Dominant lethal mutations induced in mouse spermatogonia by mechlorethamine, procarbazine and vincristine administered in 2-drug and 3-drug combinations.
Male mice were treated with mechlorethamine (2.0 mg/kg), procarbazine (100 mg/kg) and vincristine (0.67 mg/kg) alone, or in 2-drug and 3-drug combinations. 5 weeks later and continuing for 5-8 weeks, embryos fertilized by spermatozoa that were derived from drug-treated spermatogonia were evaluated for drug-induced dominant lethal mutations. Significant mutagenesis was detected for mechlorethamine alone, for 2-drug combinations including mechlorethamine and for 3-drug combinations. Combinations where mechlorethamine was given first were mutagenic whereas combinations where mechlorethamine was not given first were not. Some combinations were more cytotoxic to the germinal epithelium than others. The data suggest that mutagenesis by this combination of drugs which is used extensively in treating Hodgkin's disease is due primarily to the mechlorethamine and that the frequency of mutation-induction may be a function of the order of administration.
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D004347:Drug Interactions; D005306:Fertilization / Q000187:drug effects; D005799:Genes, Dominant; D005804:Genes, Lethal; D008297:Male; D008466:Mechlorethamine / Q000009:adverse effects / Q000633:toxicity*; D051379:Mice; D009154:Mutation / Q000187:drug effects*; D011241:Prednisone / Q000009:adverse effects; D011344:Procarbazine / Q000009:adverse effects / Q000633:toxicity*; D013093:Spermatogonia / Q000187:drug effects*; D013094:Spermatozoa / Q000187:drug effects*; D014750:Vincristine / Q000009:adverse effects / Q000633:toxicity*
D011344:Procarbazine; D008466:Mechlorethamine; D014750:Vincristine; D011241:Prednisone