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Efficacy of DMP 840: A Novel Bis-Naphthalimide Cytotoxic Agent with Human Solid Tumor Xenograft Selectivity

Cancer Research Group, The DuPont Merck Pharmaceutical Company, Glenolden Laboratory, Glenolden, Pennsylvania 19036 [R. J. M., P. E. B-H., P. M. C., R. J. D., M. A. D.,J. L. D. M., R. J. P.], and Experimental Station, Wilmington, Delaware 19880 [J-H. S., C. H. B., S. P S.]

¹ To whom requests for reprints should be addressed, at The DuPont Merck Pharmaceutical Company, Glenolden Laboratory, 500 South Ridgeway Avenue, Glenolden, PA 19036.

DMP 840, a novel bis-naphthalimide, was evaluated for antitumor efficacy in several tumor models in mice. As measured by a tumor growth inhibition assay, i.v. administration of DMP 840 to athymic nude mice at doses at or below the maximum tolerated dose resulted in curative activity against four human solid tumor xenografts, MX-1 mammary carcinoma, CX-1 and DLD-2 colon adenocarcinomas, and LX-1 lung carcinoma, producing full or incomplete regressions and/or percent tumor growth inhibition of 96%. The efficacy of DMP 840 in the models was dose dependent. The activity of DMP 840 against the human tumors surpassed that demonstrated by several clinically used and investigational anticancer agents. In long-term growth delay studies, DMP 840 induced full regressions in 20 of 20 mice bearing MX-1 tumors, and tumors in one-half of these mice remained regressed for over 5 months. In addition, DMP 840 was curative against exponentially growing DLD-2 tumors staged at 500 mg and MX-1 tumors staged at 1000 mg. The bis-naphthalimide was equally efficacious when administered i.v. or i.p. but was slightly less active after oral dosing. Against both the MX-1 mammary carcinoma and the DLD-2 colon adenocarcinoma, some measure of schedule dependence was observed; the optimum schedule was daily for 9 days. Against LI210 and P388 murine leukemias, DMP 840 demonstrated little or no activity and was inactive against B16 murine melanoma. Overall, these results suggest that DMP 840 may be a human solid tumor selective cytotoxic agent.

² Present address: 25211 271st Avenue, Holcombe, WI 54745.

³ Present address: Institute for Drug Development, 1460 Omicron, San Antonio, TX78245-3217.

⁴ Present address: ChekTec Corporation, 5210 Eastern Avenue, Baltimore, MD 21224.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/16/93. Accepted 11/ 1/93.