Inhibition of DNA Ligase from Human Thymocytes and Normal or Leukemic Lymphocytes by Antileukemic Drugs1

Human DNA ligase was purified from both normal and leukemic peripheral lymphocytes and normal thymocytes. The activity of the purified enzymes was assayed in the presence of several widely used antileukemic drugs. Melphalan and prednisone at 5 nriMhad no effect. Carmustine, chlorambucil, and cyclophosphamide were more effective at inhibiting the enzyme from leukemic cells, whereas Adriamycin and vinblastine and their derivatives were stronger inhibitors of the enzyme from normal cells. Vincristine and etoposide inhibited DNA ligase from thymocytes and normal lymphocytes with a low K, but were totally ineffective on the enzyme from leukemic cells. The three classes of intercalating anthracyclines, Vicia alka loids, and podophyllotoxin derivatives, were the only drugs found to markedly inhibit DNA ligases from normal cells. Less substi tuted molecules of the Vicia alkaloids and podophyllotoxin classes were the more active inhibitors, whereas in the interca lating anthracycline group, it was the more substituted com pounds. The clinical consequences of these observations are discussed with respect to the role of DNA ligase in DNA repli cation and repair.