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

Authors' Affiliations: Departments of ¹ Medical Physics, ² Radiology, and ³ Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York and ⁴ Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri

Requests for reprints: Jason A. Koutcher, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 212-639-8834; Fax: 212-717-3676; E-mail: koutchej{at}mskcc.org.

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 ³¹phosphorus MRS–measured tumor bioenergetics; however, a time-dependent increase in the content of extracellular inorganic phosphate (Pi_e) was observed in tumors of collagenase-treated animals. ³¹Phosphorus MRSI showed that this increase underscored a more homogeneous distribution of Pi_e in tumors of experimental mice. ¹⁹Fluorine 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.