title: Hypoxia-regulated glucose transporter Glut-1 may influence chemosensitivity to some alkylating agents: results of EORTC (First Translational Award) study of the relevance of tumour hypoxia to the outcome of chemotherapy in human tumour-derived xenografts.
abstract: Tumour hypoxia confers poor prognosis in a wide range of solid tumours, due to an increased malignancy, increased likelihood of metastasis and treatment resistance. Poorly oxygenated tumours are resistant to both radiation therapy and chemotherapy. However, although the link between radiation therapy and hypoxia is well established in a range of clinical studies, evidence of its influence on chemotherapy response is lacking. In this study, a panel of human tumour-derived xenografts that have been characterised previously for in vivo response to a large series of anti-cancer agents, and have been found to show chemosensitivities that correlate strongly with the parent tumour, were used to address this issue. Immunohistochemistry was carried out on formalin-fixed, paraffin-embedded sections of xenograft samples to detect expression of the intrinsic hypoxia marker Glut-1 and adducts of the bioreductive hypoxia marker pimonidazole. Glut-1 scores correlated significantly with T/C values for CCNU sensitivity (r = 0.439, P = 0.036, n = 23) and showed a borderline significant correlation with dacarbazine T/C (r = 0.405, P = 0.076, n = 20). However, there was no correlation between both Glut-1 and pimonidazole scores and T/C obtained for the bioreductive drug mitomycin C. The use of human tumour-derived xenografts offers a potentially useful way of using archival material to determine the influence of hypoxia and other tumour-microenvironmental factors on chemosensitivity without the direct use of human subjects.
authors.affiliation: School of Pharmacy and Chemistry, Liverpool John Moores University, Liverpool, L3 3AF, UK. r.airley@livjm.ac.uk
authors.forename: R E
authors.initials: RE
authors.lastname: Airley
authors.forename: R M
authors.initials: RM
authors.lastname: Phillips
authors.forename: A E
authors.initials: AE
authors.lastname: Evans
authors.forename: J
authors.initials: J
authors.lastname: Double
authors.forename: A M
authors.initials: AM
authors.lastname: Burger
authors.forename: H H
authors.initials: HH
authors.lastname: Feibig
authors.forename: C M L
authors.initials: CM
authors.lastname: West
authors.forename: I J
authors.initials: IJ
authors.lastname: Stratford
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D015415:Biomarkers; D015687:Cell Hypoxia; D000091342:Endoplasmic Reticulum Chaperone BiP; D051272:Glucose Transporter Type 1; D006360:Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000502:physiology; D009004:Monosaccharide Transport Proteins / Q000502:physiology*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D018906:Antineoplastic Agents, Alkylating; D015415:Biomarkers; D000091342:Endoplasmic Reticulum Chaperone BiP; D051272:Glucose Transporter Type 1; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009004:Monosaccharide Transport Proteins; C495677:SLC2A1 protein, human; C495678:Slc2a1 protein, mouse