Of mice and men


construction zone
  Limits -- and more progress
Assuming the naturally occurring chemicals that halt the growth of blood vessels and shrink cancers in mice work in people, the next step will be to figure out who can take them. "Anything that cuts off the blood supply could have wide effects," says Robert Evans, a scientist at Jackson Laboratory. "Conceptually it's very interesting, but one needs to be very careful about what blood vessels are shut off, and under what conditions."

Although adult animals form few blood vessels, the process is necessary while healing wounds, and in menstruation and pregnancy. Thus pregnant women might be poor candidates for anti-angiogenesis therapy, as would those who needed surgery or were injured.

Wanted: more weapons
In general, says University of Wisconsin-Madison zoologist Robert Auerbach, finding more blood-vessel inhibitors is a good thing. Each of the several steps involved in the formation of new blood vessels offers a separate drug target. With five points of attack, even drugs that were only 90 percent effective would give an overall reduction of 99.999 percent, Auerbach says. (Similarly, a mixture of drugs is much more effective against the AIDS virus.)

In labs around the country, angiogenesis-inhibitor research is moving ahead. University of Wisconsin-Madison hematologist Deane Mosher is working with factors produced by normal human and mouse cells called thrombospondins. Mice that are genetically unable to produce either of the two types of thrombospondin have abnormal numbers of blood vessels in normal tissue, indicating that the molecules have a role in stopping blood vessel growth.

One needs to be very careful about what blood vessels are shut off, and under what conditionsAnd Gerald Soff, a hematologist-oncologist at Department of Veterans Affairs Lakeside Medical Center, Chicago, who proved in 1996 that prostate cancer produces angiostatin, says he's found a way to make relatively large quantities of the protein by using the enzyme the cancer cells use.

Soff calls the endostatin work "a proof of principle that you can give anti-angiogenesis drugs in pharmacological amounts... that do suppress tumors and actually cause them to shrink into a dormant size and remain dormant." But he says the new findings are "not yet drugs, but two molecules" with exciting anti-cancer potential.

Thus, the major impact of endostatin and angiostatin might be the information they provide about the structure of whatever receptor they link up to, Soff says. "Somebody will figure out what receptor they bind to, and will use that to make a smaller drug, something that's easier and cheaper to make, and will mimic the effect of the proteins."

Indeed, the thrombospondin molecules are large and quickly broken down by the body, making them unlikely candidate drugs. But Mosher is trying to find their active components, which could become the basis for a drug effective against cancer or other diseases in which new blood vessels form.

Better knowledge of how the body makes angiostatin offers another line of attack, Soff says -- figuring out how to stimulate the body to make more of the proteins. "You use your knowledge of how angiostatin is made, and have the body make its own." His lab and others are trying to do just that in mice, he says, but he would not divulge details.

When oh when will The Why Files answer the question: Should I be optimistic or not?


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