[An oral repeated dose toxicity study of a new antineoplastic agent S-1 in dogs. I. A 13-week repeated dose toxicity study. II. An ophthalmologic toxicity recovery study].
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 of S-1 appeared primarily in the eyes, lymphatic tissues, and reproductive organs, and 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.
Hayashi
T
T
Drug Safety Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Yamaguchi
S
S
Kito
S
S
Tanaka
G
G
Kurokawa
K
K
Hirota
T
T
D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D003315:Cornea / Q000187:drug effects / Q000648:ultrastructure; D004285:Dogs; D004338:Drug Combinations; D004848:Epithelium / Q000187:drug effects / Q000648:ultrastructure; D005123:Eye / Q000187:drug effects* / Q000473:pathology; D005260:Female; D006403:Hematologic Tests; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010094:Oxonic Acid / Q000008:administration & dosage / Q000633:toxicity*; D011725:Pyridines / Q000008:administration & dosage / Q000633:toxicity*; D005641:Tegafur / Q000008:administration & dosage / Q000633:toxicity*; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid