Receptor-targeted therapy of human experimental urinary bladder cancers with cytotoxic LH-RH analog AN-152 (AEZS-108)

Karoly Szepeshazi, Andrew V. Schally, Gunhild Keller, Norman L. Block, Daniel Benten, Gabor Halmos, Luca Szalontay, Irving Vidaurre, Miklos Jaszberenyi, Ferenc G. Rick

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25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)686-699
Number of pages14
JournalOncotarget
Volume3
Issue number7
DOIs
Publication statusPublished - Jul 2012

Keywords

  • Cytotoxic
  • Doxorubicin
  • LH-RH receptor
  • Targeted therapy
  • Urinary bladder
  • Urothelial cancer

ASJC Scopus subject areas

  • Oncology

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    Szepeshazi, K., Schally, A. V., Keller, G., Block, N. L., Benten, D., Halmos, G., Szalontay, L., Vidaurre, I., Jaszberenyi, M., & Rick, F. G. (2012). Receptor-targeted therapy of human experimental urinary bladder cancers with cytotoxic LH-RH analog AN-152 (AEZS-108). Oncotarget, 3(7), 686-699. https://doi.org/10.18632/oncotarget.546