Peplomycin. DNA breakage and in vivo inhibition of DNA polymerases and ligase from human normal and leukemic cells.

Abstract : Peplomycin, a bleomycin-related cytostatic agent, was tested on DNA polymerases and DNA ligase. These enzymes were purified from normal human immunocompetent cells (thymocytes and lymphocytes) and from peripheral blast cells from different kinds of acute lymphoblastic and acute non-lymphoblastic leukemia. At low concentration ranges (1-25 microM) this compound was found to strongly inhibit polymerase alpha and ligase from leukemic cells while being less effective on the enzyme activity from normal thymocytes and lymphocytes. At the DNA level, low concentrations of peplomycin resulted in the induction of dose-dependent single-stranded breaks. The incubation of peplomycin (5 microM) with plasmid DNA resulted in its degradation as observed by agarose gel electrophoresis. Lowering the peplomycin concentration showed that ligase inhibition takes place prior to this phenomenon. The decreased formation of the ligase--adenylate complex under the effect of peplomycin is consistent with a direct interaction between the drug and the enzyme. These results are discussed in terms of possible selective cytostatic effects of peplomycin on leukemic cells.