DNA repair inhibitors

Abstract

DNA repair is essential for cell survival by preventing the formation of mutations 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 nucleobase or indirectly, step by step (recognition of the damage, excision, DNA resynthesis). During chemotherapeutic treatment of cancer, the action of DNA repair proteins may lead to tumour cell resistance. This resistance might be overcome by the use of DNA repair inhibitors. The better characterised repair proteins are O⁶-alkylguanine alkyltransferases (AGT) and poly(ADP-ribose) polymerase (PARP). AGT removes alkylgroups from guanine O⁶ position via a one step suicide mechanism. The inhibition of AGT activity results from alkylation of the enzyme with a reactive O⁶modified guanine analogue. Encouraging results were obtained in combination with mono-alkylating agents on cell cultures. O⁶-benzylguanine (O⁶-BG) has been used in clinical trials. PARP is implicated in single strand break repair (SSB). This enzyme 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 cultured cells. Promising results have been obtained with excision repair pathways: base excision repair (BER) and nucleotide excision repair (NER). Recently, gene therapy has been envisaged to introduce DNA repair protein antagonists or p53 protein to trigger apoptosis.

• alkyl transferase
• alkylguanine
• DNA repair inhibitors
• excision repair
• poly(ADP-ribose)polymerase