Comparative carcinogenic activity of prednimustine, chlorambucil, prednisolone and chlorambucil plus prednisolone in Sprague-Dawley rats.
This study compares long term toxic effects of equivalent doses of prednimustine (12 mg/kg) chlorambucil (3 mg/kg), prednisolone (3 mg/kg) and chlorambucil plus prednisolone (3 mg/kg each) in comparison to vehicle treated controls after regular administration over a period of 18 months to 600 female Sprague Dawley rats. Frequency of administration to subgroups (30 rats each) varied between 9 (a), 4.5 (b), 2 (c) times or once (d) a month. When comparing organ specific, age-adjusted expected versus observed incidences after natural death of animals an increased tumor risk was found in organ systems of all treatment modalities but prednisolone. Prednimustine-administration was related to an elevated risk of developing squamous-cell carcinomas of the external auditory canal only (alpha = 0.013), whereas simultaneous application of chlorambucil plus prednisolone induced significantly higher rates of adenocarcinomas of the mammary gland, of malignant tumors of the central and peripheral nervous tissue and of squamous cell carcinomas of the external auditory canal (alpha less than 0.01 for each tissue). Chlorambucil alone caused a significantly higher rate of malignancies of the hematopoietic and lymphatic tissue (alpha less than 0.01) additionally to effects observed after the unlinked mixture of chlorambucil plus prednisolone. There is evidence of carcinogenic activity of prednimustine compared to untreated controls, but the cancer-inducing potential of the linked compound is distinctly lower than that of the unlinked mixture of chlorambucil plus prednisolone or of chlorambucilalone.
D000818:Animals; D002699:Chlorambucil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D005260:Female; D009374:Neoplasms, Experimental / Q000139:chemically induced*; D011238:Prednimustine / Q000633:toxicity*; D011239:Prednisolone / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats
D002699:Chlorambucil; D011238:Prednimustine; D011239:Prednisolone