.03 in Group F. There were no noticeable adverse effects. The combined TS-1+cisplatin regimen showed considerably enhanced antitumor activities since sarcomas were significantly (p<0.05) decreased as compared with tissue. Mean AUC(0-12) (ng/ml.h) estimated in the groups receiving 5-FU+cisplatin or TS-1 alone was measured to calculate AUC(0-12) by the trapezoidal rule. 5-FU concentrations in blood and tumor from blood concentration data were 435 in Group B, 2651 in Group C, 343 in Group E and 1538 in Group F, while mean AUC(0-12) (ng/g.h) estimated from tumor tissue concentration data were 345 in Group B, 3548 in Group C, 324 in Group E and 2020 in Group F. Cisplatin acted as a modulator of 5-FU, suggesting clinical benefits of the combination of TS-1 and low-dose daily cisplatin.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Cisplatin; Dose-Response Relationship, Drug; Drug Combinations; Fluorouracil; Male; Mice; Oxonic Acid; Pyridines; Sarcoma 180; Tegafur; Tissue Distribution