An 19F magnetic resonance-based in vivo assay of solid tumor methotrexate resistance: Proof of principle

William M. Spees, Terence P.F. Gade, Guangli Yang, William P. Tong, William G. Bornmann, Richard Gorlick, Jason A. Koutcher

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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 19F-labeled methotrexate (FMTX) with 19F 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 19F 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.

Original languageEnglish (US)
Pages (from-to)1454-1461
Number of pages8
JournalClinical Cancer Research
Volume11
Issue number4
DOIs
StatePublished - Feb 15 2005

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Spees, W. M., Gade, T. P. F., Yang, G., Tong, W. P., Bornmann, W. G., Gorlick, R., & Koutcher, J. A. (2005). An 19F magnetic resonance-based in vivo assay of solid tumor methotrexate resistance: Proof of principle. Clinical Cancer Research, 11(4), 1454-1461. https://doi.org/10.1158/1078-0432.CCR-04-1439