Enhancement of the anti-tumor activity of S-1 by low-dose cisplatin in mice bearing the sarcoma-180 model.
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.
Yurimoto
Satoshi
S
Department of Coloproctological Surgery, Juntendo University School of Medicine, Tokyo, Japan, Ibaraki, Japan.
Miyakawa
Akira
A
Okuzawa
Atsushi
A
Sakamoto
Shuichi
S
Sakamoto
Kazuhiro
K
Hosoda
Seiya
S
Kamano
Toshiki
T
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001835:Body Weight; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use*; D004338:Drug Combinations; D005472:Fluorouracil / Q000032:analysis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010094:Oxonic Acid / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D012334:RNA, Neoplasm / Q000032:analysis; D012510:Sarcoma 180 / Q000737:chemistry / Q000188:drug therapy* / Q000201:enzymology; D005641:Tegafur / Q000627:therapeutic use*; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors; D014544:Uridine Triphosphate / Q000031:analogs & derivatives / Q000032:analysis
D004338:Drug Combinations; D011725:Pyridines; D012334:RNA, Neoplasm; C079198:S 1 (combination); D005641:Tegafur; C025635:5-fluorouridine 5'-triphosphate; D010094:Oxonic Acid; D013937:Thymidine Kinase; D002945:Cisplatin; D005472:Fluorouracil; D014544:Uridine Triphosphate