s-1-(combination) and Body-Weight

Compliance with S-1 adjuvant chemotherapy is not satisfactory, and the aim of the present study was to clarify risk factors for the continuation of S-1 after gastrectomy.. This retrospective study selected patients who underwent curative D2 surgery for gastric cancer, were diagnosed with stage II/III disease, had a creatinine clearance >60 ml/min, and received adjuvant S-1 at our institution between June 2010 and March 2014. The time to S-1 treatment failure (TTF) was calculated.. Fifty-eight patients were selected for the present study. When the TTF curves stratified by each clinical factor were compared using the log-rank test, lean body-mass loss (LBL) of 5 % was regarded as a critical cutoff point. Univariate Cox's proportional hazard analyses demonstrated that LBL was a significant independent risk factor for continuation. The 6-month continuation rate was 91.7 % in patients with an LBL < 5 %, and 66.3 % for patients with an LBL > 5 % (p = 0.031).. The present study demonstrated that LBL might be an important risk factor for a decrease in compliance to adjuvant chemotherapy with S-1 in patients with stage II/III gastric cancer who underwent D2 gastrectomy. A multicenter, double-blinded, prospective cohort study is necessary to confirm whether LBL would affect adjuvant S-1 continuation.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Body Composition; Body Weight; Drug Combinations; Electric Impedance; Female; Gastrectomy; Humans; Male; Medication Adherence; Middle Aged; Oxonic Acid; Proportional Hazards Models; Retrospective Studies; Risk Factors; Stomach Neoplasms; Tegafur

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.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cisplatin; Drug Combinations; Fluorouracil; Male; Mice; Mice, Inbred Strains; Oxonic Acid; Pyridines; RNA, Neoplasm; Sarcoma 180; Tegafur; Thymidine Kinase; Uridine Triphosphate

Favorable results have been reported for the novel oral anticancer agent S-1 (TS-1) in clinical studies of advanced gastric cancer with peritoneal dissemination. In the present study we assessed its pharmacokinetics, inhibitory effects, and effect on survival time in an animal model.. A model of peritoneal dissemination was created by intraperitoneally implanting 4-week-old female BALBc nu/nu mice with the human gastric cancer cell line MKN-45 after transfection with a fluorescent protein-expressing vector. Pharmacokinetics were investigated by measuring intratumor, peritoneal lining, and blood concentrations after the administration of S-1 and fluorouracil (5-FU). The effect of S-1 on survival time was also assessed, by administration once daily to seven animals per group, starting on day 7 after implantation, and survival time was compared with that of an untreated control group. The inhibitory effect of S-1 on peritoneal dissemination was evaluated by killing mice at the start of administration, and 1 and 3 weeks after the start of administration, and examining them for the presence of peritoneal dissemination under a fluorescence stereomicroscope.. Maintenance of high 5-FU concentrations in the intraperitoneal tumors was confirmed in the S-1 group, and survival time was prolonged without any decrease in oral food intake or body weight.. Assessment in a model of peritoneal dissemination of gastric cancer showed that the novel oral anticancer agent S-1 was effective against peritoneal dissemination, and that it improved the survival rate.

Topics: Animals; Antimetabolites, Antineoplastic; Body Weight; Disease Models, Animal; Drug Combinations; Eating; Female; Fluorouracil; Japan; Maximum Tolerated Dose; Mice; Mice, Inbred BALB C; Microscopy, Fluorescence; Oxonic Acid; Peritoneal Neoplasms; Pyridines; Stomach Neoplasms; Survival Analysis; Tegafur; Time Factors

S-1 is a novel oral anticancer drug, composed of tegafur (FT), gimestat (CDHP) and otastat potassium (Oxo) in a molar ratio of 1:0.4:1, based on the biochemical modulation of 5-fluorouracil (5-FU). In this study the combined effect of S-1 and low-dose CDDP as a modulator for colon 26 liver metastasis in mice was evaluated. In an experiment with S-1 (5 mg/kg/day: po) and CDDP (0.25 mg/kg/day: i.p.) for 14 days, the combined effects for both liver metastasis and tumor of spleen were not superior to those with S-1 or CDDP alone group. Body weight loss was not greater in the S-1 + CDDP group than in the control group. In an experiment with S-1 (5 mg x 2/kg/day: po) and CDDP (0.25 mg/kg/day: i.p.) for 7 days, the inhibitory effects of S-1 + CDDP of liver metastasis and tumor of the spleen were remarkable compared with the S-1 alone group. However a greater loss of body weight was seen in the S-1 + CDDP group than in other groups. This study suggests that low-dose CDDP might be a modulator of S-1 for colon 26 liver metastasis. Further study is needed to determine the optimum dose and duration of treatment.

