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An 19F magnetic resonance-based in vivo assay of solid tumor methotrexate resistance: proof of principle
- Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research. 11(4)
- Publication Year :
- 2005
-
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.
- Subjects :
- Male
Cancer Research
Pathology
medicine.medical_specialty
Antimetabolites, Antineoplastic
Magnetic Resonance Spectroscopy
medicine.drug_class
Mice, Nude
Antimetabolite
chemistry.chemical_compound
Mice
Pharmacokinetics
In vivo
Cell Line, Tumor
medicine
Animals
Humans
medicine.diagnostic_test
Dose-Response Relationship, Drug
Chemistry
Magnetic resonance imaging
Sarcoma
Fluorine
medicine.disease
Xenograft Model Antitumor Assays
Methotrexate
Treatment Outcome
Oncology
Drug Resistance, Neoplasm
Antifolate
Cancer research
Osteosarcoma
Cell Division
medicine.drug
Subjects
Details
- ISSN :
- 10780432
- Volume :
- 11
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Accession number :
- edsair.doi.dedup.....2b0afeb616008ff444c2464c54ed43ab