Abstract 4443: PB-42: Design and characterization of a glutathione pro-drug selectively delivered to normal tissue and not tumor tissue

Abstract

Abstract The vast majority of cancer treatment regimens involve cytotoxic chemotherapy or radiation with a narrow therapeutic index. More than ½ of all approved anticancer drugs are associated with generation of reactive oxygen species. We have developed a molecule that selectively increases glutathione in normal tissues while not protecting cancer cells. Our compound has a backbone of the glutathione (GSH) precursor γ-glutamyl cysteine, with each acid group protected by ethyl ester moieties. The PB-42 molecule then leverages the dramatic differences in endothelial alkaline phosphatase between normal and cancerous tissues, similar to amifostine. Selectivity is based on a phosphorothioate moiety that requires activation by alkaline phosphatase. We have developed a robust, scalable synthetic pathway for PB-42. Cultured cells incubated with PB-42 dramatically increase intracellular GSH and total nonprotein sulfhydral (NPSH) levels several fold over controls. This process is totally dependent on activation with alkaline phosphatase. Increased GSH and NPSH levels translate into dramatic resistance to the cytotoxic effects of common chemotherapeutic agents such as cisplatin or melphalan. GSH increases are not inhibited by prior incubation with the γ-glutamyl cysteine synthase inhibitor buthionine sulfoximine (BSO), demonstrating that PB-42 enters into the GSH synthetic pathway beyond the allosterically controlled step and is not simply providing intracellular cysteine. Cells initially depleted of endogenous GSH with BSO demonstrated dramatic increases in GSH after co-incubation with PB-42 and alkaline phosphatase. PB-42 was well tolerated in vivo and was able to abrogate cisplatin-induced nephrotoxicity. PB-42 could offer several advantages in selective protection against the toxic effects of chemotherapy and radiation therapy as compared to amifostine, in that it generates the natural sulfhydral GSH, that in addition to acting as a bulk thiol, also participates in a number of enzyme based protective systems. Note: This abstract was not presented at the meeting. Citation Format: James P. Thomas, Peter G. Geiger. PB-42: Design and characterization of a glutathione pro-drug selectively delivered to normal tissue and not tumor tissue. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4443. doi:10.1158/1538-7445.AM2015-4443