Mismatch repair deficiency contributes to tumor cell resistance to O-6-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 N-3-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 N-3-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 N-3-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.

Tentori, L., Vernole, P., Lacal, P.m., Madaio, R., Portarena, I., Levati, L., et al. (2000). Cytotoxic and clastogenic effects of a DNA minor groove binding methyl sulfonate ester in mismatch repair deficient leukemic cells. LEUKEMIA, 14(8), 1451-1459.

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

TENTORI, LUCIO;VERNOLE, PATRIZIA;TURRIZIANI, MARIO;BONMASSAR, ENZO;GRAZIANI, GRAZIA
2000-01-01

Abstract

Mismatch repair deficiency contributes to tumor cell resistance to O-6-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 N-3-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 N-3-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 N-3-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.
2000
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/14 - FARMACOLOGIA
English
Con Impact Factor ISI
Base excision repair; MeOSO2(CH2)2-lexitropsin; Mismatch repair; N3-methyladenine; Poly(ADP-ribose) polymerase
Tentori, L., Vernole, P., Lacal, P.m., Madaio, R., Portarena, I., Levati, L., et al. (2000). Cytotoxic and clastogenic effects of a DNA minor groove binding methyl sulfonate ester in mismatch repair deficient leukemic cells. LEUKEMIA, 14(8), 1451-1459.
Tentori, L; Vernole, P; Lacal, Pm; Madaio, R; Portarena, I; Levati, L; Balduzzi, A; Turriziani, M; Dande, P; Gold, B; Bonmassar, E; Graziani, G
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/52886
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