title: Metabolite changes in HT-29 xenograft tumors following HIF-1alpha inhibition with PX-478 as studied by MR spectroscopy in vivo and ex vivo.
abstract: The hypoxia-inducible transcription factor (HIF-1alpha) plays a central role in tumor development. PX-478 is an experimental anti-cancer drug known to inhibit HIF-1alpha in experimental tumors. The purpose of this study was to identify MRS-visible metabolic biomarkers for PX-478 response prior to phase I/II clinical trials. Single-voxel in vivo localized (1)H spectra were obtained from HT-29 tumor xenografts prior and up to 24 h after treatment with a single dose of PX-478. Profiles of water-soluble and lipophilic metabolites were also examined ex vivo with both (1)H and (31)P spectroscopy for peak identification and to interrogate the underlying biochemistry of the response. The total choline (tCho) resonance was significantly decreased in vivo 12 and 24 h following treatment with PX-478 and this was confirmed with high-resolution (1)H and (31)P MRS. In non-aqueous extracts, significant reductions in cardiolipin, PtdEtn (phosphatidylethanolamine) and PtdI (phosphatidylinositol) were seen in response to PX-478. Although there were trends to a decrease in lactate (and lipid) resonances in vivo and ex vivo, these changes were not significant. This is in contrast to inhibition of in vitro glucose consumption and lactate production by PX-478 in HT-29 cells. The significant and robust change in tCho has identified this as a potential (1)H MRS-visible biomarker for drug response in vivo while high-resolution spectroscopy indicated that GPC, PC, myoI, PE, GPE, CL, PtdEtn and PtdI are potential ex vivo response biomarkers.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Arizona Cancer Center, Tucson, AZ 85724, USA.
authors.forename: Bénédicte F
authors.initials: BF
authors.lastname: Jordan
authors.forename: Kvar
authors.initials: K
authors.lastname: Black
authors.forename: Ian F
authors.initials: IF
authors.lastname: Robey
authors.forename: Matthew
authors.initials: M
authors.lastname: Runquist
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gillies
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D002794:Choline / Q000737:chemistry; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019344:Lactic Acid / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D016513:Mice, SCID; D009150:Mustard Compounds / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010666:Phenylpropionates / Q000378:metabolism*; D014020:Tissue Extracts / Q000737:chemistry; D014183:Transplantation, Heterologous
chemical_list: C492908:2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide; D014408:Biomarkers, Tumor; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009150:Mustard Compounds; D010666:Phenylpropionates; D014020:Tissue Extracts; D019344:Lactic Acid; D002794:Choline