Topics: Animals; Antimetabolites, Antineoplastic; Body Weight; Cisplatin; Colonic Neoplasms; Drug Combinations; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Oxonic Acid; Pyridines; Splenic Neoplasms; Tegafur

An important cytotoxic effect of 5-fluorouracil (5-FU) is the inactivation of thymidylate synthase (TS) (EC 2.1.1.45) activity by the formation of a ternary complex consisting of covalently bound 5-fluorodeoxyuridine 5'-monophosphate (FdUMP), TS and 5,10-methylenetetrahydrofolate (CH2FH4). The gastrointestinal (GI) toxicity of 5-FU is also caused by its phosphorylation in the GI tract. Potassium oxonate (O(XO)) competitively inhibits pyrimidine phosphoribosyltransferase (EC 2.4.2.10), which converts 5-FU to 5-fluorouridine 5'-monophosphate (FUMP) in vitro. In this study the benefits of combining Oxo and tegafur (FT), which is a masked compound of 5-FU, in reducing the GI toxicity of 5-FU and in protecting the activity of TS in the normal GI tissues were evaluated.. We administered orally a preparation of 1 M FT and 0.4 M 5-chloro-2,4-dihydroxypyridine (CDHP) with or without 1 M O(XO) (called S-1 and FT + CDHP, respectively) or vehicle only (control) to rats for ten consecutive days and compared the toxicity, the histopathological findings and the free TS activity in the GI tissues of the treated rats.. During the experimental periods, the signs of toxicity, such as a decrease in body weight, diarrhea and death, were only observed in the rats treated with FT + CDHP. The histopathological findings in the ileum and colon samples from rats treated consecutively with S-1 on day 1, day 4, day 7 and day 10 were less frequent and more mild than in the samples from rats treated with FT + CDHP. Furthermore, the free TS activities in the ileum samples of rats given S-1 and FT + CDHP were significantly decreased compared with the activity in samples from the control rats throughout the experimental periods. The free TS activities in GI tissues of rats treated with S-1 were higher than the TS activities in tissues from rats treated with FT + CDHP daily from day 4 to day 10, although activities in S-1-treated rat were decreased to almost same low levels as in FT + CDHP-treated rats on day 1.. Our results suggest that repeated simultaneous administration of Oxo and FT can effectively protect the activity of TS by decreasing FdUMP via FUMP from 5-FU in GI tissue, and may lead to a reduction in GI toxicity.

Topics: Animals; Antimetabolites, Antineoplastic; Body Weight; Colon; Diarrhea; Digestive System; Drug Combinations; Drug Interactions; Enzyme Inhibitors; Fluorodeoxyuridylate; Fluorouracil; Ileum; Male; Oxonic Acid; Pyridines; Rats; Tegafur; Thymidylate Synthase

S-1, an antineoplastic formulation of a fluorinated pyrimidine derivative containing tegafur (FT), CDHP, and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1, was recently developed by Taiho Pharmaceutical Co., Ltd., with the aim of prolonging the effective plasma concentration of 5-fluorouracil (5-FU) over that produced by FT alone and reducing its dose-limiting gastrointestinal toxicity. As a part of the S-1 toxicity study, the single-dose toxicity of S-1 as well as that of its components, CDHP and Oxo, was investigated in mice, rats, and dogs. The following results were obtained. 1. In mice and rats, excretion of diarrheal stools, salivation, and alopecia were observed after S-1 administration. In severe cases, the animals subsequently showed emaciation due to weight loss or suppressed weight gain, decreased spontaneous motor activity, an anemic appearance, bradypnea, prone position, and death. In the CDHP and Oxo treatment groups of rats, the only toxic signs were soft or diarrheal stools on the dosing day. 2. In dogs, vomiting and excretion of diarrheal, mucous, or soft stools was observed after S-1 administration. In the CDHP and Oxo treatment groups, excretion of soft and diarrheal stools and vomiting were observed relatively frequently from the dosing day until day 1. 3. In the pathological examination of the animals given S-1, mice and rats showed pulmonary congestion/edema, dark red discoloration of the mesenteric lymph nodes, atrophy of lymphatic tissues such as the thymus and lymph nodes, decreases of lymphocytes in the splenic white pulp and mesenteric lymph nodes, a decrease in bone marrow cells, congestion of the glandular stomach, and aggregates of bacteria in the lung, liver, or spleen. In dogs, abnormal changes were observed mainly in the lymphatic organs such as the thymus and lymph nodes. 4. The LD50 values of S-1 in terms of the amount FT they contained were estimated to be 549 mg/kg for mice(male), 441-551 mg/kg for rats (both sexes) and about 53 mg/kg for dogs (male). The LD50 values of CDHP and Oxo were 2000 mg/kg or higher for both rats (both sexes) and dogs (male). 5. Hematopoietic and lymphatic impairments, immunosuppression associated with respiratory were considered to be the cause of death from S-1. The toxicity of S-1 reflects the toxicity of 5-FU and was not found the different toxicity by the addition of CDHP and Oxo.

