Abstract 1769: Significant in vivo activity of an APE1/Ref-1 redox inhibitor, E3330, alone and in combination with Bevacizumab in a glioblastoma mouse model analyzed by a whole slide digital imaging system and quantitative immunohistochemistry

Abstract

Abstract Human apurinic endonuclease/redox factor 1 (APE1/Ref-1) mediates the repair of baseless sites in DNA caused by alkylation and oxidative DNA damage as well as regulates the function of various transcription factors (TF) under redox signaling control (p53, NFkB, HIF-1, AP-1, and others). High levels of APE1 expression have been reported in numerous cancers (glioblastoma, ovarian, pancreatic, prostate, and others) such that APE1 is an emerging target for a variety of novel anticancer drugs. E3330 targets the redox signaling function of APE1 and its activity was studied in vivo using a glioblastoma xenograft mouse model. This preclinical xenograft model evaluated the use of dual anti-angiogenic agents, Bevacizumab (Bev) and E3330, in glioblastoma implanted Nude mice. Four mice groups were used to determine drug effects: E3330, Bev, a combination of E3330 and Bev, and an untreated vehicle control group. Immunohistochemistry (IHC) was used to predict the effectiveness of treatment for glioblastoma based on caspase-3, Ki67, and CD31 biomarker expression. IHC slides were quantified using both a traditional pathology hand count and an image system analysis. The positive pixel data closely mirrored the hand count for all three biomarkers. At the combined dosage, hand count data demonstrated that CD31 levels decreased significantly from the vehicle control group. Ki67 decreased slightly, and caspase-3 was not increased in any of the drug treatment groups. While each drug independently had anti-angiogenic effects, the combined drug group, E3330 and Bev, had anti-angiogenic effects that were greatly enhanced. These results support previous studies demonstrating the anti-angiogenic activity of E3330 and its enhancement of Bevacizumab. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1769. doi:1538-7445.AM2012-1769