Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 11). Testicular toxicity of 2- or 4-week repeated or single-dose administration of a novel platinum complex.
A novel platinum complex, compound C, developed as an antitumor agent, was intravenously administered at 10 mg/kg/day to 6-week-old and 8-week-old rats. After 4 weeks of administration to the former, testicular enlargement was observed at a similar incidence as testicular atrophy and dilatation or atrophy of the seminiferous tubules was observed. Degeneration/necrosis of the seminiferous epithelium, decrease of seminiferous epithelium, formation of multinucleated giant cells, and vacuolar degeneration of Sertoli cells were also seen. These lesions were more marked in seminiferous tubules with atrophy than in those without atrophy. After 2-week administration to 8-week-old rats, slight initial-phase findings such as dilatation of seminiferous tubules and degeneration/necrosis of the seminiferous epithelium were noted in all rats. In rats administered 20 mg/kg/day, for which the administration period was shortened to 1 week due to marked weight loss, very slight initial lesions were similarly observed. However, these lesions were not easy to detect in these rats. Following single administration of a sublethal dose (80 mg/kg), testicular lesions were clearly observed 14 days after administration, but the incidence and grade of lesions were very low at 7 days. In conclusion, testicular toxicity of compound C can be clearly detected after 2-week administration, although the progression of lesions differed from the case with 4-week administration.
Misawa
Y
Y
Safety Assessment Laboratory, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba-shi, Shizuoka 412-8513, Japan.
Watanabe
K
K
Sakurai
T
T
Fujii
E
E
Tsukamoto
K
K
Kato
A
A
Sugimoto
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001284:Atrophy / Q000139:chemically induced / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D008297:Male; D009929:Organ Size / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012670:Seminiferous Epithelium / Q000187:drug effects / Q000473:pathology; D013737:Testis / Q000187:drug effects* / Q000473:pathology; D013997:Time Factors; D018675:Toxicity Tests
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds