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A working thesis
In fact, just determining whether an antiangiogenesis drug works, and to what extent, is a daunting challenge. The criterion for judging whether a conventional cancer drug is effective is rather straightforward: Did it cause the tumor to shrink? With antiangiogenic therapies, that may not be a fair measure. Tumors small to begin with may simply be held in check by these agents; those that would otherwise grow ferociously may be slowed. Proving that such changes have occurred, and that an antiangiogenic compound is responsible for them, requires a new level of ingenuity on scientists' part.
"First-generation agents such as endostatin clearly inhibited angiogenesis in animals, but the actual process by which this occurred wasn't known," comments Dana-Farber's John Heymach, MD, PhD. "That made it difficult to study in humans. What kind of changes would you look for?"
One technique for exploring a compound's effectiveness is to surgically remove a portion of a tumor after treatment to see if blood flow to the mass has been reduced. Only a small proportion of tumors lend themselves to this kind of exam, however. "We need to develop noninvasive ways of measuring whether these drugs are working," says Heymach. "Ideally, we'd have a simple method of determining if blood flow to the tumor is reduced, but there is no established way of doing that."
Heymach and his colleagues are studying a technique that uses a special oxygen molecule as a "label" whose journey through the body can be tracked by a PET scanner. Injected into the bloodstream, the label allows doctors to monitor the level of blood flow to a tumor. The technique is extraordinarily complex, though, and can't readily be adapted for routine use.
Complicating matters is the possibility that antiangiogenic therapy may briefly increase the amount of blood reaching tumors. The first blood vessels to grow toward tumors tend to be twisted and inefficient. As these vessels are choked off by initial doses of drugs, they may be temporarily replaced by a new generation of straighter, higher-capacity vessels that carry a greater volume of blood to the tumor.
Heymach's lab is working to develop a blood test to determine the effectiveness of antiangiogenic agents. It's based on the fact that when blood vessels in a tumor are killed, their remains are carried off by the bloodstream and can be counted by high-speed machinery. "The number of dead cells released by the tumor vessels may be a marker of whether a drug is having an effect," he explains.
- Next: Doing the math
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