Synergistic induction of cytogenetic damage by alkylating antineoplastics and 5-azacytidine in human lymphocytes.

We studied the effects of the inhibitor of DNA methylation, 5-azacytidine (Aza-C), alone and in combination with three antitumor alkylating agents, on sister chromatid exchanges (SCEs) and lymphocyte proliferation kinetics. Aza-C was found to act synergistically on induction of SCEs when administered in combination with either melphalan (MEL) or chlorambucil (CBC) or cis-platinum-(II)diamine dichloride (cis-Pt). Cell-division delays were consistently observed in cultures treated with each of the antineoplastics when introduced concomitantly with Aza-C, compared with cultures treated with antineoplastics alone. Mitotic indices (MI) in cultures treated with each of the three alkylating agents were found to be suppressed by Aza-C. These results support the premise that hypomethylation of DNA causes cytotoxic effects by interfering with DNA repair mechanisms and by inhibiting DNA synthesis, or other cell growth mechanisms, which human lymphocytes undertake after being damaged by alkylation.