Luteinizing hormone-releasing hormone receptor-targeted chemotherapy using AN-152

The luteinizing hormone-releasing hormone (LHRH; also known as gonadotropin-releasing hormone) receptor can be utilized for targeted chemotherapy with cytotoxic LHRH analogues such as AN-152, in which doxorubicin is linked to [D-Lys(6)]LHRH. Our studies demonstrate receptor-mediated actions of the cytotoxic LHRH analogue AN-152 in LHRH receptor-positive endometrial and ovarian tumors in vivo. Intravenous administration of AN-152 is far less toxic and inhibits the growth of LHRH receptor-positive tumors better than equimolar doses of the cytotoxic agent doxorubicin. AN-152 has no antitumor activity in LHRH receptor-negative cancers. This provides evidence for the principle of targeted cytotoxic chemotherapy to tumor cells expressing LHRH receptors. In addition, we were able to show that LHRH binding sites were only slightly reduced after AN-152 treatment. Therefore, repeated therapy is considered to be possible. The majority (80%) of human endometrial and ovarian cancers and about 50% of breast cancers express LHRH receptors. In addition, apart from reproductive organs, which are normally removed during surgical therapy, other organs and hematopoietic stem cells do not express LHRH receptors. Thus, cytotoxic LHRH analogues such as AN-152 appear to be suitable drugs for a more efficacious and less toxic targeted chemotherapy for endometrial and ovarian cancers. A recently finished phase I study assessed the dose limitations, maximum tolerated dose and pharmacokinetics of AN-152 given once every 3 weeks in patients with gynecological and breast cancers. A phase II study was started in January 2008.