Taxol Pioneer Calls for Greater Emphasis on Natural Products Research

The RTI International researcher credited with discovering the cancer-fighting drug Taxol is calling for greater investment in natural products research following the discovery reported last month that Taxol slows the spread of Alzheimer’s disease. Dr. Mansukh C. Wani, who with his co-investigator the late Dr. Monroe E. Wall identified and published the structure of Taxol in 1971, said the scientific community is “simply not doing enough research related to natural compounds and as a consequence could be delaying discoveries.”

“Less than one-tenth of the world’s plant species have been assessed for pharmaceutical potential,” Wani said. “Natural products research is a much longer-term investment, but the potential for finding new ways to treat disease — and not just one disease as we have seen in the Taxol case — is enormous.”

In the late 1980s, there was tremendous interest in natural products research by pharmaceutical companies stemming in large part from findings related to Taxol and camptothecinTM, another cancer-fighting agent whose structure also was reported by Wani and Wall.

The pharmaceutical industry nevertheless shifted its resources away from natural products research after concluding in the mid-1990s that combinatorial and diversity-oriented synthesis programs represented the most efficient approach.

Combinatorial and diversity-oriented synthesis programs have been employed throughout the industry and now substantially overshadow natural products research as a discovery engine.

In natural products research, scientists isolate and identify organic compounds and then seek to understand their modes of action. This approach has yielded such medicines as aspirin and morphine.

Combinatorial and diversity-oriented synthesis programs, by comparison, typically involve synthetic compounds, particularly in the case of drug design. This approach exploits automation and miniaturization to create large populations of compounds that can be screened en masse.

There are no official statistics, but a conservative estimate would be that no more than 20 percent of the pharmaceutical investigations being conducted today could be categorized as natural products research, Wani said.

The stalwarts of natural products research are a small number of independent research organizations, such as RTI International and the Scripps Research Institute in La Jolla, Calif., which obtain their funding primarily from the National Institutes of Health (NIH).

“Because we have the focus and expertise, it is incumbent upon independent research organizations to continue to play a leadership role in natural products research by increasing our investment and related efforts,” Wani said.

Pharmaceutical companies and research universities also might consider putting more resources into natural products research, Wani said. Few universities have natural products research programs. As a consequence, there is a scarcity of postgraduate training opportunities. To address this shortfall, RTI has created a new fellowship program to help young scientists develop careers in natural products research.

The role of natural products research in drug discovery may be changing somewhat but is still vital, according to Wani.

Recently, some scientists have expressed renewed interest in natural products research following the failure of alternative drug discovery methods to deliver lead compounds in key therapeutic areas such as immunosuppression, anti-infectives, and metabolic diseases.

“Natural products research remains invaluable when it comes to providing that initial lead,” Wani said. “Before we explored the Pacific Yew tree, we had no idea that we could treat cancer and other diseases through microtubule overproduction.”

Taxol, now partially synthesized, was originally discovered from the bark of the Pacific Yew tree. It kills cancer cells by overproducing microtubules, preventing cancer cells from coordinating and completing cell division. The Taxol discovery unearthed this new mechanism of action for inhibiting cancer cell growth and has saved the lives of hundreds of thousands of cancer patients.

Taxol was approved in 1992 for treatment of ovarian cancer and subsequently was approved for treatment of several other types of malignancies, including breast, lung, and prostate cancer. More than 17 analogs of Taxol are in clinical trials for breast, prostate, brain, skin, pancreatic, colorectal, and lung cancers.

That Taxol slows the spread of Alzheimer’s disease, its most recent finding, was reported in January by scientists at the University of Pennsylvania in the Proceedings of the National Academy of Sciences. Their research in mice showed that Taxol has the potential to treat neurodegenerative disorders, such as Alzheimer’s disease.

Wani said such discoveries support his contention that “nature is the best chemist.”

Another proponent of natural products research at RTI, Dr. David Kroll researches milk thistle compounds as a possible way to treat prostate cancer. “The natural world has 10 times more chemical diversity than synthetic compounds,” said Kroll, a senior research pharmacologist. “We just have to get to it in time.”

From Research Triangle Institute


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