if any, apparent negative side effects. Although the drugs have been tested primarily in animals, they are now in clinical trials for the treatment of metastatic, late-stage, solid tumors. So far, the drugs seem to be performing well in humans, too. Sporn hopes that one day the compounds will be used to prevent cancer, not just treat it.
Sporn, Gribble, and Honda first began synthesizing the compounds, called triterpenoids, in 1995. Sporn had just left the National Institutes of Health (NIH), after 35 years there, to start a chemoprevention research laboratory at Dartmouth. That summer, he went looking for an organic chemist to partner with. He found Gribble, who had been on the Dartmouth faculty since 1968, and Honda, an expert in drug synthesis who had just arrived at Dartmouth from Japan.
"Mike had the idea [that] because trees can live a very long time—sequoia trees, for example, in California can live [thousands of years]—and because triterpenoids are ubiquitous in the plant kingdom, there might be a relationship between the presence of triterpenoids and the longevity of trees and plants," Gribble explains. "It's kind of a simple idea," he admits, "but that's what got us started."
Over the next three years, Honda synthesized numerous variations of naturally occurring triterpenoids, starting with commercial extracts from China. The goal was to magnify the mild anti-inflammatory and anticancer properties of the natural products. At first Honda changed the compounds' chemical structures randomly, sending each new derivative to the Sporn lab for bioactivity testing. "Tadashi would make something in his lab and two days later we'd tell him whether it was interesting or whether it was a dud," recalls Sporn. Getting such rapid feedback was unique, he explains. "If you go through conventional testing, this sort of stuff could take months and months and months."
"Our relationship is similar to a pair of wheels on a bicycle," Honda adds. "Good collaboration between biologists and chemists is definitely necessary for the discovery of drugs."
Honda's 46th compound was the first to show promise, but it was still not strong enough to develop into a drug. He
Sporn, Gribble, and Honda first began synthesizing the compounds, called triterpenoids, in 1995. Sporn had just left the National Institutes of Health, after 35 years there, to start a chemoprevention research laboratory at Dartmouth.
continued to modify its chemical structure, hoping to develop a compound potent enough to begin testing it in animal models and eventually in humans.
While Honda was hunting for compounds, Sporn was hunting for funds to keep the project running. In addition to the staff of his own lab, Sporn supported Honda, too. It was "difficult to get funding just based on the chemistry," Gribble explains, because the chemistry behind the synthetic triterpenoids "is fairly simple." It was the compounds' medical potential that was exciting. But even in the cancer-research realm, funds to develop new chemoprevention drugs can be difficult to come by.
The federal funding agencies, like the National Cancer Institute, "talk a good game about [chemoprevention], but that's not where the money goes," says Clifton Leaf, a senior editor at Fortune magazine. "As a financial journalist, I look at where the money trail is." And it's clear, he says, from the number of grants, scientific papers, and conferences devoted to chemoprevention, that prevention "is not where the money is going."
Leaf—himself a survivor of Hodgkin's disease—began covering cancer and cancer research in 2004 with an award-winning article titled "Why We're Losing the War on Cancer and How to Win It." He went on to author several more cancer-related articles for Fortune and is currently writing a book about the "culture of cancer research, about how we got to where we are with the war on cancer," as he puts it. He estimates that he's interviewed more than 1,500 scientists, pharmaceutical executives, physicians, and regulators for his book, to be published by Knopf in late 2007.
Leaf's reporting has even earned him a place at the table in the discussion over the future of cancer research. In the past few years, he's presented testimony to the President's Cancer Panel, served as a panelist at a Capitol Hill forum on chemoprevention and early detection, and delivered keynote lectures at meetings of the National Cancer Institute, the AACR, and several other major medical and scientific groups. He was also recently elected to the board of directors of the Susan G. Komen Breast Cancer Foundation.
When Leaf started researching the 2004 Fortune article, he "thought that we were doing really, really well in cancer," he says. But then he looked at cancer deaths and changed his mind.
Although the death rates for many common cancers have edged downward since 1971—the year the National Cancer Act was passed—the numbers of deaths have increased. For example, in 1971 about 32 women out of every 100,000 died of breast cancer versus 25 out of every 100,000 in 2003—the latest year for which data is available. Given the increase in the U.S. population, that translates into about 33,000 women in 1971 and 40,000 women in 2003. The fact that people are still dying of cancer in such massive numbers is what troubles Sporn and Leaf. "You can't talk your way around" the death figures, says Sporn. "There are so many dead bodies in the cancer pot."
Sporn and Leaf have also come to similar conclusions about why the nation has made so little progress on reducing the total number of cancer deaths. A primary reason, they say, is the lack of money available for researchers who want to look at the cancer problem globally and from a