Long-term toxicology effects of prednimustine in comparison with chlorambucil, prednisolone, and chlorambucil plus prednisolone in Sprague-Dawley rats.
Chlorambucil was linked to prednisolone to improve the therapeutic and toxic properties of this potent alkylating agent, which is known to induce second tumors in humans. To compare the carcinogenic potency of the linked compound with that of the respective individual agents and of their unlinked mixture, prednimustine (I), chlorambucil (II), prednisolone (III), chlorambucil plus prednisolone (IV), or vehicle were administered to groups of 120 female Sprague-Dawley rats for 18 months. The following doses were administered nine, four, five, two times, or once a month per subgroup of 30 rats: I, 12 mg/kg; II, 3 mg/kg; III, 3 mg/kg; IV, 3 mg/kg. After natural death of animals, median survival times were analyzed, and percentages of malignant tumors were recorded. An increased tumor risk was found in the following organs compared with those of vehicle-treated controls: I, external auditory canal (EAC); II, mammary gland (MG), central and peripheral nervous tissue (CPNT), hematopoietic and lymphatic tissue (HLT), and EAC; III, none; and IV, MG, CPNT, and EAC. There is evidence of carcinogenic activity of prednimustine compared with 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 that of chlorambucil.
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced; D002699:Chlorambucil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity*; D004359:Drug Therapy, Combination; D004428:Ear Neoplasms / Q000139:chemically induced; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced; D009374:Neoplasms, Experimental / Q000139:chemically induced*; D011238:Prednimustine / Q000633:toxicity*; D011239:Prednisolone / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D002699:Chlorambucil; D011238:Prednimustine; D011239:Prednisolone