The clinically active PARP inhibitor AG014699 ameliorates cardiotoxicity but does not enhance the efficacy of doxorubicin, despite improving tumor perfusion and radiation response in mice.

ABSTRACT: AG014699 was the first inhibitor of the DNA repair enzyme PARP-1 to enter clinical trial in cancer patients. In addition to enhancing the cytotoxic effect of DNA-damaging chemotherapies, we have previously shown that AG014699 is vasoactive, thereby having the potential to improve drug biodistribution. The effectiveness of the clinical agent doxorubicin is confounded both by poor tumor penetration and cardiotoxicity elicited via PARP hyperactivation. In this study, we analyzed the impact of AG014699 on doxorubicin tolerance and response in breast (MDA-MB-231) and colorectal (SW620, LoVo) tumor models in vitro and in vivo. As anticipated, AG014699 did not potentiate the response to doxorubicin in vitro. In vivo, AG014699 did not influence the pharmacokinetics of doxorubicin; however, it did

SUBMITTER: Ali M 

PROVIDER: S-EPMC3242069 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature