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'Smarter' Drugs May Inhibit Tumor Growth By Blocking Angiogenesis or Matrix Metalloproteinase

'Smarter' Drugs May Inhibit Tumor Growth By Blocking Angiogenesis or Matrix Metalloproteinase

TORONTO, Canada--Available cancer drugs have had little specificity,
destroying both cancer cells and normal cells. Now, says Robert
Kerbel, PhD, of Sunnybrook Health Science Centre, University of
Toronto, "we have the potential to design 'smarter' drugs
to help circumvent the problems of toxicity and resistance."
At a media conference at the American Association for Cancer Research
(AACR) annual meeting, Dr. Kerbel introduced two researchers who
have pioneered development of approaches to inhibit cancer development
without harming normal cells.

These approaches are angiogenesis blockers that stop the development
of blood vessels that feed tumors, and matrix metalloproteinase
blockers that suppress an enzyme that appears to play a key role
in tumor growth.

Judah Folkman, MD, of Harvard Medical School and Children's Hospital,
Boston, first made the connection between blood vessels and tumor
growth 25 years ago. Dr. Folkman, who chaired a session on the
topic at the AACR meeting, said that, like an invading army, growing
tumors need supply lines, ie, blood vessels that give them access
to oxygen and nutrients.

Angiogenesis inhibitors turn off the production of those blood
vessels. Dr. Folkman's latest research on mice showed that daily
doses of these drugs not only slowed the growth of tumors but
also, in some cases, stopped metastatic spread of the tumor.

Dr. Folkman's team has identified angiogenesis inhibitors from
several sources, including fungi. But some of the most promising
agents occur naturally in the body. For example, he says, platelet
factor-4 is found in blood, while angiostatin is naturally secreted
by primary tumors. "These proteins were hard to find because
they occur only in parts per million," he said.

Angiostatin, for example, was painstakingly isolated from mouse
urine--work performed by Michael O'Reilly, MD, in the Folkman
laboratory. Once purified, the researchers identified all the
amino acid constituents, and now efforts are underway to produce
human angiostatin from Escherichia coli bacteria, Dr. Folkman
said.

He is particularly excited by the potential of angiostatin because
it blocks only growing endothelial cells. The protein has been
tested in mice and has shown no toxicity, even at high doses.
"It doesn't turn off bone marrow cells, doesn't turn off
intestinal cells, and doesn't make hair fall out," he said
at the briefing.

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