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

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

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

The hypoxia-inducible transcription factor (HIF- 1α) plays a central role in tumor development. PX-478 is an experimental anti-cancer drug known to inhibit HIF- 1α i 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 1H 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 1H and 31P 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 1H and 31P 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 PtdI are potential ex vivo response biomarkers.

Original languageEnglish
Pages (from-to)430-439
Number of pages10
JournalNMR in biomedicine
Volume18
Issue number7
DOIs
StatePublished - Nov 2005

Keywords

  • Cancer chemotherapy
  • H-MRS
  • HIF-1α
  • HT-29 tumor xenografts
  • PX-478

Fingerprint

Dive into the research topics of 'Metabolite changes in HT-29 xenograft tumors following HIF-1α inhibition with PX-478 as studied by MR spectroscopy in vivo and ex vivo'. Together they form a unique fingerprint.

Cite this