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Those are only two drugs that keep EGF from doing its job. Gleevec, which reversed Reiter's and Ferber's leukemia so dramatically, is another; so is Tarceva, a drug from OSI Pharmaceuticals in Uniondale, N.Y., which is showing promise against some lung tumors as well as head and neck cancers. Neither of these compounds keeps EGF from docking with cells; instead, each worms its way inside the cells, where it intercepts growth messages percolating in from the surface. Astra Zeneca, headquartered in London, is testing a similar compound, Iressa, against some lung, stomach and prostate cancers.
And that's just the start. Gleevec, Tarceva and Iressa all break one of the most common signaling pathways by blocking an enzyme known as a tyrosine kinase. But the message that encourages a cancer cell to grow involves hundreds of biochemical signals that can travel by hundreds of different pathways. Each of those pathways represents a target, a link that could be interrupted with the properly designed drug.
Another reason cancers grow inexorably is that unlike normal cells, which die a natural death after a fixed number of divisions, cancer cells live forever. Scientists have been looking for compounds that will rewire tumor cells so they will know when it's time to go. The research is still in its early stages, but scientists in several labs have started looking at a group of enzymes called caspaces; inhibiting these enzymes disrupts the process of DNA repair that occurs each time a cell divides.
In Cambridge, Mass., Millennium Pharmaceuticals is focusing on proteins called proteasomes, which evidently play a role in giving cancer cells unnaturally long lives. The company is in Phase II trials with LDP341, a proteasome-inhibiting substance that is showing promise against multiple myeloma and chronic lymphocytic leukemia. Phase I studies on the top five solid tumors (breast, pancreatic, prostate, lung and colon) are under way, and at this point the inhibitor seems to be working--at least in mice.
By far the most celebrated of the new cancer fighters are the antiangiogenesis drugs. Like monoclonal antibodies before them, these compounds, which keep tumors from growing their own blood supplies, were briefly touted as magic one-shot cancer cures--although Folkman, who pioneered the field in the 1970s, was always circumspect about making premature claims. "I think the antiangiogenesis field got some unfair negative publicity," says Saltz. "Our expectations were too high, but there is a lot of brilliant science behind it."
Indeed, while the execution has proved difficult, the idea is very simple. Tumors, like any other cells, need oxygen and nutrients to survive. At first they eat their way through healthy tissue, looking for blood vessels to tap for these essentials. Eventually, though, they start to grow their own capillaries and vessels, like oil companies eager to guarantee a steady flow of crude.