Topics: Administration, Oral; Alopecia; Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Diarrhea; Dogs; Drug Combinations; Female; Lethal Dose 50; Lymph Nodes; Male; Mice; Motor Activity; Oxonic Acid; Pyridines; Rats; Salivation; Spleen; Survival Rate; Tegafur; Thymus Gland

S-1, an antineoplastic formulation of a fluorinated pyrimidine derivative containing tegafur (FT), CDHP, and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1, was recently developed by Taiho Pharmaceutical Co., Ltd., with the aim of prolonging the effective plasma concentration of 5-fluorouracil (5-FU) over that produced by FT alone and reducing its dose-limiting gastrointestinal toxicity. As a part of the S-1 toxicity study, a 13-week oral repeated dose toxicity study and a recovery study using male and female rats was conducted. Doses of S-1 were adjusted to deliver 1.5, 5, and 15 mg/kg/day as doses of FT, and FT was given at 15 mg/kg/day. The following results were obtained. 1. In clinical observation, edema of the limbs and face or swelling of the auricle of the ear and an anemic appearance were observed in both sexes in the 15 mg/kg/day group as dose of FT. Subsequently, males in this group developed severe anemia, decreased spontaneous motor activity, emaciation, and subnormal skin temperature, and many males died. In the survivors, keratosis of the palm, sole, or tail was observed, with necrosis and loss of the tail tip in the severe cases. 2. Body weight gain was suppressed from about week 2 of treatment in both sexes in the 15 mg/kg/day group as dose of FT, and there was almost no weight gain after week 4-5. Food consumption was consistently less than the control value for males in the 15 mg/kg/day group as dose of FT throughout the treatment period. 3. No marked changes were observed in water intake and on opthalmologic examination. 4. In the fecal test for occult blood, a positive tendency was observed in both sexes in the 15 mg/kg/day group as dose of FT. 5. Urinalysis disclosed a slight increase in protein and decrease in sodium, potassium, and chloride in males, and an increase in protein in females in the 15 mg/kg/day group as dose of FT. 6. Hematologically, both sexes in the 15 mg/kg/day group as dose of FT showed decreases in red blood cell count, hemoglobin, and hematocrit, and increases in platelet count and fibrinogen, with a slight decrease in white blood cell count in males. 7. In the blood biochemical test, abnormal findings included increases in total cholesterol and free cholesterol, and decreases in non-esterified fatty acid and albumin in both sexes in the 15 mg/kg/day group as dose of FT. 8. In organ weight measurement, abnormal changes included a decrease in thymus weight in both sexes in the 5 mg/kg/day or higher dosage gr

Topics: Administration, Oral; Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Blood Chemical Analysis; Body Weight; Bone Marrow; Drug Combinations; Edema; Female; Hematologic Tests; Lymph Nodes; Male; No-Observed-Adverse-Effect Level; Organ Size; Oxonic Acid; Pyridines; Rats; Tegafur; Thymus Gland; Urine

S-1 was administered to male and female rats by gavage for 26 weeks at 0, 1, 5, and 10 mg/kg/day followed by 5-week recovery period for the control, 5, and 10 mg/kg/day groups. Treatment at 5 or 10 mg/kg/day in both sexes produced keratosis of the tail, palm or sole. Weight gain and average food consumption were lowered by the treatment. Urine showed increases in protein and epithelial or white blood cells and a decrease in specific gravity. The blood showed decreases in red blood cell count, hemoglobin, and hematocrit as well as increases in MCH, platelet count, fibrinogen, and MCV. A/G ratio, albumin, and chloride were decreased while total cholesterol, free cholesterol, triglycerides, and phospholipids were increased. Histopathologically, treatment-related changes at 5 and 10 mg/kg/day were observed mainly in the lymphoid tissues and kidneys. Those changes included atrophy in the lymphoid tissues and chronic nephropathy-like changes in the kidneys. Other changes in the 10 mg/ kg/day group, included acanthosis and/or inflammation in the epidermis of the tail, sole, or palm, degeneration and disarrangement of ameloblasts, and atrophy of the testes. In a recovery study, although some changes in the sole, palm, or tail, and the kidneys remained, they were less extensive than they had been at the end of the treatment period. Based upon these observations, the non-toxic dose level was estimated to be 1 mg/kg/day (2.3 mg/kg/day, as the summed doses of tegafur, CDHP, and Oxo) in both sexes.

