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Metabolite changes in HT-29 xenograft tumors following HIF-1 alpha inhibition with PX-478 as studied by MR spectroscopy in vivo and ex vivo

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Jordan, Bénédicte [UCL] Black, Kvar Robey, Ian F. Runquist, Matthew Powis, Garth Gillies, Robert J.

The hypoxia-inducible transcription factor (HIF-1 alpha) plays a central role in tumor development. PX-478 is an experimental anti-cancer drug known to inhibit HIF-1 alpha 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 H-1 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 H-1 and P-31 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 P-31 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 1H MRS-visible biomarker for drug response in vivo while high-resolution spectroscopy indicated that GPC, PC, myol, PE, GPE, CL, PtdEtn and Ptdl are potential ex vivo response biomarkers. Copyright (c) 2005 John Wiley & Sons, Ltd.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2005
Language Anglais
Journal information "NMR in Biomedicine" - Vol. 18, no. 7, p. 430-439 (2005)
Peer reviewed yes
Publisher John Wiley & Sons, Ltd. ((United Kingdom) London)
issn 0952-3480
e-issn 1099-1492
Publication status Publié
Affiliation UCL - MD/FARM - Ecole de pharmacie
Keywords HT-29 tumor xenografts ; HIF-1 alpha ; PX-478 ; cancer chemotherapy ; H-MRS
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Bibliographic reference Jordan, Bénédicte ; Black, Kvar ; Robey, Ian F. ; Runquist, Matthew ; Powis, Garth ; et. al. Metabolite changes in HT-29 xenograft tumors following HIF-1 alpha inhibition with PX-478 as studied by MR spectroscopy in vivo and ex vivo. In: NMR in Biomedicine, Vol. 18, no. 7, p. 430-439 (2005)
Permanent URL http://hdl.handle.net/2078.1/38981