Combined effects of adenovirus-mediated wild-type p53 transduction, temozolomide and poly (ADP-ribose) polymerase inhibitor in mismatch repair deficient and non-proliferating tumor cells

Lack of p53 or mismatch repair (MR) function and scarce cell proliferation are commonly associated with tumor cell resistance to antineoplastic agents , Recently, inhibition of poly(ADP-ribose) polymerase(PARP) has been cons i de red as a tool to overcome resistance of MR-deficient tumors to methylati ng agents. In the present study we demonstrated that infection with p53 exp ressing adenovirus (Ad-p53), enhances chemosensitivity of MR-deficient tumo r cell lines to the methylating agent temozolomide (TZM), either used as si ngle agent or, more efficiently, when combined with PARP inhibitor. Moreove r, the association of Ad-p53 with drug treatment induced a more pronounced growth inhibitory effect than that provoked by Ad-p53 infection only. Cells , growth arrested by p53 transduction, and then subsequently exposed to the drugs, were still highly susceptible to cytotoxicity induced by TZM and PA RP inhibitor. The results suggested that this drug combination might be eff ective even in nonproliferating tumor cells, It is conceivable to envisage future possible strategies to enhance cytostatic or cytotoxic effects induc ed by Ad-p53, based on the use of TZM, alone or combined with PARP inhibito r for the therapy of resistant tumors.