1: Mol Cancer Ther. 2006 Jun;5(6):1620-7.

Reversal of temporal and spatial heterogeneities in tumor perfusion identifies
the tumor vascular tone as a tunable variable to improve drug delivery.

Martinive P, De Wever J, Bouzin C, Baudelet C, Sonveaux P, Gregoire V, Gallez B,
Feron O.

Unit of Pharmacology and Therapeutics, UCL Medical School, 53 Ave E. Mounier,
B-1200 Brussels, Belgium.

Maturation of tumor vasculature involves the recruitment of pericytes that
protect the endothelial tubes from a variety of stresses, including
antiangiogenic drugs. Mural cells also provide mature tumor blood vessels with
the ability to either relax or contract in response to substances present in the
tumor microenvironment. The observed cyclic alterations in tumor blood flow and
the associated deficit in chemotherapeutic drug delivery could in part arise
from this vasomodulatory influence. To test this hypothesis, we focused on
endothelin-1 (ET-1), which, besides its autocrine effects on tumor cell growth,
is a powerful vasoconstrictor. We first document that an ET(A) receptor
antagonist induced relaxation of microdissected tumor arterioles and selectively
and quantitatively increased tumor blood flow in experimental tumor models. We
then combined dye staining of functional vessels, fluorescent microsphere-based
mapping, and magnetic resonance imaging to identify heterogeneities in tumor
blood flow and to examine the reversibility of such phenomena. Data from all
these techniques concurred to show that administration of an ET(A) receptor
antagonist could reduce the extent of underperfused tumor areas, proving the key
role of vessel tone variations in tumor blood flow heterogeneity. We also
provide evidence that ET(A) antagonist administration could, despite an increase
in tumor interstitial fluid pressure, improve access of cyclophosphamide to the
tumor compartment and significantly influence tumor growth. In conclusion, tumor
endogenous ET-1 production participates largely in the temporal and spatial
variations in tumor blood flow. ET(A) antagonist administration may wipe out
such heterogeneities, thus representing an adjuvant strategy that could improve
the delivery of conventional chemotherapy to tumors.

PMID: 16818522 [PubMed - in process]

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