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

Fluorine-19 Magnetic Resonance Angiography of the Mouse

“…The coil was then tuned to 19 F, after which the PCE 19 F resonance frequency was determined with a pulse-acquire [11] sequence (1 shot). 19 F GRE imaging at the same exact anatomical level was then repeated (64×64 resolution, TR/TE = 4.3/1.8 ms, 1024 averages, 4.7 min/slice).…”

Correction: Fluorine-19 Magnetic Resonance Angiography of the Mouse

“…Non-triggered 1 H 1286128 TOF-GRE (TR/TE = 6.1/2.8 ms) and 64664 TOF-GRE (TR/TE = 4.7/2.0 ms) images with a high radiofrequency excititation angle (not quantifiable since it varies with distance from the surface coil) were acquired in the 3 principal directions (field of view 30630 cm 2 , slice thickness 2 or 3 mm, 32 averages, 25 s/slice and 10 s/slice, respectively) as well as 64664 ECG-triggered axial TOF-GRE images through the heart at the same location (4 averages, ,1 min/slice). The coil was then tuned to 19 F, after which the PCE 19 F resonance frequency was determined with a pulse-acquire [11] sequence (1 shot). 19 F GRE imaging at the same exact anatomical level was then repeated (64664 resolution, TR/TE = 4.3/1.8 ms, 1024 averages, 4.7 min/slice).…”

VatuximabTM: Optimizing Therapeutic Strategies for Prostate Cancer Based on Dynamic MR Tumor Oximetry

“…Spees et al [156] followed pharmacokinetics of fluorine-labeled methotrexate in sensitive and resistant tumor xenografts in mice and found an inverse correlation between surviving fraction and area under the curve. …”