[Reproductive and developmental toxicity study of a new antineoplastic agent, S-1 (III)--Teratological study in rabbits by oral administration].
S-1 is a newly developed antineoplastic agent consisting of the mixture of tegafur (FT), 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. As part of a reproductive and developmental toxicity study of S-1, a teratogenicity study was carried out in rabbits administered daily oral doses of S-1 0, 0.5, 1, or 1.5 mg/kg/day (as a dose of FT). S-1 was administered from day 6 to day 18 of pregnancy. Two additional studies were conducted in order to evaluate the effect on embryos or fetuses at higher S-1 dosage. One study (additional study I) tested during organogenesis dividing it into 3 periods (Day 6-10, Day 10-14, and Day 14-18) at doses of 2, 4 or 6 mg/kg/day. Another study (additional study II) tested during organogenesis dividing it into 4 periods (Day 8 x 9, Day 10 x 11, Day 12 x 13, and Day 14 x 15) at doses of 3 or 6 mg/kg/day due to many embryo deaths at high dose level in the additional study I. The results were as follows. 1. Teratogenicity study One dam died on day 16 of pregnancy and there was a weak teratogenic potential in the 1.5 mg/kg/day group. There were no remarkable other changes in dams and fetuses. The non-observed effects dose level of S-1 for general toxicity in dams was 1 mg/kg/day, for pregnancy in dams was 1.5 mg/kg/day, and for development of fetuses was 1 mg/kg/day under the conditions of this study. 2. Additional study I Abortion was observed at 6 mg/kg/day in the day 14-18 administration group. General toxicity in dams were observed in all administration groups. Fetal lethality was observed at 4 mg/kg/day or more in the day 6-10 and day 10-14 groups, and at 6 mg/kg/day in the day 14-18 administration group. Inhibition of fetal growth was observed at 2 mg/kg/day in the day 10-14 group and at 2 mg/kg/day or more in the day 14-18 administration group. There was a week teratogenic potential at 2 mg/kg/day or more in the day 10-14 groups and at 4 mg/kg/day in the day 14-18 administration group. 3. Additional study II Abortion was observed at 6 mg/kg/day in the day 8-9, day 10-11, and day 12-13 administration groups. General toxicity in dams were observed in all administration groups. Fetal lethality was observed at 3 mg/kg/day in the day 8-9 group and at 6 mg/kg/day in all administration groups. Inhibition of fetal growth and teratogenic potential were clearly observed at 3 mg/kg/day in the day 8-9 and day 10-11 groups, and at 6 mg/kg/day in the day 12-13 and day 14-15 administration groups. 4. In conclusion, when S-1 was administered at a low dose (< = or 1.5 mg/kg/day) during organogenesis effects were not detected clearly. When higher doses were administered (2-6 mg/kg/day), fetal lethality, inhibition of fetal growth, and teratogenicity were observed.
Shinomiya
M
M
Drug Safety Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Yukiyama
S
S
Ikebuchi
K
K
D000014:Abnormalities, Drug-Induced; D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000002:abnormalities / Q000187:drug effects; D004338:Drug Combinations; D004435:Eating / Q000187:drug effects; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D010012:Osteogenesis / Q000187:drug effects; D010094:Oxonic Acid / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects*; D011725:Pyridines / Q000008:administration & dosage / Q000633:toxicity*; D011817:Rabbits; D012098:Reproduction / Q000187:drug effects; D005641:Tegafur / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid