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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