title: Effective targeted chemotherapy using AEZS-108 (AN-152) for LHRH receptor-positive pancreatic cancers.
abstract: Pancreatic cancer is the fourth commonest cause of cancer-related mortality across the world. Because of the poor response to conventional chemotherapy, small molecules, radiation therapy and surgery, development of new targeted therapies is necessary. In the present study, we have analyzed expression of the luteinizing hormone releasing hormone (LHRH) receptor in specimens of human pancreatic cancers. Furthermore, we have investigated in vitro and in vivo whether the cytotoxic LHRH agonist AEZS-108 (AN-152) induces apoptosis in human pancreatic cancer cells that express LHRH receptors. LHRH receptor expression in tumor specimens of human pancreatic cancers was assessed using immunohistochemistry. Cell proliferation was analyzed using the alamar blue proliferation assay. Induction of apoptosis was analyzed using the TUNEL assay and quantified by measurement of loss of mitochondrial membrane potential. In vivo experiments were performed using nude mice bearing xenografted human pancreatic tumors. Thirteen of 40 human pancreatic adenocarcinomas (32.5%) expressed LHRH receptors. We were able to show that treatment of LHRH receptor-positive MiaPaCa-2 and Panc-1 human pancreatic cancer cells with AEZS-108 (AN-152) resulted in apoptotic cell death in vitro. The antitumor effects could be confirmed in nude mice. AEZS-108 (AN-152) inhibited the growth of xenotransplants of human pancreatic cancers in nude mice significantly, without any apparent side effects. The cytotoxic LHRH agonist AEZS-108 (AN-152) seems to be a suitable drug for treatment of LHRH receptor-positive human pancreatic cancers with little toxicity.
authors.affiliation: Department of Gynecology and Obstetrics, Georg-August University, Robert Koch Street 40, Göttingen 37075, Germany. grundker@med.uni-goettingen.de
authors.forename: Carsten
authors.initials: C
authors.lastname: Gründker
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ernst
authors.forename: Madita D
authors.initials: MD
authors.lastname: Reutter
authors.forename: B Michael
authors.initials: BM
authors.lastname: Ghadimi
authors.forename: Günter
authors.initials: G
authors.lastname: Emons
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D053938:DNA Fragmentation; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011966:Receptors, LHRH / Q000819:agonists / Q000378:metabolism*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D011966:Receptors, LHRH; C080883:LHRH, lysine(6)-doxorubicin; D007987:Gonadotropin-Releasing Hormone; D004317:Doxorubicin