Toxicological studies on (2"R)-4'-tetrahydropyranyladriamycin, a new antitumor antibiotic. Chronic toxicity study in rats.
(2"R)-4'-O-Tetrahydropyranyladriamycin X HCl (THP), a new anthracycline antitumor antibiotic, was administered to Sprague-Dawley rats (each group 20 rats) intraperitoneally at dosages of 0.001, 0.008, 0.06 and 0.3 mg/kg/day for 53 weeks. Piloerection, loose feces or perianal staining and thin or emaciated build were observed from week 12 in rats receiving 0.06 or 0.3 mg/kg/day. All rats receiving 0.3 mg/kg/day and 3 males and 1 female receiving 0.06 mg/kg/day died or were prematurely sacrificed in the period from weeks 13 to 44. The overall food consumption and body weight gain of both sexes receiving 0.06 or 0.3 mg/kg/day were lower than those of the controls. Hematological examination showed low leucocyte counts, disturbance in neutrophil and lymphocyte number and low erythrocytic characteristics in animals receiving 0.06 or 0.3 mg/kg/day. At necropsy, macroscopic changes were found at the injection site, throughout the gastrointestinal tract and in the male reproductive system in rats receiving 0.06 or 0.3 mg/kg/day. Microscopic examination revealed decrease in the small lymphocyte population in the hematopoietic and lymphoid system in rats receiving 0.008 to 0.3 mg/kg/day. Degeneration of the germinal epithelium of the subcapsular tubules of the testes, gastric ulceration, epithelial adnexal atrophy of the skin and chronic cellulitis and necrosis at the injection sites were also observed. No rats receiving 0.001 mg/kg/day were affected in these respects.
Tone
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H
Shirai
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Danks
A P
AP
Lee
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Finn
J P
JP
Ashby
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R
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000633:toxicity*; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005123:Eye / Q000187:drug effects; D005260:Female; D006403:Hematologic Tests; D007274:Injections, Intraperitoneal; D008099:Liver / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013154:Spleen / Q000473:pathology; D014556:Urine
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; C027260:pirarubicin