Imaging intratumoral convection: Pressure-dependent enhancement in chemotherapeutic delivery to solid tumors Journal Article


Authors: Gade, T. P. F.; Buchanan, I. M.; Motley, M. W.; Mazaheri, Y.; Spees, W. M.; Koutcher, J. A.
Article Title: Imaging intratumoral convection: Pressure-dependent enhancement in chemotherapeutic delivery to solid tumors
Abstract: 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 seems to be augmented by reductions in tumor interstitial fluid pressure, an effect typically associated with high - molecular weight molecules that 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 magnetic resonance spectroscopy (MRS) and magnetic resonance spectroscopic imaging (MRSI) to examine the influence of type I collagenase on tumor bioenergetics and the delivery of 5-fluorouracil (5FU) to HT29 human colorectal tumors grown s.c. in mice. Results: Collagenase effected a 34% reduction in tumor interstitial fluid pressure with an attendant disintegration of intratumoral collagen. Neither mice-administered collagenase nor controls receiving PBS showed changes in <sup>31</sup>phosphorus MRS - measured tumor bioenergetics; however, a time-dependent increase in the content of extracellular inorganic phosphate (Pi<sub>e</sub>) was observed in tumors of collagenase-treated animals. <sup>31</sup>Phosphorus MRSI showed that this increase underscored a more homogeneous distribution of Pi<sub>e</sub> in tumors of experimental mice. <sup>19</sup>Fluorine MRS 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 show the potential role for noninvasive imaging of this process in vivo. © 2009 American Association for Cancer Research.
Keywords: controlled study; unclassified drug; human cell; fluorouracil; nonhuman; solid tumor; antineoplastic agents; magnetic resonance imaging; mouse; animals; mice; animal experiment; animal model; in vivo study; colorectal neoplasms; drug uptake; mice, nude; image enhancement; colorectal tumor; collagen; magnetic resonance spectroscopy; nuclear magnetic resonance spectroscopy; thermodynamics; drug cytotoxicity; tumor growth; pressure; collagenase; collagenase type 1; phosphate; bioenergy; cell strain ht29; distribution volume; drug transport; extracellular fluid; fluorine nuclear magnetic resonance; membrane transport; molecular weight; non invasive procedure; phosphorus nuclear magnetic resonance; tissue pressure; collagenases; convection; energy metabolism; ht29 cells; phosphates
Journal Title: Clinical Cancer Research
Volume: 15
Issue: 1
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2009-01-01
Start Page: 247
End Page: 255
Language: English
DOI: 10.1158/1078-0432.ccr-08-0611
PUBMED: 19118052
PROVIDER: scopus
PMCID: PMC4217124
DOI/URL:
Notes: --- - "Cited By (since 1996): 3" - "Export Date: 30 November 2010" - "CODEN: CCREF" - "Source: Scopus"
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MSK Authors
  1. Jason A Koutcher
    266 Koutcher
  2. Terence P Gade
    13 Gade
  3. Matthew W Motley
    2 Motley