During poly (ADP) ribosylation, PARP1 utilizes NAD+ to synthesize poly (ADP)-ribose units either on itself or on a variety of nuclear target proteins such as histones, topoisomerases, DNA polymerases and DNA ligases. This results in highly negative charged nuclear proteins, which in turn leads to the unwinding and repair of the damaged DNA through the base excision repair (BER) pathway. PARP inhibitors offer potential therapies for a wide variety of diseases such as inflammatory conditions, diabetes complications, neurological diseases, stroke and myocardial infarction. However, presently, the most prominent clinical role for PARP inhibitors lies within the field of oncology especially the breast cancer susceptibility proteins (BRCA) resistant breast and ovarian cancers. Inhibition of PARP sensitizes tumor cells to cytotoxic drugs that induce DNA damage that would normally be repaired through the BER pathway. PARP1 inhibitors have consistently demonstrated potentiating effects on the DNAalkylating agent temozolomide (TMZ) in preclinical studies, including experimental models of solid tumors such as glioma, melanoma, colorectal, and breast cancer. PARP1 inhibitors have been demonstrated to sensitize tumors to DNA-alkylating agents (TMZ and cyclophosphamide) as well as topoisomerase I poisons such as camptothecin and irinotecan (CPT-11) . The PARP1 counteracts camptothecin action by facilitating resealing of DNA strand breaks. Hence, PARP1 inhibition hampers topoisomerase-I activity favoring the toxic effects of the enzyme poisons. Indeed, preclinical in vivo studies have shown that the combination of the PARP1 inhibitor CEP-6800 and CPT-11 significantly reduces tumor volume of HT-29 colon carcinoma subcutaneous xenografts compared to CPT-11 monotherapy. TMZ is a second generation DNA-alkylating agent and although TMZ was not effective in a phase II clinical trial against metastatic breast cancer as a monotherapy. It is currently in phase II clinical trial in combination with the PARP1 inhibitor AG014699 from Pfizer and demonstrated promising results in a phase I trial.
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