Chemopotentiation by PARP inhibitors in cancer therapy

Poly(ADP-ribose) polymerases (PARP) constitute a family of enzymes involved in the regulation of many cellular processes such as DNA repair, gene transcription, cell cycle progression, cell death, chromatin functions and genomic stability. Among the 18 members identified so far, PARP-1 and PARP-2 are the only proteins stimulated by DNA strand breaks and implicated in the repair of DNA injury. Therefore, these molecules have been exploited as potential targets for the development of pharmacological strategies to increase the antitumor efficacy of chemotherapeutic agents, which induce DNA damage. PARP inhibitors have been shown to restore sensitivity of resistant tumors to methylating agents or topoisomerase 1 inhibitors, drugs presently used for the treatment of primary and secondary brain tumors or malignancies refractory to standard chemotherapy. Interestingly, PARP inhibitors may also provide protection from the untoward effects exerted by certain anticancer drugs, which cause oxidative stress and consequent PARP overactivation. The aim of this article is to provide a brief overview of the recent literature on preclinical studies with the specific and potent inhibitors newly synthesized. (c) 2005 Elsevier Ltd. All rights reserved