Zoptarelin doxorubicin

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Zoptarelin doxorubicin
Zoptarelin doxorubicin.svg
Systematic (IUPAC) name
[2-[(2S,4S)-4-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1H-tetracen-2-yl]-2-oxo-ethyl] 5-[[(5R)-6-[[(1S)-1-[[(1S)-1-[(2S)-2-[(2-amino-2-oxo-ethyl)carbamoyl]pyrrolidine-1-carbonyl]-4-guanidino-butyl]carbamoyl]-3-methyl-butyl]amino]-5-[[(2S)-2-[[(2S)-3-hydroxy-2-[[(2S)-2-[[(2S)-3-(1H-imidazol-5-yl)-2-[[(2S)-5-oxopyrrolidine-2-carbonyl]amino]propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-oxo-hexyl]amino]-5-oxo-pentanoate
Clinical data
Legal status
  • Investigational
ATC code None
PubChem CID 16134409
ChemSpider 17290938
Synonyms AN-152; AEZS-108
Chemical data
Formula C91H117N19O26 
Molecular mass 1893.01 g/mol

Zoptarelin doxorubicin consists of doxorubicin linked to a small peptide agonist to the luteinizing hormone-releasing hormone (LHRH) receptor.[1] It has been developed as a potential treatment for a number of human cancers. The LHRH receptor is aberrantly present on the cell surface of approximately 80% of endometrial and ovarian cancers, 86% of prostate cancers and about 50% of breast cancers. Whereas in normal tissues, expression of this receptor is mainly confined to the pituitary gland, reproductive organs and hematopoietic stem cells. To a lesser extent the LHRH receptor is also found on the surface of bladder, colorectal, and pancreatic cancers, sarcomas, lymphomas, melanomas, and renal cell carcinomas.[2]

The proposed method of action is that upon administration zoptarelin doxorubicin binds to the LHRH receptor and is subsequently internalized, concentrating the toxic doxorubicin within cancer cells and the small subset of normal tissues, as opposed to the completely systemic distribution observed with untargeted chemotherapeutics. The specific targeting of the doxorubicin to LHRH receptor bearing cells is also proposed to reduce the cardiotoxicity observed in the administration of unconjugated doxorubicin.

Zoptarelin doxorubicin is also known as AEZS-108 (previously AN-152).

Zoptarelin doxorubicin was developed by Andrew V. Schally while at the Tulane University School of Medicine, New Orleans and subsequently at the Sylvester Comprehensive Cancer Center, University of Miami.

The U.S. Food and Drug Administration (FDA) has granted it orphan drug status for ovarian cancer and endometrial cancer.

Clinical trials[edit]

Promising results have been reported from a phase II clinical trial for ovarian cancer[3] and endometrial cancer.[4] Phase II trials have also been undertaken for prostate, breast and bladder cancer, although no results for these trials have been reported in peer-reviewed literature. A phase I trial in prostate cancer indicated that nine out ten evaluable patients achieved disease stabilization through administration of zoptarelin doxorubicin.[5]

A phase III trial for endometrial cancer was initiated in April 2013 and it the primary completion date is estimated to be December 2015.[6]


  1. ^ Rékási, Z; Szöke, B; Nagy, A; Groot, K; Rékási, E. S.; Schally, A. V. (1993). "Effect of luteinizing hormone-releasing hormone analogs containing cytotoxic radicals on the function of rat pituitary cells: Tests in a long term superfusion system". Endocrinology 132 (5): 1991–2000. doi:10.1210/endo.132.5.8477650. PMID 8477650.  edit
  2. ^ Engel, J; Emons, G; Pinski, J; Schally, A. V. (2012). "AEZS-108 : A targeted cytotoxic analog of LHRH for the treatment of cancers positive for LHRH receptors". Expert Opinion on Investigational Drugs 21 (6): 891–9. doi:10.1517/13543784.2012.685128. PMID 22577891.  edit
  3. ^ Emons, G; Gorchev, G; Sehouli, J; Wimberger, P; Stähle, A; Hanker, L; Hilpert, F; Sindermann, H; Gründker, C; Harter, P (2014). "Efficacy and safety of AEZS-108 (INN: Zoptarelin doxorubicin acetate) an LHRH agonist linked to doxorubicin in women with platinum refractory or resistant ovarian cancer expressing LHRH receptors: A multicenter phase II trial of the ago-study group (AGO GYN 5)". Gynecologic Oncology 133 (3): 427–32. doi:10.1016/j.ygyno.2014.03.576. PMID 24713545.  edit
  4. ^ Emons, G; Gorchev, G; Harter, P; Wimberger, P; Stähle, A; Hanker, L; Hilpert, F; Beckmann, M. W.; Dall, P; Gründker, C; Sindermann, H; Sehouli, J (2014). "Efficacy and safety of AEZS-108 (LHRH agonist linked to doxorubicin) in women with advanced or recurrent endometrial cancer expressing LHRH receptors: A multicenter phase 2 trial (AGO-GYN5)". International Journal of Gynecological Cancer 24 (2): 260–5. doi:10.1097/IGC.0000000000000044. PMC 3921259. PMID 24418927.  edit
  5. ^ Liu, S. V.; Tsao-Wei, D. D.; Xiong, S; Groshen, S; Dorff, T. B.; Quinn, D. I.; Tai, Y. C.; Engel, J; Hawes, D; Schally, A. V.; Pinski, J (2014). "Phase I, Dose-Escalation Study of the Targeted Cytotoxic LHRH Analog AEZS-108 in Patients with Castration- and Taxane-Resistant Prostate Cancer". Clinical Cancer Research. doi:10.1158/1078-0432.CCR-14-0489. PMID 25278449.  edit
  6. ^ Clinicaltrials.gov identifier NCT01767155