An 19F magnetic resonance-based in vivo assay of solid tumor methotrexate resistance: proof of principle. Academic Article uri icon

Overview

abstract

  • PURPOSE: Studies in oncology have implicated multiple molecular mechanisms as contributors to intrinsic and acquired tumor resistance to antifolate therapy. Here we show the utility of an (19)F-labeled methotrexate (FMTX) with (19)F magnetic resonance to differentiate between sensitive and resistant tumors in vivo and thus predict therapeutic response. EXPERIMENTAL DESIGN: Human sarcoma xenografts in nude mice were used in this study. The sarcoma cell lines chosen for this study (HT-1080, HS-16, and M-805) are well characterized in terms of their methotrexate sensitivity and molecular mechanisms of resistance. The pharmacokinetics of tumor uptake/washout of FMTX were monitored via in vivo (19)F magnetic resonance spectroscopy (pulse/acquire with surface coil localization) following an i.v. bolus injection. Response post-therapy, following leucovorin rescue, was monitored via tumor growth. RESULTS: The three tumor models show differences in both the peak concentrations of tumor FMTX and the dynamics of uptake/retention. These differences are most pronounced for time points late in the magnetic resonance observation period (225-279 minutes post-injection). A statistically significant linear correlation between tumor tissue concentrations of FMTX at these late time points and therapeutic response in the days/weeks post-treatment is shown (R = 0.81, F = 9.27, P < 0.001). Interestingly, a 400 mg/kg i.v. bolus injection of FMTX is a more potent cytotoxic agent in vivo against methotrexate-sensitive tumors than is the parent compound (P = 0.011). CONCLUSIONS: In principle, the assay method described herein could be implemented in the clinic as a diagnostic tool to make decisions regarding therapeutic protocol for the treatment of osteosarcoma on a case-by-case basis.

publication date

  • February 15, 2005

Research

keywords

  • Drug Resistance, Neoplasm
  • Methotrexate
  • Sarcoma

Identity

Scopus Document Identifier

  • 14644388186

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-04-1439

PubMed ID

  • 15746046

Additional Document Info

volume

  • 11

issue

  • 4