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 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.
Tentori
L
L
Department of Neurosciences, University of Rome Tor Vergata, Italy.
Vernole
P
P
Lacal
P M
PM
Madaio
R
R
Portarena
I
I
Levati
L
L
Balduzzi
A
A
Turriziani
M
M
Dande
P
P
Gold
B
B
Bonmassar
E
E
Graziani
G
G
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002869:Chromosome Aberrations; D004273:DNA, Neoplasm / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D019073:HT29 Cells; D006801:Humans; D019169:Jurkat Cells; D009153:Mutagens / Q000494:pharmacology*; D009429:Netropsin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D000076105:X-ray Repair Cross Complementing Protein 1
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009153:Mutagens; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016159:Tumor Suppressor Protein p53; D000076105:X-ray Repair Cross Complementing Protein 1; C053654:lexitropsin; D009429:Netropsin