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

Leukemia. 2000 Aug;14(8):1451-9. doi: 10.1038/sj.leu.2401842.


Mismatch repair deficiency contributes to tumor cell resistance to O6-guanine methylating compounds and to other antineoplastic agents. Here we demonstrate that MeOSO2(CH2)2-lexitropsin (Me-Lex), a DNA minor groove alkylating compound which generates mainly N3-methyladenine, has cytotoxic and clastogenic 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 cytotoxicity induced by Me-Lex, with respect to p53-null and 3-methylpurine DNA glycosylase-proficient Jurkat cells. In both cell lines, the poly(ADP-ribose) polymerase inhibitor 3-aminobenzamide, which inhibits base excision repair capable of removing N-methylpurines, increases cytotoxicity and clastogenicity induced by Me-Lex or by temozolomide, which generates low levels of N3-methyl adducts. The enhancing effect is more evident at low Me-Lex concentrations, 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 expression of p53 protein and of the X-ray repair cross-complementing 1 transcript (a component of base excision repair). These results indicate that N3-methyladenine inducing agents, alone or combined with poly(ADP-ribose) polymerase inhibitors, could open up novel chemotherapeutic strategies to overcome drug resistance in mismatch repair-deficient leukemic cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Chromosome Aberrations
  • DNA, Neoplasm / drug effects*
  • DNA-Binding Proteins / genetics
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation
  • HT29 Cells
  • Humans
  • Jurkat Cells
  • Mutagens / pharmacology*
  • Netropsin / analogs & derivatives*
  • Netropsin / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Tumor Suppressor Protein p53 / biosynthesis
  • X-ray Repair Cross Complementing Protein 1


  • Antineoplastic Agents
  • DNA, Neoplasm
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Mutagens
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Tumor Suppressor Protein p53
  • X-ray Repair Cross Complementing Protein 1
  • lexitropsin
  • Netropsin