Topics: Administration, Oral; Animals; Antimetabolites, Antineoplastic; Blood Chemical Analysis; Body Weight; Drug Combinations; Epidermis; Female; Hematologic Tests; Hyperplasia; Inflammation; Kidney; Lymphoid Tissue; Male; No-Observed-Adverse-Effect Level; Organ Size; Oxonic Acid; Pyridines; Rats; Tegafur; Testis

S-1, an antineoplastic formulation of a fluorinated pyrimidine derivative containing tegafur (FT), CDHP, and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1, was recently developed by Taiho Pharmaceutical Co., Ltd., with the aim of prolonging the effective plasma concentration of 5-fluorouracil (5-FU) over that producted by FT alone and reducing its dose-limiting gastrointestinal toxicity. As a part of the S-1 toxicity study, a 13-week repeated dose toxicity study and a recovery study of opthalmologic effects were conducted in dogs. The following results were obtained. All S-1 doses are expressed in terms of their FT content. 1. Concerning the general condition, dark brown pigment was deposited on the sclera of the eye in all S-1 treated groups starting at the second week of treatment, and clouding of the cornea was noted in the 3 mg/kg/day group starting after 3-4 weeks of treatment. In the 3 and 6 mg/kg/day groups, general signs such as salivation, reduction in spontaneous movements, and sedation appeared, and 1 male and 2 females of the 3 mg/kg/day group died or were moribund 4-5 weeks after treatment began. All animals of the 6 mg/kg/day died or were sacrificed within 2 weeks of the start of the study. 2. Food consumption and body weight were reduced in the groups administered 1 mg/kg/day or more S-1. 3. No apparent drug-induced changes were observed on electrocardiography, urinalysis, fecal occult blood test, hematological examination, liver and kidney function tests, or ocular mucosa infection tests. 4. Blood biochemical examinations showed decreases in creatinine and chloride levels in males, an increase in LDH activity, and decreases in the albumin level and A/G ratio in females of the 3 mg/kg/day group. 5. Organ weighing showed that the relative weight of the kidney was increased in males and females of the 3 mg/kg/day group. 6. Histopathological examination revealed melanin deposition in the conjunctiva or cornea and atrophy inflammation, neutrophil infiltration, and neovascularization in the corneal epithelium. Atrophy of lymphatic tissues, such as the thymus, spleen and various lymph nodes, and changes in the reproductive system such as aspermatogenesis and uterine atrophy, which are commonly observed side effects of anticancer drugs, were also noted. 7. In the group administered FT, vacuolation of the cerebral fornix and commissura anterior was observed in 1 animal, but no changes were observed in other examinations. 8. The toxic effects

Topics: Administration, Oral; Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Bone Marrow; Cornea; Dogs; Drug Combinations; Epithelium; Eye; Female; Hematologic Tests; Lung; Male; Organ Size; Oxonic Acid; Pyridines; Tegafur; Thymus Gland

52-week oral repeated-dose S-1 toxicity studies were conducted. Male and female dogs were orally treated with 0, 0.1, 0.5 or 2.5 mg/kg/day for 52 weeks and permitted to recover for 13 weeks. Furthermore, to estimate the no-toxic dose, male and female dogs were given S-1 orally for 52 weeks at doses of 0, 0.004 and 0.02 mg/kg/day. The 2.5 mg/kg/day regimen produced one dead or moribund dog of each sex; black-brown patch (melanin deposition) and inflammatory changes in the eyes and skin; decreased in body weight gains; increases in MCV, MCH, monocyte ratio, and serum protein and uric acid; decreases in lymphocyte ratio and erythrocyte count, hematocrit, hemoglobin, albumin, A/G ratio, cholesterol (esterified, total and free), phospholipids, triglycerides, cholinesterase activity and creatinine; increases in relative liver and adrenal weights. Histopathological examinations revealed melanin deposits in superficial lymph nodes, increases in macrophage and plasma cell accumulation, and corneal atrophy accompanied by melanin deposits and capillary proliferation. A slight black-brown patch (melanin deposition) in the conjunctiva and skin was observed in the 0.1 and 0.5 mg/kg/day groups. No drug-related changes were observed in groups that received 0.02 and 0.004 mg/kg/day. All changes observed during the treatment period disappeared during recovery except for melanin deposits in the conjunctiva and superficial lymph nodes, corneal opacity, and a few hematological and blood chemistry parameters. In conclusion, the no-toxic dose in these 52-week studies was estimated to be 0.02 mg/kg/day.

