An 19F magnetic resonance-based in vivo assay of solid tumor methotrexate resistance: proof of principle.
OBJECTIVE
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.


METHODS
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.
Spees
William M
WM
Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. koutchej@mskcc.org
Gade
Terence P F
TP
Yang
Guangli
G
Tong
William P
WP
Bornmann
William G
WG
Gorlick
Richard
R
Koutcher
Jason A
JA
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005461:Fluorine; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008727:Methotrexate / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D000964:Antimetabolites, Antineoplastic; D005461:Fluorine; D008727:Methotrexate