The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 21 , Issue SupplementIII
Showing 1-13 articles out of 13 articles from the selected issue
  • Yosuke NAKAMURA, Hiroshi KATO, Fumio KISHIDA, Shigefumi KOGISO, Iwao N ...
    1996 Volume 21 Issue SupplementIII Pages 485-493
    Published: November 27, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The effect of fenitrothion on experimental allergic conjunctivitis was studied using guinea pigs. Guinea pigs were passively sensitized with anti-sera against ovalbumin (OVA) or Japanese cedar pollen. Eight days after the sensitization, 6×10-5 mg/kg to 6 mg/kg of fenitrothion were administered subcutaneously. Two days after the injection, OVA or Japanese cedar pollen was given in the conjunctival sac and the allergic conjunctivitis was examined. OVA or Japanese cedar pollen induced the allergic conjunctivitid, depending on the challenge dosage (OVA). However, no adverse effect of fenitrothion was observed on allergic conjunctivitis challenged with OVA or Japanese cedar pollen. An anti-allergic agent, ketotifen, suppressed the allergic intensity. These results indicate that fenitrothion has no adverse effect on the experimental allergic conjunctivitis.
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  • Taiji HAYASHI, Gotaro TANAKA, Kenji IRIMURA, Tomio HIROTA, Sigeo OHMAE
    1996 Volume 21 Issue SupplementIII Pages 495-504
    Published: November 27, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    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, 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.
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  • Taiji HAYASHI, Hiroyuki HASEGAWA, Gotaro TANAKA, Sigeo OHMAE
    1996 Volume 21 Issue SupplementIII Pages 505-526
    Published: November 27, 1996
    Released: February 21, 2008
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    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 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 wad given at 15mg/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, ma1es in ithis group developed severe anemia, decrdased 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 ophthalmologic 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 groups and a decrease in the testis weight in mdles and an increase in the liver weight in females in the 15mg/kg/day group as dose of FT. 9. Histopathologically, both sexes in the 15 mg/kg/day group as dose of FT showed a decrease in the red pulp of the bone marrow; atrophy of the thymus, white pulp of the spleen, and testes, degeneration of the renal tubules, and ulcerative changes of the skin or oral mucosa. 10. The findings were unremarkable in the FT group. 11. During the recovery study, all the toxic effects tended to reverse. 12. The NOAEL of S-1 was estimated to be 1.5 mg/kg/day as dose of FT for both sexes.
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  • Taiji HAYASHI, Shuji YAMAGUCHI, Suguru KITO, Gotaro TANAKA, Kyoko KURO ...
    1996 Volume 21 Issue SupplementIII Pages 527-544
    Published: November 27, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    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 ophthalmologic 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 ard 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 of S-1 appeared primarily in the eyes, lymphatic tissues, and reproductive organs, find deaths were ascribed to weakening due to exacerbation of the general effects accompanied by disorders of immunological function. The NOAEL of S-1 in this study was estimated to be the dose that delivered less than 0.5 mg/kg/day in both males and females. 9. Changes in the eye observed after S-1 administration are such as pigmentation of the sclera and white turbidity of the cornea. Though it may be produced vision decreased, these changes are considered to be unaccompanied by functional disorders and to be reversible.
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  • Kazuo HAKOI, Taiji HAYASHI, Sigeo OHMAE, Kazuhiko BESSHI
    1996 Volume 21 Issue SupplementIII Pages 545-560
    Published: November 27, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    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.
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  • Shogo KITAJIMA, Takashi OKAMURA, Kazuo KOBAYASHI, Nobuaki WATARI, Hiro ...
    1996 Volume 21 Issue SupplementIII Pages 561-588
    Published: November 27, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    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 dnd 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.
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  • Mitsuhiro SHINOMIYA, Kenji IMAMURA, Katsuhiko IZUMI
    1996 Volume 21 Issue SupplementIII Pages 589-602
    Published: November 27, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    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 is 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.
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  • Shiro YUKIYAMA, Mitsuhiro SHINOMIYA, Kazuya IKEBUCHI, Toshikazu SATO
    1996 Volume 21 Issue SupplementIII Pages 603-618
    Published: November 27, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    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 O, 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 affected 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.
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  • Mitsuhiro SHINOMIYA, Shiro YUKIYAMA, Kazuya IKEBUCHI
    1996 Volume 21 Issue SupplementIII Pages 619-641
    Published: November 27, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    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 teratogenecity 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 8·9, Day 10·11, Day 12·13, and Day 14·15) 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. Teratogenecity 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 weak teratogenic potential at 2 mg/kg/day or more in the day 10-14 group 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 administratlon 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 (≤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 teratogenecity were observed.
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  • Tadakazu FURUHASHI, Masashi KATO, Takasi FUJIMURA, Masahiro KOIDA
    1996 Volume 21 Issue SupplementIII Pages 643-659
    Published: November 27, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    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, wearing 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.
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  • Yasuhiro MAEDA, Hidenobu MORINAGA, Katsuhiko IZUMI, Kazuya IKEBUCHI, Y ...
    1996 Volume 21 Issue SupplementIII Pages 661-673
    Published: November 27, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The antigenicity was tested of a new antineoplastic agent S-1 (a combination of tegafur (FT), CDHP and potassium oxonate (Oxo)) in mice and guinea pigs. 1. Male BALB/c or C3H/He mice were sensitized with S-1, CDHP, Oxo, and conjugates of CDHP (or Oxo) and human serum albumin (HSA). S-1 was administered by oral gavage, and the other compounds were administered intraperitoneally with adjuvant (alum). In the heterologous passive cutaneous anaphylaxis (PCA) test, using Sprague-Dawley rats as recipients, no IgE antibodies against S-1, CDHP, or Oxo were detected to any serum obtained from the sensitized mice, and no eliciting antigenicities were seen for CDHP or Oxo. 2. Male Hartley guinea pigs were sensitized with S-1, CDHP, Oxo, and conjugates of CDHP (or Oxo) and HSA. S-1 was administered by oral gavage, and the other compounds were administered subcutaneously with Freund's complete adjuvant (FCA). The homologous PCA test, active systemic anaphylaxis test, and passive hemagglutination test showed no production of antibodies against S-1, CDHP, or Oxo in any sensitized guinea pig, and no eliciting antigenicities for CDHP or Oxo. 3. Female Hartley guinea pigs were sensitized with S-1 subcutaneously with FCA. The active cutaneous anaphylaxis test revealed that S-1 did not induce cell-mediated delayed type hypersensitivity. 4. These results indicated that S-1, Oxo, and CDHP were not antigenic in mice and guinea pigs.
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  • Akinobu OHUCHIDA, Yasuhide KOUCHI, Sachiko SATO, Yasuhiro MAEDA
    1996 Volume 21 Issue SupplementIII Pages 675-689
    Published: November 27, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    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. Al1 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 μg/plate, on CDHP at 39.1-5000 μg/plate, and on Oxo at 78.1-5000 μg/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 μg/ml for 24 hr or at 6.88-27.5 μg/ml for 48 hr without S9 Mix, and at 110-880 μg/ml with S9 Mix, with CDHP at 365-1460 μg/ml (10mM), and with Oxo at 122-1950 μg/ml (10mM), with and without S9 Mix. S-1 with and without S9 Mix, and Oxo only for 48h 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.
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  • Yasuhide KOUCHI, Yasuhiro MAEDA, Hidenobu MORINAGA, Akinobu OHUCHIDA
    1996 Volume 21 Issue SupplementIII Pages 691-701
    Published: November 27, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    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.
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