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MEN4901/T-0128, a New Camptothecin Derivative–Carboxymethyldextran Conjugate, Has Potent Antitumor Activities in a Panel of Human Tumor Xenografts in Nude Mice

¹ Experimental Cancer Chemotherapy Research Laboratories Co., Ltd.; ² Association for Anticancer Drug Search; ³ Tanabe Seiyaku Co., Ltd.; and ⁴ First Department of Internal Medicine, Osaka City University, Osaka, Japan

Requests for reprints: Masatoshi Kakushima, Tanabe Seiyaku Co., Ltd., 2-50 Kawagishi, 2-Chome, Toda, Saitama 335-8505, Japan. Phone: 81-48-433-8086; Fax: 81-48-433-8027; E-mail: kakusima{at}tanabe.co.jp.

Purpose: The purpose of the present study was to evaluate the antitumor activity and pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human tumor xenografts in comparison with irinotecan (CPT-11) and T-2513.

Experimental Design: We have determined the antitumor activity of MEN4901/T-0128, CPT-11, and T-2513 in BALB/cA Jcl nude mice bearing human gastric (H-81), colon (H-110), lung (Mqnu-1, H-74), esophageal (H-204), liver (H-181), and pancreatic (H-48) cancer lines, which had been serially transplanted s.c. and maintained in nude mice, and characterized the pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human gastric carcinoma St-4.

Results: MEN4901/T-0128 administered i.v. showed a marked antitumor activity in each of these tumor models, producing tumor shrinkage in the models of H-204 and H-181 carcinomas at its maximum tolerated dose of 80 mg/kg (expressed as T-2513) weekly for 4 weeks (q7d x 4) and tumor-shrinking or marked growth-inhibitory effects in the models of H-81, H-110, Mqnu-1, H-74, and H-48 carcinomas at 1/3 of its maximum tolerated dose (q7d x 4). Pharmacokinetic analysis showed that MEN4901/T-0128 had an extended plasma half-life with sustained tumor levels of T-2513, which may explain the superior activity of MEN4901/T-0128 in vivo.

Conclusions: Because the efficacies of some drugs in this human cancer-nude mouse panel correlated well with their clinical outcomes in patients with the same type of cancers, the findings provide direct support that MEN4901/T-0128 is more efficacious than CPT-11 and is an excellent candidate for clinical trials for the treatment of solid tumors.

Key Words: camptothecin derivative • polysaccharide conjugate • antitumor activity • human tumor xenograft model • chemotherapy