Powerful Inhibition of Experimental Human Pancreatic Cancers by Receptor Targeted Cytotoxic LH-RH analog AEZS-108
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Karoly Szepeshazi1,2, Andrew V. Schally1,2,3,4,5, Norman L. Block1,2,3,4, Gabor Halmos1,2,3,6, Mehrdad Nadji3, Luca Szalontay1,2, Irving Vidaurre1,2, Andrew Abi-Chaker1,2,3, Ferenc G. Rick1,2,7
1 Veterans Affairs Medical Center, Miami, FL
2 South Florida VA Foundation for Research and Education, Miami, FL
3 Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL
4 Division of Hematology/Oncology, University of Miami, Miller School of Medicine, Miami, FL
5 Division of Endocrinology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL
6 Department of Biopharmacy, School of Pharmacy, University of Debrecen, Hungary;
7 Department of Urology, Florida International University, Herbert Wertheim College of Medicine, Miami, FL
Andrew V Schally, email:
Ferenc G. Rick, email:
Keywords: pancreatic carcinoma, targeted therapy, LH-RH receptor, cytotoxic LHRH analog, GnRH, doxorubicin, peptide therapy
Received: May 20, 2013 Accepted: June 1, 2013 Published: June 3, 2013
Pancreatic carcinoma is one of the cancers with the worse prognosis, thus any therapeutic improvement is imperative. Cytotoxic LH-RH analog, AN-152 (proprietary designation, AEZS-108), consisting of doxorubicin (DOX) conjugated to D-Lys6LH-RH, is now in clinical trials for targeted therapy of several sex hormone-dependent tumors that express LH-RH receptors. We investigated LH-RH receptors in human pancreatic carcinoma and the effects of AN-152 (AEZS-108) on experimental pancreatic cancers. We determined LH-RH receptor presence in human pancreatic cancer samples by immunohistochemistry and, in three human pancreatic cancer lines (SW-1990, Panc-1 and CFPAC-1), by binding assays and Western blotting. The effects of the cytotoxic LH-RH analog were investigated on growth of these same cancer lines xenografted into nude mice. We also analyzed differences between the antitumor effects of the cytotoxic analog and its cytotoxic radical alone, doxorubicin (DOX), on the expression of cancer-related genes by PCR arrays. LH-RH receptors were expressed in two randomly selected surgically removed human pancreatic cancer samples and in all three cancer lines. Cytotoxic LH-RH analogs powerfully inhibited growth of all three tumor lines in nude mice; AN-152 was significantly stronger than DOX on Panc-1 and CFPAC-1 cancers. PCR array showed that cytotoxic LH-RH analog AN-152 affected the expression of genes associated with cellular migration, invasion, metastasis and angiogenesis more favorably than DOX, however the changes in gene expression varied considerably among the three cancer lines. Cytotoxic LH-RH analog, AEZS-108, may be a useful agent for the treatment of LH-RH receptor positive advanced pancreatic carcinoma.
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