title: Targeting of cytotoxic luteinizing hormone-releasing hormone analogs to breast, ovarian, endometrial, and prostate cancers.
abstract: Targeted chemotherapy is a modern approach aimed at increasing the efficacy of systemic chemotherapy and reducing its side effects. The peptide receptors expressed primarily on cancerous cells can serve as targets for a selective destruction of malignant tumors. Binding sites for LHRH (now known in genome and microarray databases as GNRH1), were found on 52% of human breast cancers, about 80% of human ovarian and endometrial cancers, and 86% of human prostatic carcinoma specimens. Because LHRH receptors are not expressed on most normal tissues, they represent a specific target for cancer chemotherapy with antineoplastic agents linked to an LHRH vector molecule. To test the efficacy of targeted chemotherapy based on LHRH analogs, we recently developed a cytotoxic analog of LHRH, designated AN-152, which consists of [D-Lys6]LHRH covalently linked to one of the most widely used chemotherapeutic agents, doxorubicin (DOX). In addition, we designed and synthesized a highly active derivative of DOX, 2-pyrrolino-DOX (AN-201), which is 500-1000 times more potent than DOX in vitro. AN-201 is active against tumors resistant to DOX, and noncardiotoxic. As in the case of DOX, AN-201 was coupled to carrier peptide [D-Lys6]LHRH to form a superactive targeted cytotoxic LHRH analog, AN-207. Both AN-152 and AN-207 can effectively inhibit the growth of LHRH receptor-positive human breast, ovarian, endometrial, and prostate cancers xenografted into nude mice. DOX-containing cytotoxic LHRH analog AN-152 is scheduled for clinical phase I/IIa trials in patients with advanced ovarian and breast cancers in 2005.
authors: Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
authors: Attila
authors: A
authors: Nagy
authors: Andrew V
authors: AV
authors: Schally
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008297:Male; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D011966:Receptors, LHRH / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011758:Pyrroles; D011966:Receptors, LHRH; C098751:AN 204; C104648:AN 207; C080883:LHRH, lysine(6)-doxorubicin; D007987:Gonadotropin-Releasing Hormone; D004317:Doxorubicin