DNA repair inhibitors

DNA repair is essential for cell survival by preventing the formation of mu tations which can be lethal and in some cases at the origin of tumours. The DNA repair may occur directly by enzymatic removal of damage from the nucl eobase or indirectly, step by step (recognition of the damage, excision, DN A resynthesis). During chemotherapeutic treatment of cancer, the action of DNA repair proteins may lead to tumour cell resistance. This resistance mig ht be overcome by the use of DNA repair inhibitors. The better characterise d repair proteins are O-6 -alkylguanine alkyltransferases (AGT) and poly(AD P-ribose) polymerase (PARP). ACT removes alkylgroups from guanine O-6 posit ion via a one step suicide mechanism. The inhibition of AGT activity result s from alkylation of the enzyme with a reactive O-6 modified guanine analog ue. Encouraging results were obtained in combination with mono-alkylating a gents on cell cultures. O-6-benzylguanine (O-6-BG) has been used in clinica l trials. PARP is implicated in single strand break repair (SSB). This enzy me catalyses the formation of branched (ADP-ribose) polymers using NAD as a unique source of nucleotides. Various compounds including nicotinamide and benzamide analogues appeared to inhibit PARP activity in vitro and in cult ured cells. Promising results have been obtained with excision repair pathw ays: base excision repair (BER) and nucleotide excision repair (NER). Recen tly, gene therapy has been envisaged to introduce DNA repair protein antago nists or p53 protein to trigger apoptosis.