We have previously demonstrated that KS119W, a novel hypoxia-selective anticancer agent, possesses antitumor activities against murine EMT-6 and human H460 tumors in mice. Based on these results, we predicted that combination therapy of KS119W and a chemotherapeutic agent that targets the normoxic tumor cells would produce an additive or synergistic effect. The present study was undertaken to evaluate this strategy by using KS119W at doses below the maximum tolerated dose in combination with non-toxic doses of cyclophosphamide (CTX) or gemcitabine (GEM) against murine EMT-6 and human H460 tumors in nude mice. Treatments began when the size of the tumors reached approximately 150 mm3. In the H460 tumor model, animals were treated intraperitoneally (ip) with 180-240mg/kg per dose of KS119W, on days 1, 7, 14, and 22. CTX was given at 100mg/kg, ip, on the same days. In a different experiment, GEM was given at 75-120mg/kg, on days 1, 7, 14 and 21. CTX or GEM was given two hours after KS119W dosing. KS119W alone inhibited H460 tumor growth by 78.2% (p=0.006) whereas CTX produced 54.5% inhibition (p=0.039). The combination treatment of KS119W and CTX resulted in 89.8% inhibitory effects (p=0.003), comparing to untreated controls. In the EMT-6 model, treatment of KS119W at 97mg/kg (7 daily doses) inhibited tumor growth by 58.5%. CTX at 100mg/kg, ip, once per week for 4 weeks, generated a negligible tumor growth inhibition. Combination treatment of KS119W and CTX inhibited tumor growth by 91.8% (p=0.0001, comparing to untreated controls). Similar antitumor effects were also observed in animals treated with a combination of KS119W and GEM. Immunohistochemical studies were also used to evaluate the effects of KS119W in tumors. KS119W profoundly reduced tumor cell proliferation around hypoxic areas. KS119W enhanced the cytotoxic effect of GEM and significantly increased the necrotic area. These results show that KS119W, in combination with conventional antitumor agents, could present a therapeutic advantage for future cancer therapy.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]