Receptor-targeted therapy of human experimental urinary bladder cancers with cytotoxic LH-RH analog AN-152 (AEZS-108)
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Karoly Szepeshazi 1,2, Andrew V. Schally1,2,3,4,5, Gunhild Keller6, Norman L. Block1,2,3,4, Daniel Benten7, Gabor Halmos1,2,3,8, Luca Szalontay1,2, Irving Vidaurre1,2, Miklos Jaszberenyi1,2,3, Ferenc G. Rick1,2,3
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 Section of Hematology/Oncology, University Clinic, Hamburg, Germany
7 Department of Gastroenterology University Clinic, Hamburg, Germany
8 Department of Biopharmacy, School of Pharmacy, University of Debrecen, Hungary
Andrew V. Schally, email:
Ferenc G. Rick, email:
Keywords: urinary bladder, urothelial cancer, targeted therapy, LH-RH receptor, cytotoxic, doxorubicin
Received: July 11, 2012, Accepted: July 20, 2012, Published: July 22, 2012
Many bladder cancers progress to invasion with poor prognosis; new therapeutic methods are needed. We developed a cytotoxic LH-RH analog, AN-152 (AEZS-108) containing doxorubicin (DOX), for targeted therapy of cancers expressing LHRH receptors. We investigated the expression of LH-RH receptors in clinical bladder cancers and in HT-1376, J82, RT-4 and HT-1197 human bladder cancer lines. The effect of analog, AN-152, on growth of these tumor lines xenografted into nude mice was analyzed. Using molecular and functional assays, we also evaluated the differences between the effects of AN-152, and DOX alone. We demonstrated the expression of LH-RH receptors on 18 clinical bladder cancers by immunohistochemistry and on four human urinary bladder cancer lines HT-1376, J82, RT-4 and HT-1197 by Western blotting and binding assays. AN-152 powerfully inhibited growth of these bladder cancers in nude mice. AN-152 exerted greater effects than DOX and was less toxic. DOX activated strong multidrug resistance mechanisms in RT-4 and HT-1197 cancers, while AN-152 had no or less such effect. PCR assays and in vitro studies revealed differences in the action of AN-152 and DOX on the expression of genes involved in apoptosis. These results suggest that targeted cytotoxic LH-RH analog, AN-152 (AEZS-108), should be examined for treatment of patients with LH-RH receptor positive invasive bladder cancers.
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