DE-310, a novel macromolecular carrier system for the camptothecin analog DX-8951f: potent antitumor activities in various murine tumor models.

Abstract

DE-310 is a novel macromolecular conjugate composed of DX-8951f, a camptothecin analog, and a carboxymethyldextran polyalcohol carrier, which are covalently linked via a peptidyl spacer. In a murine Meth A (fibrosarcoma) solid tumor model, once daily x 5 treatments (qd x 5) with DX-8951f at the maximum tolerated dose (MTD) were required to shrink the tumor, and DX-8951f (qd x 5) at 1/4 MTD was required to inhibit tumor growth. A single treatment (qd x 1) with DE-310 at the MTD or 1/4 MTD shrank the tumor, with no body weight loss occurring at 1/4 MTD. Even at 1/16 MTD, DE-310 inhibited tumor growth. In a long-term assay, Meth A solid tumors disappeared in mice treated with DE-310 (qd x 1) at the MTD and 1/2 MTD, and all 6 mice remained tumor-free on the 60th day after administration. Repeated injection (4 times) on schedules of every 3 days, 7 days or 14 days demonstrated that multiple treatment with DE-310 produced greater tumor growth delay than a single treatment with DE-310. Against 5 human tumor (colon and lung cancer) xenografts in mice, DE-310 (qd x 1) was as effective as DX-8951f administered once every 4 days, 4 times. The life-prolonging activity of DE-310 was assessed in lung (3LL, Lewis lung carcinoma) and liver (M5076, histiocytoma) metastasis models. Against 3LL, DE-310 (qd x 1) at the MTD to 1/3 MTD significantly prolonged survival, with an increase in life span (ILS) of 4.8- to 1.6-fold, respectively, over that in untreated control mice. Also, DE-310 (qd x 1) significantly prolonged survival in the liver metastasis model of M5076. These results demonstrate that DE-310 is a promising agent for the treatment of cancer.