Topics: Administration, Oral; Animals; Antimetabolites, Antineoplastic; Blood Chemical Analysis; Blood Coagulation; Body Weight; Dogs; Drug Combinations; Eye; Eye Diseases; Female; Hematologic Tests; Hyperpigmentation; Lymph Nodes; Male; Organ Size; Oxonic Acid; Pyridines; Skin; Skin Diseases; Tegafur; Urinalysis

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 in a molar ratio of 1:0.4:1 mixture of tegafur (FT), 5-chloro-2, 4, dihydroxypyridine (CDHP) and potassium oxonate (Oxo) was administered orally to SD rats at doses of 0, 1, 4 and 7 mg/kg/day (as a dose of FT) during the perinatal and postnatal periods to examine its effect on dams and postnatal growth of the offspring. A group as the control was treated only with medium (0.5% hydroxypropyl methylcellulose) solution. The administration of 7 mg/kg/day to dams caused suppression in body weight gains and in food consumption during the treatment period. No adverse effects of S-1 on the length of gestation, gestation index, delivery and nursing ability were found. The administration of 4 and 7 mg/kg/day caused suppression in body weight gains in offspring of both sexes. Significant decrease in kidney weights were observed in females of the 4 mg/kg/day group and in both sexes of the 7 mg/kg/day group. No adverse effects of S-1 were found in number of live offspring at birth, sex ratio of live offspring, number of dead offspring at birth, birth index, viability index, weaning index, incidence of external anomalies, general conditions, postnatal development, reflex responses, motor coordination, emotional behavior, learning ability, skeletons, necropsy findings or reproductive functions. No adverse effects of S-1 on F2 offspring were found in any treatment groups. Under the conditions of the present study, the non-observed effect dose levels of S-1 was 4 mg/kg/day for general toxicology of dams, 7 mg/kg/day for reproductive ability of dams, 1 mg/kg/day for postnatal growth in F1 offspring and 7 mg/kg/day for postnatal growth in F2 offspring.

Topics: Administration, Oral; Animals; Animals, Newborn; Antimetabolites, Antineoplastic; Behavior, Animal; Body Weight; Drug Combinations; Eating; Estrus; Female; Kidney; Male; No-Observed-Adverse-Effect Level; Organ Size; 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. 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

The immunotoxicity of S-1, which is a new antineoplastic agent, was investigated in BALB/c mice. S-1 contains tegafur (FT), CDHP, and potassium oxonate (Oxo) in a molecular ratio of 1:0.4:1. 5-fluorouracil (5-FU) and UFT were used as reference drugs. S-1 and reference drugs were administered by oral gavage for 7 days. The high dose employed in this study was determined as the maximally tolerated dose of a 9-day repeated-dose study in sarcoma 180-bearing mice. Decreased body weight was observed in mice treated with 5-FU and UFT but not in those treated with S-1. A significant decrease in thymus and spleen weight was observed in S-1-, UFT- and 5-FU-treated mice, and the degree was same for the three drugs. Though the number of white blood cells decreased dose-dependently for the three drugs, S-1 had the weakest effect. The number of red blood cells also decreased, but the effect was not dose-dependent, and its magnitude was the same for the 3 drugs. S-1 induced a dose-dependent decrease in the IgM antibody PFC response to sheep erythrocytes. The delayed type hypersensitivity response used a footpad reaction method was significantly suppressed at the highest dose of S-1. 5-FU and UFT suppressed humoral and cell-mediated immunity in almost the same manner as S-1. The degree of suppressive effects was greater on the humoral immune response than on the cell-mediated immune response. The number of CFU-GM colonies was significantly decreased in the highest dose group of each drug and in a lower group as well in S-1-treated mice. This finding might reflect the fact that S-1 induced continuous high levels of 5-FU in the blood. Under these experimental conditions, S-1 induced immunosuppressive effects in BALB/c mice, and the degree of suppression was almost same as that induced by 5-FU and UFT.

Topics: Animals; Antibody Formation; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Body Weight; Dose-Response Relationship, Drug; Drug Combinations; Fluorouracil; Immune System; Immune Tolerance; Immunologic Tests; Mice; Mice, Inbred BALB C; Organ Size; Oxonic Acid; Pyridines; Spleen; Tegafur; Thymus Gland; Uracil