[Mutagenicity study of a new antineoplastic agent S-1, and its components, CDHP, and Oxo].
S-1 is a new antineoplastic agent of a fluorinated pyrimidine derivative containing tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1 with the aim of prolonging the effective plasma concentration of 5-fluorouracil (5-FU) and reducing its dose-limiting gastrointestinal toxicity. As a part of the safety evaluation of S-1, reverse mutation tests using bacteria and chromosomal aberration tests using cultured cells, CHL/IU, were conducted to test the in vitro mutagenicity of S-1, CDHP and Oxo. All S-1 doses are expressed as the content of FT. 1. The reverse mutation tests were carried out on S-1 at 1.02-520 micrograms/plate, on CDHP at 39.1-5000 micrograms/plate, and on Oxo at 78.1-5000 micrograms/plate using Salmonella typhimurium strains TA100, TA1535, TA98, and TA1537 and Escherichia coli WP2uvrA. None of the test compounds induced a significant increase over solvent controls in the number of mutant colonies in any tester strains in either system, with or without mammalian metabolic activation (S9 Mix). 2. For the in vitro chromosomal aberration tests, Chinese hamster lung cells (CHL/IU), were treated with S-1 at 27.5-220 micrograms/ml for 24 hr or at 6.88-27.5 micrograms/ml for 48 hr without S9 Mix, and at 110-880 micrograms/ml with S9 Mix, with CDHP at 365-1460 micrograms/ml (10 mM), and with Oxo at 122-1950 micrograms/ml (10 mM), with and without S9 Mix. S-1 with and without S9 Mix, and Oxo only for 48 h treatment without S9 Mix, induced chromosomal aberrations, while CDHP did not. 3. The present study indicates that S-1 was nonmutagenic in bacteria, but clastogenic in vitro. CDHP had no in vitro mutagenic or clastogenic activity. Oxo was positive in the in vitro chromosomal aberration test, but negative in the reverse mutation test.
Ohuchida
A
A
Drug Safety Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Kouchi
Y
Y
Sato
S
S
Maeda
Y
Y
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D001711:Biotransformation; D002478:Cells, Cultured / Q000187:drug effects; D002869:Chromosome Aberrations; D006224:Cricetinae; D004338:Drug Combinations; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D009152:Mutagenicity Tests; D010094:Oxonic Acid / Q000633:toxicity*; D011725:Pyridines / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D005641:Tegafur / Q000633:toxicity*
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; C104201:gimeracil