AEZS-108 : a targeted cytotoxic analog of LHRH for the treatment of cancers positive for LHRH receptors.
Abstract | INTRODUCTION: Receptors for the luteinizing hormone-releasing hormone [ LHRH, also known as gonadotropin-releasing hormone ( GnRH)] can be regarded as an ideal target for a personalized medicine approach in cancer therapy. LHRH receptors are expressed in about 80% of human endometrial and ovarian cancers, 86% of prostate cancer, and about 50% of breast cancers including triple-negative breast cancer, as well as bladder, colorectal, and pancreatic cancers, sarcomas, lymphomas, melanomas, and renal cell carcinomas. Apart from the pituitary and reproductive organs, other organs and hematopoietic stem cells express LHRH receptors. Thus, a targeted cytotoxic LHRH analog such as AEZS-108 (formerly known as AN-152), in which doxorubin is linked to the LHRH agonist [D-Lys(6)] LHRH, appears to be a suitable drug for targeted chemotherapy of cancers expressing receptors for LHRH, which would be more efficacious and less toxic than standard systemic chemotherapy. AREAS COVERED: This review discusses the development of AEZS-108, its targeting mechanism, preclinical studies, and clinical trials in patients with endometrial, ovarian, prostatic, and bladder cancers. We emphasize its development as a personalized medicine approach. The studies reviewed demonstrate the effects of the cytotoxic LHRH analog, AEZS-108, mediated by LHRH receptors, in in vivo models of LHRH-receptor-positive human endometrial, ovarian, breast, prostatic, colorectal, pancreatic, and bladder cancers xenografted into nude mice. Intravenous administration of AEZS 108 inhibits the growth of LHRH-receptor-positive tumors better than equimolar doses of the cytotoxic agent doxorubicin and is far less toxic. AEZS 108 has no antitumor activity in cancers negative to LHRH receptor. This strongly supports the concept of targeting cytotoxic chemotherapy to tumor cells expressing LHRH receptors. Early clinical trials have demonstrated the efficacy of AEZS-108. A Phase I trial assessed the maximum tolerated dose and pharmacokinetics and pharmacodynamics of AEZS-108 given once every 3 weeks in patients with gynecological cancers. Two Phase II studies in heavily pretreated ovarian and recurrent endometrial cancers showed good clinical activity after a maximum of six courses of AEZS-108 as a single agent. Ongoing clinical studies with AEZS-108 in men with castration-resistant prostate cancer and patients with chemotherapy refractory bladder cancer had shown early signs of clinical efficacy. Side effects are moderate and easily manageable. In particular, no pituitary or cardiac toxicity is observed. EXPERT OPINION:
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Authors | Joerg Engel, Guenter Emons, Jacek Pinski, Andrew V Schally |
Journal | Expert opinion on investigational drugs
(Expert Opin Investig Drugs)
Vol. 21
Issue 6
Pg. 891-9
(Jun 2012)
ISSN: 1744-7658 [Electronic] England |
PMID | 22577891
(Publication Type: Journal Article, Review)
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Chemical References |
- Antineoplastic Agents
- Receptors, LHRH
- LHRH, lysine(6)-doxorubicin
- Gonadotropin-Releasing Hormone
- Doxorubicin
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Topics |
- Animals
- Antineoplastic Agents
(adverse effects, pharmacology, therapeutic use)
- Clinical Trials as Topic
- Doxorubicin
(adverse effects, analogs & derivatives, pharmacology, therapeutic use)
- Drug Delivery Systems
- Drug Evaluation, Preclinical
- Female
- Gonadotropin-Releasing Hormone
(adverse effects, analogs & derivatives, pharmacology, therapeutic use)
- Humans
- Male
- Mice
- Mice, Nude
- Neoplasms
(drug therapy, pathology)
- Receptors, LHRH
(metabolism)
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