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

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 do...

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Bibliographic Details
Published in:Clinical cancer research 2005-12, Vol.11 (24), p.8782-8788
Main Authors: PRIMEAU, Andrew J, RENDON, Augusto, HEDLEY, David, LILGE, Lothar, TANNOCK, Ian F
Format: Article
Language:English
Subjects:
Animals
Antibiotics, Antineoplastic - analysis
Antibiotics, Antineoplastic - pharmacokinetics
Antineoplastic agents
Biological and medical sciences
blood vessels
Blood Vessels - chemistry
Blood Vessels - pathology
chemotherapy
doxorubicin
Doxorubicin - analysis
Doxorubicin - pharmacokinetics
Drug Resistance, Neoplasm
Humans
hypoxia
Medical sciences
Mice
Microscopy - methods
Neoplasm Transplantation
Neoplasms - blood supply
Neoplasms - metabolism
Neoplasms - pathology
Pharmacology. Drug treatments
Solid tumors
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-05-1664