History Shows New Cancer Drugs Often
Fall Short in Human Testing

By Rick Weiss, Washington Post Staff Writer
Copyright 1998 The Washington Post Company
May 6, 1998

The two experimental cancer drugs whose ability to shrink tumors in mice triggered a stampede of interest earlier this week are unlikely to have a huge effect on human cancer if experience with similar drugs is an indication, several experts said yesterday.

More than a dozen similar drugs have been in human clinical trials for several years now, researchers said. Those drugs use the same cancer-fighting strategy used by the new drugs, and they too looked very promising in mice. But after years of testing in people, none has yet lived up to the hopes generated by the animal experiments.

Drugs of this class differ from standard cancer therapies because they cut off the blood vessels that feed a tumor, rather than attack tumors themselves -- an approach that in theory could have more lasting efficacy while causing fewer side effects.

But of the compounds for which preliminary human data are now available, most have triggered troubling side effects. And although it is still too early to know how effective they may prove, no researchers have reported any evidence of the immediate and dramatic effects that so impressed scientists who tested them initially in mice.

To many scientists, that suggests that the newer drugs, though perhaps better than older versions, will not be the last word in cancer therapy.

"This is not the first time we've been able to take mice with large tumors and cure them," said James Pluda, who oversees research on these kinds of compounds for the investigational drug branch of the National Cancer Institute (NCI). "We have to remember that the field of oncology is littered with the bodies of therapeutic agents that were going to be the next cure."

The drugs, called endostatin and angiostatin and under development by Rockville-based EntreMed Inc., were featured Sunday in a New York Times front-page story about promising results in mice. In that story, James D. Watson, a world-renowned molecular biologist, predicted that the scientist who pioneered the new drug strategy would cure cancer within two years -- a comment that inspired some readers but infuriated others.

"In my assessment, to be mild about it, that is an exaggeration," said Anton Wellstein, the professor of pharmacology and medicine at Georgetown University's Lombardi Cancer Center who heads a program that regularly reviews research on such drugs, called angiogenesis inhibitors.

Seminal studies in this approach to cancer began decades ago, Wellstein and others said, and human trials were already underway in the early 1990s.

"None of those are in the clinic [for patients] yet, which tells you something," said Barry Meisenberg, director of the University of Maryland's Greenebaum Cancer Center in Baltimore, where some of the compounds have been studied.

Muscle inflammation, skeletal stiffness, loss of sensation in the limbs and brain cell toxicity have been among the drugs' unexpected side effects. In some cases, those effects forced researchers to limit doses to levels they believe are too low to get any therapeutic effect.

The new compounds do appear to be more potent than previous ones, Pluda said, and there is always hope they will cause fewer problems.

Yet there are many reasons to remain less than overwhelmed, said Edward Sausville, chief of developmental therapeutics at the NCI. For one thing, they showed their strongest effects against a kind of tumor (called Lewis lung cancer) not found in people, and lesser effects against human tumors.

"Let's be honest," Sausville said. "The Lewis lung cancer model is a mouse tumor model growing in a mouse, and its relationship to any human tumor is not clear. And when these compounds were tested against human tumors in mice, the response has been very heterogeneous. So the efficacy issue is a problem."

Another concern is that tumors often figure out alternative ways to get what they need. "Realistically speaking, tumors have a variety of ways of getting around inhibitors and can use other factors to revascularize themselves," said Robert J. Tressler, associate director of cancer biology at Chiron Corp. in Emeryville, Calif. "The hype on these drugs is problematic. These are simply additional pieces that are going to be placed in the armamentarium."

A third potential problem is that the drugs may interfere with useful blood vessels. "We have to be very cautious that in our rush to inhibit or disrupt these processes that we maintain other blood vessels in a stable state," said Pluda.

Encouragingly, mice have not suffered such problems, Pluda said. But nothing will be certain until human trials begin, probably some time next year.

Others noted another potential complication: Unlike synthetic angiogenesis inhibitors, which are manufactured in pure form, the two new ones are proteins made inside genetically engineered yeast. That means a complex purification process will be needed to make batches clean enough for use in people. Other drugs have cleared that hurdle, but it is "not a trivial task," Wellstein said, to satisfy the Food and Drug Administration that an engineered drug is fit for human consumption.

So why all the excitement? In part it's honest enthusiasm about drugs that genuinely look at least incrementally better than previous ones, experts said, but there is also an element of caprice.

"There are a series of fads in cancer research that come and are hot, and then invariably cool off, and this is another one of those," said David Van Echo, head of the new drug development program at the University of Maryland Medical School. "These [new drugs] certainly represent a new angle and hopefully they'll offer a new adjunct to existing therapies. But I would bet that by themselves, as single agents, they won't be a cure for cancer."

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