In vivo antitumor efficacy of CW252053, a folate-based thymidylate synthase inhibitor

Previous studies have demonstrated that CW252053, a quinazoline antifolate, exhibits potent inhibitory activity against thymidylate synthase (TS) as w ell as cytotoxic activity against tumor cell lines in vitro. In this study, we evaluated the in vivo antitumor efficacy of CW252053 in the mouse tumor model. Female B6D2F(1) mice were injected with LY3.7.2C TK-/- (thymidine k inase deficient mouse lymphoma) cells into the gastrocnemius muscle. Then, CW252053 was administered twice daily by intraperitoneal injection for 10 d ays, and tumor growth was monitored daily by leg diameter measurement. All animals in the vehicle, 5-FU, and low dose (30 mg/kg) CW252053 treated grou ps died between days 12 and 23 because of the tumor burden. In contrast, do sing with 60 mg/kg of CW252053 produced a cure rate against tumor growth of 37.5% and a survival rate of 50%. Even more significantly, a higher dose o f CW252053 (120 mg/kg) elicited both a 100% cure rate and a 100% survival r ate at the termination of the study, confirming that this compound has very potent in vivo antitumor activity against tumor growth. During the experim ental period of this study no signs of toxicity were observed even at the h igh CW252053 dosage rate of 120 mg/kg.