Author:Constantin, Sarah

THE FIRST ATTEMPT to treat cancer in humans with chemotherapy happened within days of doctors realizing that it reduced the size of tumors in mice.

The year was 1942, and we were at war. Yale pharmacologist Alfred Gilman was serving as chief of the pharmacology section in the Army Medical Division at Edgewood Arsenal, Maryland, working on developing antidotes to nerve gases and other chemical weapons the Army feared would be used against American troops.

After a few months of researching mustard gas in mice, Gilman and his collaborator, Louis S. Goodman, noticed that the poison also caused a regression of cancer in the rodents. Just a few days later, they persuaded a professor of surgery at Yale to run a clinical trial on a patient with terminal cancer; within 48 hours, the patient's tumors had receded.

In 1971, three decades after Gilman's discovery, the U.S. government declared a "war on cancer." Since then, we have spent nearly $200 billion in federal money on research to defeat the disease. But we haven't gotten much bang for our buck: Cancer deaths have fallen by a total of just 5 percent since 1950. (In comparison, heart disease deaths are a third of what they were then, thanks to innovations like statins, stents, and bypass surgery.) The American Cancer Society estimates that more than 600,000 Americans die of cancer annually; 33 percent of those diagnosed will be dead within five years.

Chemotherapy drugs remain the most common treatments for cancer, and most of them were developed before the federal effort ramped up. Out of 44 such drugs used in the U.S. today, more than half were approved prior to 1980. It currently takes 10-15 years and hundreds of millions of dollars for a drug to go from basic research to human clinical trials, according to a 2009 report funded by the National Institutes of Health (NIH). It is now nearly impossible to conceive of going from a eureka moment to human testing in a few years, much less a few days.

Beating cancer is not a lost cause. But if we're going to break new ground, we need to recapture the urgency that characterized the work of pioneers like Gilman and Goodman. And in order to do that, we need to understand how we managed to turn the fight against humanity's most pernicious pathology into a lethargic slog.


LOOK AT THE history of chemotherapy research and you'll find a very different world than the one that characterizes cancer research today: fast bench-to-bedside drug development; courageous, even reckless researchers willing to experiment with deadly drugs on amenable patients; and centralized, interdisciplinary research efforts. Cancer research was much more like a war effort before the feds officially declared war on it.

One reason that's true is that research on chemotherapy started as a top-secret military project. Medical records never mentioned nitrogen mustard by name, for example--it was referred to only by its Army code name, "Substance X." By 1948, close to 150 patients with terminal blood cancers had been treated with a substance most Americans knew of only as a battlefield killer. After World War II, Sloan Kettering Institute Director Cornelius "Dusty" Rhoads recruited "nearly the entire program and staff of the Chemical Warfare Service" into the hospital's cancer drug development program, former National Cancer Institute (NCI) Director Vincent DeVita recalled in 2008 in the pages of the journal Cancer Research.

Researchers turned swords into ploughshares, and they did it quickly. In February 1948, Sidney Farber, a pathologist at Harvard Medical School, began experiments with the antifolate drug aminopterin. This early chemotherapy drug, and its successor methotrexate, had been synthesized by Yellapragada Subbarrow, an Indian chemist who led the research program at Lederle Labs, along with his colleague Harriet Kiltie. Using their compounds, Farber and his team produced the first leukemia remissions in children in June 1948.

In a July 1951 paper, Jane C. Wright, an African-American surgeon, reported she had extended the successes of methotrexate from blood to solid cancers, achieving regressions in breast and prostate tumors by using the substance.

Chemist Gertrude Elion, who'd joined Wellcome Labs in 1944 despite being too poor to afford graduate school, quickly developed a new class of chemotherapy drugs-2,6-diaminopurine in 1948 and 6-mercaptopurine in 1951--for which she and George H. Hitchings would later win the Nobel Prize.

In 1952, Sloan Kettering's Rhoads was running clinical trials using Elion's drugs to treat leukemia. After popular columnist Walter Winchell reported on the...

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