This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Swenson, S. Articles by Markland, F. S. Search for Related Content PubMed PubMed Citation Articles by Swenson, S. Articles by Markland, F. S., Jr.

¹ Department of Biochemistry and Molecular Biology and Norris Comprehensive Cancer Center, ² Department of Pathology, and ³ Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA and ⁴ Molecular Express, Los Angeles, CA

Requests for Reprints: Francis S. Markland Jr., Cancer Research Laboratory 106, Keck School of Medicine, University of Southern California, 1303 North Mission Road, Los Angeles, CA 90033. Phone: (323) 224-7981; Fax: (323) 224-7679. E-mail: markland{at}usc.edu

Despite significant research in this area, metastatic breast cancer remains a disease with a poor prognosis. Until an effective therapy is developed, it is imperative that new treatment modalities be investigated. In this report, we describe an effective method for delivery of a novel snake venom disintegrin, contortrostatin (CN), in an orthotopic, xenograft model of human mammary cancer in immunodeficient mice. CN (M_r 13,500) is a homodimeric disintegrin isolated from venom of the Southern Copperhead snake. The homodimer possesses two Arg-Gly-Asp sites, which modulate its interaction with integrins on tumor cells and angiogenic vascular endothelial cells. Although our laboratory has previously described the antitumor activity of CN in a mouse model of human mammary cancer, the method of delivery, daily intratumor injection, was not translatable to clinical application. We now describe a clinically relevant method of administering CN, liposomal delivery (LCN). A unique liposomal system has been designed for i.v. administration of a biologically active protein with full retention of biological activity. Pharmacokinetics, biodistribution, platelet reactivity, and immunogenicity of LCN were determined and compared with similar characteristics of native, unencapsulated CN. There are several advantages to liposomal delivery of CN: (1) LCN has a significantly prolonged circulatory half-life compared with native CN; (2) LCN is passively accumulated in the tumor; (3) LCN has no platelet reactivity; and (4) LCN is not recognized by the immune system. Finally, antiangiogenic activity is an important component of CN's mechanism of antitumor action. We have demonstrated that i.v. delivery of LCN leads to potent antiangiogenic activity in the orthotopic, xenograft human mammary tumor model.

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.

Note: F. S. Markland has declared a financial interest in Pivotal BioSciences, Inc., the product of which, contortrostatin, was studied in the work presented in this article.

Received 12/ 9/03; revised 1/21/04; accepted 2/ 9/04.