New strategy identified for improving effectiveness of cancer therapies

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Controlling nitric oxide levels could further improve effectivness of anticancer therapies

Manipulating levels of nitric oxide, a gas involved in many biological processes, may improve the disorganized
network of blood vessels supplying tumors, potentially improving the
effectiveness of radiation and chemotherapy

In advance on-line publication by the
Nature Medicine, researchers from the Steele Laboratory of Radiation
at Massachusetts General Hospital (MGH) report an experiment in which nitric oxide production was selectively suppressed in tumor cells while being maintained
in blood vessels.  The result was a significant improvement in the
appearance and function of the tumor’s blood supply.

“Our finding suggest that the creation of
perivascular nitric oxide gradients – differences between the levels produced in blood
vessels and those found in tumor tissue – may be able to normalize tumor
vasculature,” says Dai Fukumura of the Steele Laboratory
, who led the
study.  “Combining the use of angiogenesis inhibitors, which normalize
vasculature through a different mechanism, with the blockade of nonvascular nitric oxide
production may produce even greater improvement in therapeutic

The blood vessels that develop around and within
tumors are leaky and disorganized, interfering with delivery of chemotherapy
drugs and with radiation treatment, which requires an adequate oxygen
supply.  Combining angiogenesis inhibitors, drugs that suppress the growth
of blood vessels, with traditional anticancer therapies has improved patient
survival in some tumors. That success supports a theory developed by Rakesh K.
, director of the Steele Laboratory, that the agents temporarily
‘normalize’ blood vessels, creating a period during which other treatments can
be more effective.

Since angiogenesis is one of many physiologic
activities mediated by nitric oxide, the MGH research team hypothesized that restricting nitric oxide production to blood vessels also could improve tumor vasculature.  Using
cancer cells from human brain tumors, they suppressed the enzyme that controls nitric oxide production in nonvascular tissue.  When the modified tumor cells were
implanted into mice, analysis of the resulting tumors showed that nitric oxide was present
primarily in blood vessels, with significant reductions in tumor cells. 
Vessels in the growing tumors were more evenly distributed and less distorted
than those in tumors grown from untreated tissue.

“Angiogenesis inhibitors block formation of new
vessels by directly or indirectly inhibiting the proliferation and survival of
vascular endothelial cells.  But since their overall effect is to reduce
the density of blood vessels, the ability of those agents to normalize tumor
vasculature may not last long,” says Fukumura. “Blocking nonvascular nitric oxide
production and maintaining nitric oxide levels around the vessels appears to keep
endothelial cell function at the proper level.” An associate professor of
Radiation Oncology at Harvard Medical School, Fukumura notes that the strategy
now should be investigated in other types of tumors.