Cytotoxic and clastogenic effects of a DNA minor groove binding methyl sulfonate ester in mismatch repair deficient leukemic cells

Mismatch repair deficiency contributes to tumor cell resistance to O-6-guan ine methylating compounds and to other antineoplastic agents. Here we demon strate that MeOSO2(CH2)(2)-lexitropsin (Me-Lex), a DNA minor groove alkylat ing compound which generates mainly N-3-methyladenine, has cytotoxic and cl astogenic effects in mismatch repair-deficient leukemic cells. Moreover, MT -1 cells, which express p53 upon drug treatment and possess low levels of 3 -methylpurine DNA glycosylase activity, are more susceptible to cytotoxicit y induced by Me-Lex, with respect to p53-null and 3-methylpurine DNA glycos ylase-proficient Jurkat cells. In both cell lines, the poly(ADP-ribose) pol ymerase inhibitor 3-aminobenzamide, which inhibits base excision repair cap able of removing N-methylpurines, increases cytotoxicity and clastogenicity induced by Me-Lex or by temozolomide, which generates low levels of N-3-me thyl adducts, The enhancing effect is more evident at low Me-Lex concentrat ions, which induce a level of DNA damage that presumably does not saturate the repair ability of the cells. Nuclear fragmentation induced by Me-Lex 3-aminobenzamide occurs earlier than in cells treated with the single agent . Treatment with Me-Lex and 3-aminobenzamide results in augmented expressio n of p53 protein and of the X-ray repair cross-complementing 1 transcript ( a component of base excision repair). These results indicate that N-3-methy ladenine inducing agents, alone or combined with poly(ADP-ribose) polymeras e inhibitors, could open up novel chemotherapeutic strategies to overcome d rug resistance in mismatch repair-deficient leukemic cells.