Emergence of truly “Individualized” therapy: The poly (adenosine diphosphate-ribose) polymerase inhibitors

Abstract

Introduction: The process of DNA surveillance for, and repair of, intrinsic and extrinsic injury is complex, redundant, and necessary for cell viability. An enzyme family involved in this oversight is the poly (adenosine diphosphate [ADP]-ribose) polymerases (PARPs), which primarily function to repair single strand injury [1]. PARP enacts this function through a process known as nucleotide base excision and repair. It was recently discovered that the inhibition of PARP promotes the probability for double strand DNA breaks at replication forks. Under normal conditions, these injuries are managed through successful error-free homologous recombination [2]. However, if this function is further thwarted, DNA damage ensues, leading to catastrophic genetic aberrations and mortality. Such is the case in cells that harbor mutations in BRCA1 or BRCA2. These tumor suppressor genes, known for their association with familial breast, ovarian, and prostate cancer, among others, play an active role in homologous recombination under normal conditions. BRCA1 appears to function predominately in the signaling of DNA double strand breaks, whereas BRCA2 appears mechanistically important to the homologous repair process itself [3]. Nevertheless, when tumors develop in patients who are heterozygous for a mutant allele, the otherwise compensating normal BRCA allele becomes compromised or inactivated, enabling cumulative DNA injury. The apparent signifi cant role of PARP in DNA repair under these circumstances led to the hypothesis that PARP inhibition in cells lacking BRCA-directed homologous recombination would be lethal. Further, because PARP inhibition in cells heterozygous for BRCA is no more toxic than in cells with normal BRCA, the hypothetical therapeutic window would appear to be large [4,5].