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


Authors: Spees, W. M.; Gade, T. P. F.; Yang, G.; Tong, W. P.; Bornmann, W. G.; Gorlick, R.; Koutcher, J. A.
Article Title: An 19F magnetic resonance-based in vivo assay of solid tumor methotrexate resistance: Proof of principle
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. © 2005 American Association for Cancer Research.
Keywords: osteosarcoma; controlled study; human cell; cytotoxic agent; nonhuman; solid tumor; methotrexate; mouse; animal experiment; animal model; in vivo study; cancer cell culture; sarcoma; correlation analysis; drug mechanism; xenograft; nude mouse; folinic acid; nuclear magnetic resonance spectroscopy; tumor growth; folic acid antagonist; drug sensitivity; nuclear magnetic resonance; fluorine
Journal Title: Clinical Cancer Research
Volume: 11
Issue: 4
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2005-02-15
Start Page: 1454
End Page: 1461
Language: English
DOI: 10.1158/1078-0432.ccr-04-1439
PROVIDER: scopus
PUBMED: 15746046
DOI/URL:
Notes: --- - "Cited By (since 1996): 3" - "Export Date: 24 October 2012" - "CODEN: CCREF" - "Source: Scopus"
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MSK Authors
  1. William M Spees
    5 Spees
  2. William Bornmann
    107 Bornmann
  3. William Ping-Yiu Tong
    119 Tong
  4. Richard G Gorlick
    120 Gorlick
  5. Jason A Koutcher
    233 Koutcher
  6. Guangli Yang
    21 Yang
  7. Terence P Gade
    13 Gade