Content area
Full Text
Screening potential anticancer drugs sounds easy. Just take a candidate drug, add it to a tumor type of choice, and then monitor whether the agent kills the cells or inhibits cancer growth. Too bad it hasn't been that simple. Even as investigators try to develop a new generation of more effective and less toxic anticancer drugs that directly target the gene changes propelling cells toward uncontrollable division (see p. 1036), they face a long-standing problem: sifting through potential anticancer agents to find ones promising enough to make human clinical trials worthwhile.
Indeed, since formal screening began in 1955, many thousands of drugs have shown activity in either cell or animal models, but only 39 that are used exclusively for chemotherapy, as opposed to supportive care, have won approval from the U.S. Food and Drug Administration. "The fundamental problem in drug discovery for cancer is that the model systems are not predictive at all," says Alan Oliff, executive director for cancer research at Merck Research Laboratories in West Point, Pennsylvania.
Pharmaceutical companies often test drug candidates in animals carrying transplanted human tumors, a model called a xenograft. But not only have very few of the drugs that showed anticancer activity in xenografts made it into the clinic, a recent study conducted at the National Cancer Institute (NCI) also suggests that the xenograft models miss effective drugs. The animals apparently do not handle the drugs exactly the way the human body does. And attempts to use human cells in culture don't seem to be faring any better, partly because cell culture provides no information about whether a drug will make it to the tumor sites.
The pressure is on to do better. So researchers are now trying to exploit recent discoveries about the subtle genetic and cellular changes that lead a cell toward cancer to create cultured cells or animal models that accurately reproduce these changes. "The real challenge for the 1990s is how to maximize our screening systems so that we are using the biological information that has accumulated," says Edward Sausville, associate director of the division of cancer treatment and diagnosis for the developmental therapeutics program at the NCI. "In short, we need to find faithful representations of carcinogenesis."
The first efforts to do so...