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Molecular Biology

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

Leukemia volume 14, pages 1451–1459 (2000)Cite this article

Abstract

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.

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Acknowledgements

This study was supported by a grant from the Italian Association for Cancer Research (AIRC) and, partly, by MURST funds to E Bonmassar (Molecular bases for the pharmacological control of neoplastic diseases). The study on chromosome aberrations was supported by MURST funds to P Vernole.

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Authors and Affiliations

  1. Department of Neurosciences, Section of Pharmacology and Medical Oncology University of Rome Tor Vergata, Rome, Italy

    L Tentori, R Madaio, I Portarena, A Balduzzi, M Turriziani, E Bonmassar & G Graziani

  2. Department of Public Health and Cell Biology University of Rome Tor Vergata, Rome, Italy

    P Vernole

  3. ‘Istituto Dermopatico dell'Immacolata’ (IDI-IRCCS), Rome, Italy

    PM Lacal, L Levati & E Bonmassar

  4. Eppley Institute for Research in Cancer and Allied Diseases and Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA

    P Dande & B Gold

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Tentori, L., Vernole, P., Lacal, P. et al. Cytotoxic and clastogenic effects of a DNA minor groove binding methyl sulfonate ester in mismatch repair deficient leukemic cells. Leukemia 14, 1451–1459 (2000). https://doi.org/10.1038/sj.leu.2401842

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