1: Cancer Res.  2004 May 1;64(9):3209-14.  

Endothelin-1 is a critical mediator of myogenic tone in tumor arterioles:
implications for cancer treatment.

Sonveaux P, Dessy C, Martinive P, Havaux X, Jordan BF, Gallez B, Gregoire V,
Balligand JL, Feron O.

University of Louvain Medical School, Unit of Pharmacology and Therapeutics
(FATH 5349), Brussels, Belgium.

Although derived from the host tissue, the tumor vasculature is under the
influence of the tumor microenvironment and needs to adapt to the resistance to
blood flow inherent to the dynamics of tumor growth. Such vascular remodeling
can offer selective targets to pharmacologically modulate tumor perfusion and
thereby improve the efficacy of conventional anticancer treatments. Radiotherapy
and chemotherapy can, indeed, take advantage of a better tumor oxygenation and
drug delivery, respectively, both partly dependent on the tumor blood supply.
Here, we showed that isolated tumor arterioles mounted in a pressure myograph
have the ability, contrary to size-matched healthy arterioles, to contract in
response to a transluminal pressure increase. This myogenic tone was exquisitely
dependent on the endothelin-1 pathway because it was completely abolished by the
selective endothelin receptor A (ETA) antagonist BQ123. This selectivity was
additionally supported by the large increase in endothelin-1 abundance in tumors
and the higher density of the ETA receptors in tumor vessels. We also documented
by using laser Doppler microprobes and imaging that administration of the ETA
antagonist led to a significant increase in tumor blood flow, whereas the
perfusion in control healthy tissue was not altered. Finally, we provided
evidence that acute administration of the ETA antagonist could significantly
stimulate tumor oxygenation, as determined by electron paramagnetic resonance
oximetry, and increase the efficacy of low-dose, clinically relevant
fractionated radiotherapy. Thus, blocking the tumor-selective increase in the
vascular endothelin-1/ETA pathway led us to unravel an important reserve of
vasorelaxation that can be exploited to selectively increase tumor response to
radiotherapy.

PMID: 15126361 [PubMed - in process]