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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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

Fingerprint

Methotrexate
Magnetic Resonance Spectroscopy
Neoplasms
Sarcoma
Injections
Therapeutics
Folic Acid Antagonists
Leucovorin
Cytotoxins
Osteosarcoma
Clinical Protocols
Heterografts
Nude Mice
Research Design
Pharmacokinetics
Observation
fluoresceinated methotrexate
Cell Line
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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

An 19F magnetic resonance-based in vivo assay of solid tumor methotrexate resistance : Proof of principle. / Spees, William M.; Gade, Terence P F; Yang, Guangli; Tong, William P.; Bornmann, William G.; Gorlick, Richard; Koutcher, Jason A.

In: Clinical Cancer Research, Vol. 11, No. 4, 15.02.2005, p. 1454-1461.

Research output: Contribution to journalArticle

Spees, WM, Gade, TPF, Yang, G, Tong, WP, Bornmann, WG, Gorlick, R & Koutcher, JA 2005, 'An 19F magnetic resonance-based in vivo assay of solid tumor methotrexate resistance: Proof of principle', Clinical Cancer Research, vol. 11, no. 4, pp. 1454-1461. https://doi.org/10.1158/1078-0432.CCR-04-1439
Spees, William M. ; Gade, Terence P F ; Yang, Guangli ; Tong, William P. ; Bornmann, William G. ; Gorlick, Richard ; Koutcher, Jason A. / An 19F magnetic resonance-based in vivo assay of solid tumor methotrexate resistance : Proof of principle. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 4. pp. 1454-1461.
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N2 - 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.

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