Induction of mutant lymphocytes in cyclophosphamide- and chlorambucil-treated patients

Monitoring patients treated with single antineoplastic agents is aiding our understanding of what hazard these drugs pose in vivo. In this study, the frequency of mutant 6-thioguanine-resistant (TG(R)) peripheral blood Lympho cytes was monitored before treatment and for 135 weeks after treatment of p atients with cyclophosphamide (CP) or chlorambucil (CAB), The mean mutant f requency before treatment for six multiple sclerosis patients treated with high-dose CP was 2.53 x 10(-5) and increased after treatment to 4.61 x 10(- 5) (P = 0.08, paired t-test), Using each patient as their own control, ther e were significant increases (each at P < 0.04) detectable within 2-4 weeks in four of the multiple sclerosis patients treated with CP. There was no i ncrease in an untreated control monitored over the same period. In a patien t receiving five sequential CP treatments at 1 month intervals, there were cumulative increases in the frequency of mutant cells. The mutant frequency increased from 0.31 x 10(-5) before treatment to 3.54 x 10(-5) after the f inal treatment and had decreased to 0.53 x 10(-5) at less than or equal to 35 weeks after treatment. In one of two CAB-treated patients with indolent non-Hodgkin's lymphoma, there was a significant increase in mutant frequenc y (P < 0.03) after treatment. Freshly isolated peripheral blood lymphocytes treated with 4-hydroperoxy-CP in vitro demonstrate a dose-dependent increa se in mutant frequency. The increment in mutant frequency observed ill vivo is of the order expected from the in vitro experiments. Although this stud y demonstrates that single or multiple doses of a single antineoplastic age nt are mutagenic in vivo for some patients, further studies are needed to d etermine the extent and mechanism of the interindividual variations in muta genic response.