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

L. Tentori, P. Vernole, P. M. Lacal, R. Madaio, I. Portarena, L. Levati, A. Balduzzi, M. Turriziani, P. Dande, B. Gold, E. Bonmassar, G. Graziani

Research output: Contribution to journalArticle

Abstract

Mismatch repair deficiency contributes to tumor cell resistance to O6-guanine methylating compounds and to other antineo-plastic 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 agents. 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.

Original languageEnglish
Pages (from-to)1451-1459
Number of pages9
JournalLeukemia
Volume14
Issue number8
Publication statusPublished - 2000

Keywords

  • Base excision repair
  • MeOSO(CH)-lexitropsin
  • Mismatch repair
  • N-methyladenine
  • Poly(ADP-ribose) polymerase

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

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    Tentori, L., Vernole, P., Lacal, P. M., Madaio, R., Portarena, I., Levati, L., Balduzzi, A., Turriziani, M., Dande, P., Gold, B., Bonmassar, E., & Graziani, G. (2000). Cytotoxic and clastogenic effects of a DNA minor groove binding methyl sulfonate ester in mismatch repair deficient leukemia cells. Leukemia, 14(8), 1451-1459.