Paclitaxel is a prominent natural compound used for the treatment of refractory cancers. It was discovered as part of a National Cancer Institute program where extracts of thousands of plants were screened for anticancer activity more than half a century ago.
Paclitaxel is derived from Taxus brevifolia is a rare and slow-growing evergreen found in the old-growth forests of the Pacific Northwest (also known as the yew tree). Humanity has made use of the yew since the beginning of time in order to make spear points and other weapons, household implements and diverse tools. Although throughout history it had mythological associations with death, today yew is responsible for one of the most widely used anticancer agents in the world.
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Discovery of paclitaxel
Samples of the Pacific yew's bark were initially collected in 1962 by Arthur Barclay and other investigators from the US Department of Agriculture (USDA), contracted by the National Cancer Institute (NCI) to find natural products that might treat cancer. They were then sent to Wisconsin Alumni Research Foundation in order to prepare crude extracts to be tested on oral epidermoid carcinoma cell culture – a cell line derived from human cancer.
Two years later, doctors Monroe Wall and Mansukh Wani, together with their colleagues at the Research Triangle Institute's Natural Product Laboratory in Research Triangle Park of North Carolina discovered that extracts from this bark showed significant cytotoxic activity. Wall decided to name the substance "taxol" because they were sure it was alcohol, and also because it was a common practice to name a discovered molecule after the genus of the originating plant.
In 1965 more samples of bark were collected and sent to Wall's group for identification and subsequent purification of the active component. Even though the isolation of paclitaxel (or "taxol") in pure form took several years, the chemical structure was finally published in 1971.
Antitumor activity of paclitaxel was confirmed in 1977 in the mouse melanoma B16 model, after which it was selected as a candidate drug for clinical development. Significant activity was also demonstrated in animal models against LX-1 lung, MX-1 mammary and CX-1 colon tumors. In the same year, an order for 7,000 pounds of bark was made, which meant sacrificing 1,500 trees scattered over millions of acres of old-growth forest in the Pacific Northwest.
In August 1978, researcher Susan Horwitz from Albert Einstein College of Medicine of Yeshiva University contacted Monroe Wall asking for some radiolabeled paclitaxel in order to conduct experiments on its mechanism of action. She was provided a grant by NCI for studies on this substance due to her ongoing interest in the use of naturally occurring small molecules against cancer cells.
She successfully demonstrated that paclitaxel was able to prevent cell division via an interesting mechanism – stimulating the development of microtubules (cell's ultrafine filaments). While previous compounds killed cancer cells by preventing the production of microtubules and thus inhibiting the division, the overproduction of microtubules disrupts proper coordination of cell division.
Commercialization of the drug
Due to the difficulties of harvesting and complexities involved in synthesizing the active compound, the clinical development of paclitaxel was lagging. In addition, it was difficult to formulate an adequate delivery system acceptable for human use. Nevertheless, the drug was shown effective against mammary tumors and ovarian cancer, motivating researchers to find a way of isolating large quantities for clinical usage.
In December 1992, thirty years after USDA investigators initially sampled Taxus brevifolia, and more than twenty years after researchers Wall and Wani reported the isolation and structure of paclitaxel, the Food and Drug Administration (FDA) finally granted approval for its use against refractory ovarian cancer. In the following years, it has also been approved for the treatment of advanced breast cancer, AIDS-related Kaposi’s sarcoma and other malignancies. During that time, paclitaxel was the most expensive drug on the market.
In the mid-1990s, researchers began to investigate the antiangiogenic activity of paclitaxel as a possible additional mechanism contributing to its antineoplastic activity in vivo. In 2003, Schmitt-Sody with his colleagues demonstrated the antitumor and antiangiogenic efficacy of novel neovascular targeting therapy consisting of paclitaxel encapsulated in cationic liposomes. In-depth research on paclitaxel activity continues to this day.
Further Reading