Mutagenesis in murine spermatogonia by MOPP therapy

Male mice were given mechlorethamine (2.0 mg/kg) followed immediately or 1, 2, 4, or 8 h later by procarbazine (100 mg/kg) and vincristine (0.67 mg/kg) in a protocol that stimulated the drugs and dosages used in a single cycle of clinical MOPP therapy. Seven weeks later and continuing for the next five weeks, the mice were mated to females and the dominant lethal mutant frequencies determined in their offspring by an in vitro assay. Significant (Student's t-test, p less than 0.05) mutant frequencies were detected when the interval between drug administration was between 2 and 8 h. In another series of experiments, mice were injected with these drugs using a 4-h interval between mechlorethamine and the vincristine and procarbazine (MOPP), two cycles of MOPP separated by one week, one cycle of MOPP and 2.0 Gy x-radiation separated by one week, or 2.0 Gy x-radiation alone. When each group was assayed for its dominant lethal mutant frequency, all were found to have similar, highly significant (0.001 less than p less than 0.005) induction. Together these data suggest that stable mutagenic lesions are induced in spermatagonial stem cells by both x-radiation and chemotherapeutic drugs and the frequency with which they are produced can be approximated by a single treatment. Clinical strategies to minimize genetic effects should concentrate on the sequence and timing of drug administration on those days when the drugs are administered in combination.