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An ¹⁹F Magnetic Resonance–Based In Vivo Assay of Solid Tumor Methotrexate Resistance: Proof of Principle

Departments of ¹ Medical Physics, ² Organic Synthesis Core Facility, ³ Molecular Pharmacology, ⁴ Pediatrics, ⁵ Medicine, and ⁶ Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: Jason A. Koutcher, Department of Medical Physics/MRI, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 212-639-8834; E-mail: koutchej{at}mskcc.org.

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.

Key Words: methotrexate, osteosarcoma • ¹⁹F magnetic resonance • antifolates • chemotherapy