Camptothecin and Taxol: A Long Road from RTI Labs to FDA Approval
"I have come here not to praise camptothecin, but to bury it"
Human clinical trials of camptothecin–the chemical compound discovered by RTI chemist Mansukh C. Wani in 1965–began in the early 1970s. Initially, RTI was buoyed by the announcement of the National Cancer Institute that camptothecin stood "front stage center" in the search for drugs inhibiting colon and rectal cancer. Unfortunately, this was a premature assessment. As Wani remembers, an oncologist at the Mayo Clinic changed his mind about the compound, saying it had "unpredictable toxicity" and "no clinical value at all in the treatment of gastrointestinal cancers." At a 1971 meeting of the American Association for Cancer Research, this researcher went so far as to announce, "I have come here not to praise camptothecin, but to bury it."
Although dismayed by camptothecin's apparent failure, the Natural Products Laboratory pressed on, synthesizing more than 60 analogues of this compound by 1989. That year, Science magazine reported that one of the analogues caused total tumor regression and enhanced the long-term survival of immunodeficient mice carrying human colon cancer cell lines. Unlike previous analogues, this one had low toxicity and produced fewer adverse side effects. "If we had abandoned camptothecin when the initial clinical trials showed it to be toxic, we never would have discovered the more promising camptothecin analogues," Wani says.
In the 1960s, Wani, Monroe E. Wall and colleagues had isolated another groundbreaking compound, paclitaxel (better known by its trade name Taxol), after samples of Taxus brevifolia, a yew tree indigenous to the Pacific Northwest, were mailed to the Natural Products Laboratory. "We tested hundreds of fractions from the tree and isolated one compound in the tree bark that generated anticancer activity," Wani recalls. Another 12 kilos of yew bark were then shipped to the lab, which used a process called bioassay-directed fractionation to isolate the most active compound.
Wani, meanwhile, was tasked with determining the structure of this extremely large molecule, pursuing the task for two years, without success, and even working on nights and weekends. In 1970, Taxol finally yielded its structure, and the following year, the lab published a paper asserting that it showed experimental promise as an anticancer agent. Unfortunately, the supply of the chemical was constrained by the endangered status of Taxus brevifolia. "It would have taken all the Pacific yew trees left to treat five patients," former RTI board member William Little said only half-jokingly.
Scientists outside RTI finally built upon the Institute's pioneering research. Interest in Taxol was revived in the 1980s after it was discovered that the compound attacked cancer in an unprecedented way–and after researchers at Florida State University had invented a technique for mass production. By the 1990s, Taxol had received an excellent evaluation based on Phase I and Phase II clinical trials, and it emerged successfully from Phase III trials conducted by Bristol-Myers Squibb. In 1992, Taxol was approved for the treatment of ovarian cancer, and it has since been approved for numerous other cancers as well.