title: Potentiation of mammary cancer inhibition by combination of antagonists of growth hormone-releasing hormone with docetaxel.
abstract: Antagonists of growth hormone-releasing hormone (GHRH) are being developed for the treatment of various cancers. In this study, we investigated the effectiveness of treatment with GHRH antagonist JMR-132 alone and in combination with docetaxel chemotherapy in nude mice bearing MX-1 human breast cancers. Specific high-affinity binding sites for GHRH were found on MX-1 tumor membranes using ligand competition assays with (125)I-labeled GHRH antagonist JV-1-42. JMR-132 displaced radiolabeled JV-1-42 with an IC(50) of 0.14 nM, indicating a high affinity of JMR-132 to GHRH receptors. Treatment of nude mice bearing xenografts of MX-1 with JMR-132 at 10 microg per day s.c. for 22 days significantly (P < 0.05) inhibited tumor volume by 62.9% and tumor weight by 47.8%. Docetaxel given twice at a dose of 20 mg/kg i.p. significantly reduced tumor volume and weight by 74.1% and 58.6%, respectively. Combination treatment with JMR-132 (10 microg/day) and docetaxel (20 mg/kg i.p.) led to growth arrest of most tumors as shown by an inhibition of tumor volume and weight by 97.7% and 95.6%, respectively (P < 0.001). Because no vital cancer cells were detected in some of the excised tumors, a total regression of the tumors was achieved in some cases. Treatment with JMR-132 also strongly reduced the concentration of EGF receptors in MX-1 tumors. Our results demonstrate that GHRH antagonists might provide a therapy for breast cancer and could be combined with docetaxel chemotherapy to enhance the efficacy of treatment.
authors.affiliation: Veterans Affairs Medical Center and Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Buchholz
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Engel
authors.forename: Florian
authors.initials: F
authors.lastname: Hohla
authors.forename: Elmar
authors.initials: E
authors.lastname: Heinrich
authors.forename: Frank
authors.initials: F
authors.lastname: Koester
authors.forename: Jozsef L
authors.initials: JL
authors.lastname: Varga
authors.forename: Gabor
authors.initials: G
authors.lastname: Halmos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000517:prevention & control*; D051379:Mice; D008819:Mice, Nude; D043823:Taxoids / Q000494:pharmacology*; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D013007:Growth Hormone-Releasing Hormone