s-1-(combination) and Abnormalities--Drug-Induced

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 fertility study was carried out in Sprague-Dawley rats. Twenty-four male rats were administered S-1 orally starting at 64 days before mating and 24 female rats were administered S-1 orally from 15 days before mating to day 7 of pregnancy at doses of 0, 1, 4, or 7 mg/kg/day (as a dose of FT) in order to investigate the effect of S-1 on the reproductive ability and development of embryos and fetuses. There were no dose-related changes in clinical signs. Body weight gains and food consumption were decreased and were associated with the decreased weights of thymus, testis and epididymis in male rats receiving S-1 at the 7 mg/kg/day group. In females, the only organ affected was the kidney at 7 mg/kg/day. There were no dose-related changes in copulation, fertility, pre-implantation loss and implantation. Decreases in live fetal body weight and retardation of fetal ossification were observed in the 7 mg/kg/day group. There were no dose-related changes in post-implantation loss, and no fetal malformations were observed. The results suggest that the non-observed effects dose level of S-1 for general toxicity in male and female rats in 4 mg/kg/day, for reproductive toxicity in adults is more than 7 mg/kg/day, and for developmental toxicity in utero is 4 mg/kg/day.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Antimetabolites, Antineoplastic; Body Weight; Bone and Bones; Drug Combinations; Eating; Embryonic and Fetal Development; Female; Fertility; Male; No-Observed-Adverse-Effect Level; Organ Size; Osteogenesis; Oxonic Acid; Pregnancy; Pyridines; Rats; Tegafur

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. The teratogenic potential of S-1 was studied in rats given S-1 at the daily oral doses of 0, 1, 3, 5 and 7 mg/kg/day (as a dose of FT). S-1 was given from day 7 to day 17 of pregnancy. The study included postnatal evaluation of the growth, development, and reproductive performance of the F1 generation. In rats receiving 7 mg/kg of S-1, maternal body weight gain and food consumptions were reduced, stillbirths increased, livebirths decreased slightly and F1 viability decreased. Fetal body weights decreased significantly in rats receiving 5 mg/kg or more of S-1. External and skeletal anomalies did not increase, but hydrocephaly increased slightly and total number of visceral anomalies increased significantly in the fetuses of rats receiving 7 mg/kg of S-1. Hydrocephaly was observed also in F1 offspring from the rats receiving 7 mg/kg of S-1 during lactation period. Body weight gains of F1 offspring from the rats receiving 7 mg/kg of S-1 during lactation period was reduced. Functional development, emotional tests, learning tests, reproductive performance of the F1 generation and development of the F2 generation were not effected by the S-1 administration. In conclusion, under the condition of this study, the non-observed effect dose levels (NOELs) of S-1 for general toxicity for dams was 5 mg/kg/day, however, NOELs of S-1 was determined to be 7 mg/kg/day or more for reproductive ability. The NOELs of S-1 for the offspring was established to be 3 mg/kg/day.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Animals, Newborn; Antimetabolites, Antineoplastic; Body Weight; Bone and Bones; Drug Combinations; Eating; Embryonic and Fetal Development; Female; Fertility; Male; No-Observed-Adverse-Effect Level; Oxonic Acid; Pregnancy; Pregnancy, Animal; Pyridines; Rats; Reproduction; Tegafur

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 grou

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Antimetabolites, Antineoplastic; Body Weight; Bone and Bones; Drug Combinations; Eating; Embryonic and Fetal Development; Female; Male; No-Observed-Adverse-Effect Level; Osteogenesis; Oxonic Acid; Pregnancy; Pregnancy, Animal; Pyridines; Rabbits; Reproduction; Tegafur; Time Factors