TLK286 is a novel glutathione analog cancer prodrug that has shown significant antitumor activity and improved survival in multiple Phase 2 clinical trials in ovarian, breast, non-small cell lung and colorectal cancers. TLK286 is activated by glutathione S-transferase P1-1 (GST P1-1), an enzyme upregulated in many cancers and often over-expressed in tumor cells resistant to chemotherapeutic agents. The activation of TLK286 is catalyzed by GST P1-1 and involves the cleavage of the molecule to release two electophilic moieties, a vinyl sulfone and a phosphorodiamidate, that induce apoptosis mediated through the stress response pathway. Genetic polymorphism of the human GST P1-1 class exists in codons 105 and 114. Two GST P1-1 alleles, designated as GSTP1*A (Ile105/Ala114) and GSTP1*B (Val105/Ala114), account for over 90% occurrence of the polymorphism in the general population. We report the comparison of GST P1-1/Ile105 and GST P1-1/Val105 variants in the activation TLK286. Using HPLC to monitor and quantitate the cleavage of TLK286, both GST P1-1 variants were equally effective in catalyzing the cleavage. These results suggest that individuals with polymorphism at position 105 of GST P1-1 should have similar capability to activate TLK286 to its proapoptotic fragments.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]