Intravenous liposomal delivery of the snake venom disintegrin contortrostatin limits breast cancer progression.

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 (Mr 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.

Topographical distribution of bronchial eosinophilia: significance for biopsy diagnosis.

Field-by-field (0.324 x 0.09 microM) counts of eosinophils were applied to the lamina propria of cartilaginous bronchi from 47 Los Angeles and 22 Miami residents 11 to 30 years of age who died suddenly from violence. A highly variable topographical distribution was found that appeared to be due mainly to variations in confluent eosinophil-positive fields and "hot spots" (>or=3 eosinophils per field). Since biopsy is the gold standard for the diagnosis of bronchial eosinophilia, there is a need to resolve the problem of non-uniformity. New measurements applicable to biopsy diagnosis are presented having potential usefulness for providing insight into the severity and topographical distribution of eosinophilia within bronchi that are the sites of biopsy. The additional finding of a 30.4% incidence of moderate to marked eosinophilia (>1.5 eosinophils/mm reticular basement membrane) suggests a high level of asthma or asthmatic-like disease in the young subjects of this study.