title: Growth hormone receptor antagonism suppresses tumour regrowth after radiotherapy in an endometrial cancer xenograft model.
abstract: Human GH expression is associated with poor survival outcomes for endometrial cancer patients, enhanced oncogenicity of endometrial cancer cells and reduced sensitivity to ionising radiation in vitro, suggesting that GH is a potential target for anticancer therapy. However, whether GH receptor inhibition sensitises to radiotherapy in vivo has not been tested. In the current study, we evaluated whether the GH receptor antagonist, pegvisomant (Pfizer), sensitises to radiotherapy in vivo in an endometrial tumour xenograft model. Subcutaneous administration of pegvisomant (20 or 100 mg/kg/day, s.c.) reduced serum IGF1 levels by 23% and 68%, respectively, compared to vehicle treated controls. RL95-2 xenografts grown in immunodeficient NIH-III mice were treated with vehicle or pegvisomant (100 mg/kg/day), with or without fractionated gamma radiation (10 × 2.5 Gy over 5 days). When combined with radiation, pegvisomant significantly increased the median time tumours took to reach 3× the pre-radiation treatment volume (49 days versus 72 days; p = 0.001). Immunohistochemistry studies demonstrated that 100 mg/kg pegvisomant every second day was sufficient to abrogate MAP Kinase signalling throughout the tumour. In addition, treatment with pegvisomant increased hypoxic regions in irradiated tumours, as determined by immunohistochemical detection of pimonidazole adducts, and decreased the area of CD31 labelling in unirradiated tumours, suggesting an anti-vascular effect. Pegvisomant did not affect intratumoral staining for HIF1α, VEGF-A, CD11b, or phospho-EGFR. Our results suggest that blockade of the human GH receptor may improve the response of GH and/or IGF1-responsive endometrial tumours to radiation.
authors.affiliation: Liggins Institute, University of Auckland, Auckland 1023, New Zealand.
authors.forename: Angharad
authors.initials: A
authors.lastname: Evans
authors.affiliation: Auckland Cancer Society Research Centre, University of Auckland, Auckland 1023, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand.
authors.forename: Stephen M F
authors.initials: SM
authors.lastname: Jamieson
authors.affiliation: Liggins Institute, University of Auckland, Auckland 1023, New Zealand.
authors.forename: Dong-Xu
authors.initials: DX
authors.lastname: Liu
authors.affiliation: Auckland Cancer Society Research Centre, University of Auckland, Auckland 1023, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand.
authors.forename: William R
authors.initials: WR
authors.lastname: Wilson
authors.affiliation: Liggins Institute, University of Auckland, Auckland 1023, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand. Electronic address: j.perry@auckland.ac.nz.
authors.forename: Jo K
authors.initials: JK
authors.lastname: Perry
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D059248:Chemoradiotherapy; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology*; D019382:Human Growth Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011986:Receptors, Somatotropin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D000072258:Tumor Hypoxia; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D006727:Hormone Antagonists; C583557:IGF1 protein, human; D011838:Radiation-Sensitizing Agents; D011986:Receptors, Somatotropin; C519530:insulin-like growth factor-1, mouse; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases; C406545:pegvisomant
keywords: Endometrial cancer; Growth hormone; Pegvisomant; RL95-2; Radiation; Xenograft