Anti-tumor Effects of Targeted Follicle-stimulatingHormone-lytic Peptide Conjugates in ProstateCancer (PC-3) Xenograft Mouse Model

Conjugates of membrane disrupting lytic peptides with a 15-amino acid segment of the β chain of chorionic gonadotropin (CG) or luteinizing hormone releasing hormone (LHRH) target and destroy cancer cell xenografts in nude mouse model. Follicle stimulating hormone receptors (FSHR) have been detected in tumor neo-vascular endothelial cells of a variety of cancers and tumor tissue in prostate and ovarian cancers. In the present study, we have conjugated a lytic peptide (Phor18) to each of three segments of the β chain of FSH that bind to FSHR, and tested these conjugates (FSH90-95-Phor18, FSH81-95-Phor18 and FSH33-53-Phor18) for their ability to target and inhibit growth of prostate cancer cells in vivo. We found that intravenous administration of FSH90-95-Phor18, FSH81-95-Phor18 and FSH33-53-Phor18 significantly (p<0.05) inhibited the growth of prostate cancer (PC-3) xenografts in nude mice. The minimal effective dose of FSH81-95-Phor18 was 0.1 mg/kg and 1 mg/kg for FSH9095-Phor18 and FSH33-53-Phor18. Immunohistochemical analyses of tumor sections at necropsy showed dense expression of FSHR on vascular endothelial cells in control mice, reduced expression in tumors of mice treated with FSH90-95-Phor18, FSH81-95-Phor18 or FSH33-53-Phor18. FSH8195-Phor18 had the most potent anti-angiogenic activity of the three conjugates tested. These data show that a lytic peptide conjugated to FSH β chain segments bind to FSHR and are capable of inhibiting prostate cell tumor growth by targeting and destroying endothelial cells that express