Biol. Pharm. Bull. 28(2) 217—223 (2005)

new blood vessels to provide an adequate supply of nutrients to cancer cells and sustain their growth and invasiveness, has been shown to be fundamental for the growth and metastasis of solid tumors. The use of antiangiogenic molecules may represent a novel approach to cancer treatment and more than 35 antiangiogenic inhibitors are currently being tested in clinical trials in cancer patient. Among the most potent inhibitors of angiogenesis is the fumagillin family of natural products. The antiangiogenic activity of fumagillin was discovered serendipitously from a fungal contamination of an endothelial cell culture. An analog of fumagillin, known as TNP-470 or AGM-1470 has been undergoing clinical cancers, and TNP-470 has been shown to inhibit endothelial cell growth with high potency both in culture and in vivo. Newly, CKD-732 (Fig. 1), a fumagillin anticancer drug, was developed by Chong Kun Dang Co. and this compound possesses the antiangiogenic activity in tumor treatment. According to information from company, CKD-732 showed much better efficacy than other fumagillol derivatives in vivo and vitro. It was demonstrated that effect of CKD-732 (IC50 4.36 10 3 ng/ml) on HUVEC proliferation was superior to that of Fumagillin (IC50 0.21 ng/ml) and TNP-470 (IC50 7.4 10 2 ng/ml). In human tumor PC-3 (prostate adenocarcinoma) and A375-SM bearing athymic nude mice, the effect of CKD-732 on increasing of life span was twofold better than that of Fumagillin. In examination on stasis of tumor growth in nude mice, the effect of CKD-732 was also shown to be similar to that of Fumagillin (unpublished data). The present studies were conducted to examine the general pharmacologic properties of high doses of CKD-732. The study of general pharmacologic properties is intended to provide an indication of the potential side effects resulting from the secondary pharmacologic activity of high doses of agents. The doses utilized in the present studies were selected in order to fully examine the potential pharmacologic activity of CKD-732, and therefore represent vast multiples of clinically effective doses of drug.