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[Reproductive and developmental toxicity study of a new antineoplastic agent, S-1 (III)--Teratological study in
M Shinomiya1, S Yukiyama, K Ikebuchi
1Drug Safety Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Abstract:
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.
Insights
S-1, an antineoplastic agent, showed weak teratogenic potential at doses of 1.5 mg/kg/day in rabbits. Higher doses (2-6 mg/kg/day) during organogenesis led to fetal lethality, growth inhibition, and teratogenicity.
Area of Science:
- Pharmacology
- Toxicology
- Oncology
Context:
- S-1 is a novel antineoplastic agent comprising tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate.
- Reproductive and developmental toxicity studies are crucial for evaluating the safety of new therapeutic agents.
Purpose:
- To assess the teratogenic potential and developmental toxicity of S-1 in rabbits during organogenesis.
- To determine the no-observed-adverse-effect level (NOAEL) for S-1 in pregnant rabbits.
Summary:
- A teratogenicity study in rabbits administered S-1 (0-1.5 mg/kg/day) showed weak teratogenic potential at 1.5 mg/kg/day, with a NOAEL of 1 mg/kg/day for fetal development.
- Additional studies at higher doses (2-6 mg/kg/day) revealed dose-dependent fetal lethality, inhibition of fetal growth, abortion, and teratogenicity, particularly during specific organogenesis periods.
- The timing of S-1 administration during gestation significantly influenced the observed developmental toxicities.
Impact:
- This study provides critical data on the reproductive and developmental risks associated with S-1, informing its clinical use.
- Findings highlight the importance of dose selection and administration timing to mitigate potential teratogenic effects of S-1 in pregnant patients.
- Establishes a foundation for further research into the mechanisms of S-1-induced developmental toxicity.