In vivo 5‐fluorouracil and fluoronucleotide <i>T</i><sub>1</sub> relaxation time measurements using the variable nutation angle method

Gade, T.; Spees, William M.; Le, H. Carl; Zakian, Kristen L.; Ponomarev, Vladimir; Doubrovin, Mikhail; Gelovani, Juri G.; Koutcher, Jason A.

doi:10.1002/mrm.20131

Cited by 8 publications

(7 citation statements)

References 17 publications

(28 reference statements)

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“…Each mouse was briefly anesthetized using methoxyflurane and allowed to regain consciousness two hours prior to positioning in order to facilitate the calibration of in vivo pulse-angles as described previously(29). One hour later a 100 μL injection of 0.1% collagenase (n=5) or PBS (n=5) was administered intravenously.…”

Section: Methodsmentioning

confidence: 99%

Imaging Intratumoral Convection: Pressure-Dependent Enhancement in Chemotherapeutic Delivery to Solid Tumors

Gade¹,

Buchanan²,

Motley³

et al. 2008

Clinical Cancer Research

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Purpose Low molecular weight (LMW) chemotherapeutics are believed to reach tumors through diffusion across capillary beds as well as membrane transporters. Unexpectedly, the delivery of these agents appears to be augmented by reductions in tumor interstitial fluid pressure (TIFP), an effect typically associated with high molecular weight molecules which reach tumors principally through convection. We investigated the hypothesis that improved intratumoral convection can alter tumor metabolism and enhance the delivery of a LMW chemotherapeutic agent to solid tumors. Experimental Design For this purpose we applied 31P/19F MR spectroscopy and spectroscopic imaging to examine the influence of type I collagenase on tumor bioenergetics and the delivery of 5-fluorouracil (5FU) to HT29 human colorectal tumors grown subcutaneously in mice. Results Collagenase effected a 34% reduction in TIFP with an attendant disintegration of intratumoral collagen. Neither mice administered collagenase nor controls receiving PBS demonstrated changes in 31PMRS-measured tumor bioenergetics; however, a time-dependent increase in the content of extracellular inorganic phosphate (Pie) was observed in tumors of collagenase-treated animals. 31PMRSI demonstrated that this increase underscored a more homogeneous distribution of Pie in tumors of experimental mice. 19FMRS showed that these changes were associated with a 50% increase in 5FU uptake in tumors of experimental versus control animals; however, this increase resulted in an increase in 5FU catabolites rather than fluoronucleotide intermediates that are required for subsequent cytotoxicity. Conclusions These data indicate that the modulation of convective flow within tumors can improve the delivery of (LMW) chemotherapeutics and demonstrate the potential role for non-invasive imaging of this process in vivo.

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Section: Methodsmentioning

confidence: 99%

Imaging Intratumoral Convection: Pressure-Dependent Enhancement in Chemotherapeutic Delivery to Solid Tumors

Gade¹,

Buchanan²,

Motley³

et al. 2008

Clinical Cancer Research

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“…With these recording conditions, the saturation factor (F sat ) (which represents the fraction of the signal intensity detected relative to that obtained under fully relaxed conditions) calculated using the relation F sat = (1 − E 1 )/(1 − E 1 cos α) with E 1 = e −RT/T 1 and T 1 = 2.3 s (that of FU in rat tumours at 37 • C [78]) is 0.90. Since the T 1 of FU metabolites in vivo at 37 • C are lower than that of FU (1.3 s for FNUCt in rat tumours [78] and 1.6 s for FBAL in human liver [79]), the T 1 values of FU and metabolites at 4 • C are certainly less than 2.3 s. Therefore, the error in metabolite concentrations due to differences in T 1 relaxation times is less than 10%.…”

Section: Spectra Recording Conditions For Quantitative Analysis Of Exmentioning

confidence: 99%

Fluorine-19 or phosphorus-31 NMR spectroscopy: A suitable analytical technique for quantitative in vitro metabolic studies of fluorinated or phosphorylated drugs

Martino

Gilard

Desmoulin

et al. 2005

Journal of Pharmaceutical and Biomedical Analysis

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“…F-MRS. Mice were prepared and positioned for the experiments as described previously (12). Spectral variables included 700 signal averages, 1,024 data points, a 60j flip angle, a 1.7-s repetition time, and a 12-kHz spectral width.…”

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confidence: 99%

Imaging Transgene Activity In vivo

Gade¹,

Koutcher

Spees³

et al. 2008

Cancer Research

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The successful translation of gene therapy for clinical application will require the assessment of transgene activity as a measure of the biological function of a therapeutic transgene. Although current imaging permits the noninvasive detection of transgene expression, the critical need for quantitative imaging of the action of the expressed transgene has not been met. In vivo magnetic resonance spectroscopic imaging (MRSI) was applied to quantitatively delineate both the concentration and activity of a cytosine deaminase-uracil phosphoribosyltransferase (CD-UPRT) fusion enzyme expressed from a transgene. MRSI enabled the generation of anatomically accurate maps of the intratumoral heterogeneity in fusion enzyme activity. We observed an excellent association between the CD-UPRT concentration and activity and the percentage of CD-UPRT + cells. Moreover, the regional levels of UPRT activity, as measured by imaging, correlated well with the biological affect of the enzyme. This study presents a translational imaging paradigm for precise, in vivo measurements of transgene activity with potential applications in both preclinical and clinical settings. [Cancer Res 2008;68(8):2878-84]

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In vivo 5‐fluorouracil and fluoronucleotide T₁ relaxation time measurements using the variable nutation angle method

Cited by 8 publications

References 17 publications

Imaging Intratumoral Convection: Pressure-Dependent Enhancement in Chemotherapeutic Delivery to Solid Tumors

Imaging Intratumoral Convection: Pressure-Dependent Enhancement in Chemotherapeutic Delivery to Solid Tumors

Fluorine-19 or phosphorus-31 NMR spectroscopy: A suitable analytical technique for quantitative in vitro metabolic studies of fluorinated or phosphorylated drugs

Imaging Transgene Activity In vivo

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In vivo 5‐fluorouracil and fluoronucleotide T1 relaxation time measurements using the variable nutation angle method

Cited by 8 publications

References 17 publications

Imaging Intratumoral Convection: Pressure-Dependent Enhancement in Chemotherapeutic Delivery to Solid Tumors

Imaging Intratumoral Convection: Pressure-Dependent Enhancement in Chemotherapeutic Delivery to Solid Tumors

Fluorine-19 or phosphorus-31 NMR spectroscopy: A suitable analytical technique for quantitative in vitro metabolic studies of fluorinated or phosphorylated drugs

Imaging Transgene Activity In vivo

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In vivo 5‐fluorouracil and fluoronucleotide T₁ relaxation time measurements using the variable nutation angle method