Treatment with temozolomide and poly(ADP-ribose) polymerase inhibitors induces early apoptosis and increases base excision repair gene transcripts inleukemic cells resistant to triazene compounds

Methylating triazenes have shown marked antileukemic effects, possibly thro ugh generation of a variety of DNA adducts. Cells tolerant to O-6-methylgua nine due to a defect in the mismatch repair system (MRS), might become sens itive to other methyl adducts, by inhibiting the N-methylpurine repair, whi ch requires base excision repair (BER) and poly(ADP-ribose) polymerase (PAD PRP). Therefore, MRS-deficient Jurkat leukemic cells resistant to methylati ng triazenes, have been treated with temozolomide (TZM) and PADPRP inhibito rs. Expression of PADPRP or molecules involved in the BER system [3-methylp urine-DNA glycosylase (MPG) and X-ray repair cross-complementing 1 (XRCC1)] , have been explored. Cytotoxic effects of TZM associated with PADPRP inhib itors are evident shortly after treatment, suggesting that completion of ce ll division is not required for the lethal effect of the drug combination. Increase of PADPRP or MPG transcripts was found after treatment with TZM al one or combined with PADPRP inhibitor. XRCC1 transcript was positively modu lated only in the case of drug combination. This could suggest that in the presence of PADPRP inhibitor, persistence of DNA damage triggers XRCC1 tran scription. Our results suggest that association of TZM and PADPRP inhibitor s might be of benefit for MRS-deficient malignancies unresponsive to the me thylating agent.