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The Distribution of the Anticancer Drug Doxorubicin in Relation to Blood Vessels in Solid Tumors

Authors' Affiliations: ¹ Divisions of Applied Molecular Oncology, ² Biophysics and Bioimaging, and ³ Medical Oncology and Hematology, Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada

Requests for reprints: Ian F. Tannock, Princess Margaret Hospital, Suite 5-208, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9. Phone: 416-946-2000; Fax: 416-946-2082; E-mail: ian.tannock{at}uhn.on.ca.

Purpose: Anticancer drugs gain access to solid tumors via the circulatory system and must penetrate the tissue to kill cancer cells. Here, we study the distribution of doxorubicin in relation to blood vessels and regions of hypoxia in solid tumors of mice.

Experimental Design: The distribution of doxorubicin was quantified by immunofluorescence in relation to blood vessels (recognized by CD31) of murine 16C and EMT6 tumors and human prostate cancer PC-3 xenografts. Hypoxic regions were identified by injection of EF5.

Results: The concentration of doxorubicin decreases exponentially with distance from tumor blood vessels, decreasing to half its perivascular concentration at a distance of about 40 to 50 µm, The mean distance from blood vessels to regions of hypoxia is 90 to 140 µm in these tumors. Many viable tumor cells are not exposed to detectable concentrations of drug following a single injection.

Conclusions: Limited distribution of doxorubicin in solid tumors is an important and neglected cause of clinical resistance that is amenable to modification. The technique described here can be adapted to studying the distribution of other drugs within solid tumors and the effect of strategies to modify their distribution.

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