The in vivo selection of the R-enantiomer of KS119W (VNP40541) as a potential anticancer agent

4717 KS119W, a novel hypoxia-selective anti-tumor agent, was recently shown to be active against a variety of solid tumor models including murine breast carcinoma (EMT-6), human non-small cell lung carcinoma (H460) and human small cell lung carcinoma (SHP77) in mice. However, KS119W is a racemic compound consisting of two enantiomers, R-KS119W and S-KS119W. In cell culture studies utilizing EMT-6 cells exposed to a hypoxic environment, both enantiomers of KS119W appeared to have similar cytotoxic effects. We then compared the efficacy and toxicity of R-KS119W with those of S-KS119W and racemic KS119W in murine tumor models. EMT-6-bearing Balb/c mice, H460-bearing Nu/nu CD1 mice and SHP77-bearing SCID/Beige mice were grouped randomly when the size of the tumors reached approximately 120-150 mm3, and then treated with daily intraperitoneal injections of racemic KS119W, R-KS119W, or S-KS119W from low dose to a maximum tolerated dose (MTD). The results demonstrated that the isomers were clearly different from one another in terms of drug potency; R-KS119W was less potent than but equally efficacious as S-KS119W. Using the same dosing schedule, the MTD of R-KS119W was 140 mg/kg on athymic Nu/nu mice and 100 mg/kg on Balb/c mice, whereas the MTD of S-KS119W was 80 mg/kg on athymic Nu/nu mice and 85 mg/kg on Balb/c mice. However, the efficacy and therapeutic windows of the two enantiomers were very similar. In H460 tumor-bearing athymic Nu/nu mice, R-KS119W, at doses from 80-140 mg/kg, yielded 52-80% tumor growth inhibition, whereas S-KS119W, with doses at 40-80 mg/kg, yielded 53-80% tumor growth inhibition. In EMT-6 tumor-bearing Balb/c mice, the treatment with R-KS119W at doses ranging from 85-100 mg/kg resulted in 58-69% tumor growth inhibition, whereas S-KS119W administered at doses ranging from 55-85 mg/kg resulted in 52-78% of tumor inhibition. The adverse side effects of the two enantiomers, however, were different. The mice treated with S-KS119W showed more weight loss and anemia, and developed irreversible edema at higher doses, but the mice treated with R-KS119W had mild toxicity, much fewer edemas, and could recover from the drug toxicities. In summary, racemic KS119W, R-KS119W and S-KS119W have similarities in efficacy and therapeutic window, but, unlike S-KS119W, R-KS119W at the MTD showed mild and reversible side effects. Therefore, R-KS119W is considered a better candidate for potential human clinical trials in the treatment of solid cancers.