Human Apurinic/Apyrimidinic Endonuclease is a Novel Drug Target in Cancer

Abstract

Genomic DNA possesses an inherent instability, at risk from damage by spontaneous base lesions, metabolic by-products, and exogenous sources such as ultraviolet light, ionising radiation and chemical agents. Unrepaired, this damage could result in non-canonical base pairing during replication, leading to the propagation of potentially mutagenic lesions. A number of DNA repair mechanisms have evolved to ensure genomic integrity can be preserved. So critical are these repair pathways that mutations within constituent genes are associated with several cancer predisposition syndromes such as hereditary non-polyposis carcinoma coli (HNPCC) or BRCA-deficient breast and ovarian cancer syndromes (Sweasy, Lang, and DiMaio 2006). Cancer therapies commonly rely upon the induction of DNA damage to exert their effects. Upregulation of DNA repair pathways in cancer is common and may impact upon response to therapy and contribute to development of treatment resistance. Inhibition of DNA repair offers exciting possibilities for the future treatment of cancer. DNA repair constituents may also be used as biomarkers to predict tumour response to treatment and improve outcome prognostication. Pharmacological inhibition of DNA repair might potentiate the effects of anticancer agents, improving response rates, overcoming resistance, and improving outcomes. Furthermore, there may be scope to specifically target tumour cells using DNA repair inhibitors by exploiting genetic differences with normal tissue. Base excision repair (BER) is critical for the repair of damage induced by alkylating chemotherapy agents such as temozolomide and dacarbazine. Targeting BER has shown considerable promise in the form of poly (ADP-ribose) polymerase (PARP) inhibitors, and a number of groups are now focusing on other BER targets. This chapter will provide an overview of the BER pathway, with specific consideration of the compelling evidence base for targeting the critical enzyme apurinic/apyrimidinic endonuclease I (APE1) for cancer therapy.