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The first clinical trial of a PARP inhibitor was designed shortly before the concept of synthetic lethality emerged. Single agent activity was not anticipated and, based upon pre-clinical evaluation, PARP inhibition was envisaged as a means to overcome tumour resistance to chemotherapy. The mechanism of action of methylating agents and topoisomerase 1 poisons made these the agents of choice in early combinations, as they were for other DNA repair inhibitors. The pleiotropic effects of PARP inhibition and in vitro evidence supported widening the potential partner drugs to include platinums. The emergence of synthetic lethality brought combinations with drugs used to treat BRCA deficient tumours into play and the clinical trials with these agents are also discussed in this chapter. More recently the interaction between hypoxia, DNA damage processing and PARP sensitivity has suggested new combinations with novel agents, particularly anti-angiogenics, although clinical data are sparse.

Original publication




Journal article


Cancer Drug Discovery and Development

Publication Date





511 - 531