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A phase I–II evaluation of veliparib (NSC#737664), topotecan, and filgrastim or pegfilgrastim
Poly(ADP-ribose) polymerase (PARP) acts as a constitutively-expressed nuclear tankyrase enzyme primarily involved in mammalian base excision DNA repair [1–3]. PARP rapidly catalyzes the new synthesis of ADP-ribose branching polymers from its substrate nicotinamide adenine dinucleotide, creating negatively-charged, branching scaffolds upon which other nuclear proteins such as DNA polβ, X-ray repair cross-complementing factor 1 (XRCC1), and DNA ligase III co-localize to DNA [4,5]. As such, PARP functions as a key regulator of both base excision DNA damage repair and DNA duplication [5–10].
In PARP knockout mouse models, 80–90% of PARP-dependent base excision repair in DNA becomes significantly impaired after deletion of PARP-1 [8,9]. Residual DNA repair occurs through PARP-2 activity [9]. PARP activity rises 500-fold when the enzyme binds to DNA strand breaks—in the absence of such binding, poly(ADP-ribose) polymer synthesis is negligible. These findings suggest that only PARP-1 and PARP-2 need to be pharmacologically blocked to disrupt base excision repair in mammalian DNA [3]. PARP inhibition sensitizes cancer cells both to cytotoxic chemotherapy, such as alkylators (temozolomide, cyclophosphamide) or topoisomerase inhibitors (irinotecan, topotecan, camptothecin), and to ionizing radiation—all of which induce DNA damage requiring base excision repair [11–15]. Expression of PARP has been shown to be higher in cancer cells as compared to normal cells [16], and its overexpression associates with cytotoxic drug resistance. Two-fold elevated PARP-1 expression has been detected in uterine cervix cancer cells as compared to normal cells [16].
Veliparib (ABT-888) is an orally available equipotent small molecule pharmacological inhibitor of PARP-1 and PARP-2, whose single oral dose of 10 mg reduces PARP activity by at least 75–85% in cancer cells [12,13]. Preclinical pharmacologically-relevant veliparib-topotecan treatments in in vitro uterine cervix squamous cancer cells demonstrated enhanced cancer cell death after exposure to the combination [5]. A molecular mechanism for this finding involved collapsed topotecan-poisoned replication forks, formation of topotecan-related single-strand DNA nicks, and conversion of those nicks into lethal double-strand breaks when DNA repair was impeded by veliparib [5].
