Taxol
Kendall Peddie
ChipolaCollege Honors Project
Chemistry 1045
Fall Semester 2005
Since its beginning some forty years ago, Taxol has become the number one cancer-fighting drug sold today. It is primarily used to treat ovarian, breast, and lung cancer, but is now undergoing tests against other forms including leukemia and lymphoma. The world wide sales of Taxol are approaching 3 billion dollars, with 90 million of this going to FSU, placing it seventh in the ranking of schools making money off faculty produced materials. Analogs (or derivatives) of Taxol are now being developed which have also proven to be very successful.
By researching cancer statistics, it is very easy to see how Taxol can relate to most everyone. There’s an estimated 1,372,910 new cases of cancer each year and approximately 570,280 deaths. Those numbers include 321,050 cases of breast cancer and 22,220 cases of ovarian cancers- the two types that Taxol has shown most promising results against. In Florida alone, an estimated 39,960 will die of cancer this year. These staggering figures show the significance that Taxol has in the lives of everyone.
The beginning of Taxol started around forty years ago when a young botanist team was doing research in South Africa. They added a few samples of bark and twigs from a pacific yew tree to their collection for study. They had no idea the interest and controversy they would spur, or the purpose it would later serve. The National Cancer Institute had been busily looking for chemicals with the ability to fight cancer, and in 1960 they turned their focus from man made materials to extracts from plants. Their job was to determine, through lab testing, which of the raw collections had an affect on cancer cells in a petri dish.
In 1965, Monroe Wall, a medicinal chemist in North Carolina received samples of plants that included those of the pacific yew. Wall was known as a fractionator because his job was to isolate different parts of a plant’s chemical makeup. He was able to concentrate and purify the yew into a solution he call K172. He was surprised to observe that it had an effect on mouse leukemia unlike any seen before.
Wall presented his achievements at the 153rd meeting of the American Cancer Society. He introduced the isolated substance as Taxol, “a yew tree extract exhibiting an unusually broad spectrum of anti-tumor activity”. The name had been derived from the yew’s surname Taxus combined with the ending ol, which represented that it contained alcohol.
It wasn’t until three years after its debut that chemists finally worked out the actual molecular structure for Taxol. They discovered that it consisted of a large and complicated base molecule with an attached “tail”.
After many years of “shelf-warming”, Taxol came back out in 1975. It showed encouraging results against melanoma and lung cancer tumors. Taxol also proved itself in a confrontation with a human breast cancer cell implanted in a lab rat. “Nude rats”, which have no hair and no immune system, proved very useful for experiments because they do not reject foreign tissue. When Taxol was implanted in the tumor, it shriveled up. The NCI was persuaded to take action and two years later, formulation tests were approved to see how Taxol could be made into a useful drug for the market.
In 1979, Susan Horwitz, a pharmacologist of New York, discovered the way Taxol functions. Most compounds fight cancer cells by destroying the proteins used to make the microtubules of a cell. By doing so, they prevent them from being able to divide. Taxol actually works to over stimulate the growth of these microtubules. This results in the cells “choking” and dying. It is considered to be more efficient because it’s an irreversible process.
Further progress was allowed when the NCI team found a way to dissolve this virtually insoluble compound by using a mixture of castor oil. As a result, Taxol was cleared by the FDA for clinical trials in humans in 1984. By 1988 they had released very satisfying results from tests against ovarian cancers. At least three out of every ten victims treated with Taxol experienced a shrink in their tumors. Some of the testing had an even higher response rate of sixty percent.
Problems soon followed this breakthrough. Wall had concluded that the yew bark was the primary source of Taxol, and thousands of pounds were being requested. The NCI was discouraged to find that for every thirty pounds of dried bark, only about half a gram of K172 was produced. Thousands of yew trees were being cut down, and by 1988, environmentalists had grown furious. Researchers soon found that cultivating the tree was not an option since it could take nearly 200 years for the yew to fully mature. It was costing the NCI more than 250,000 dollars a pound and the government soon realized they could not afford to support this chemical that was rapidly headed for the market.
Despite these difficulties, Taxol was able to overcome. In the 1980’s, French scientists found a way to make Taxol artificially. Their process involved using large pieces of molecules found in a more common species than the Pacific Yew. They extracted a substance they called 10-DAB from an English Yew, and they were able to combine it with Taxol’s “tail” to form a nearly identical molecule. The process only delivered at most a 52% yield, and about half the 10-DAB was wasted, but semi synthetic Taxol was proven possible.
Robert Holton of FSU was later able to improve the French’s process. He succeeded in synthesizing a naturally occurring cousin to Taxol which contained the same core atomic structure. His yield was twice that of the French scientists’. He soon found a pharmaceutical company willing and able to turn Taxol into a marketable drug- Bristol Myers Squibb. An agreement was signed allowing them to use his process in exchange for royalties for FSU. A research deal for Holton was also included that stated Bristol would cover the costs of patenting any derivatives that he might develop.
By 1933 Taxol was the most important cancer fighting drug, and Holton had even developed a much improved and version of his semi synthesis. One gram of the drug was now selling for 5,846 dollars. By 1955 it was trademarked in over fifty countries and brought in more than half a billion dollars in that year alone. Many of the analogs of Taxol were showing even more promising development.
Holton and FSU had problems getting Bristol to live up to their part of the deal. They were not eager to develop any of the analogs or pay for any patenting. In other words, they were trying to make a lot of money while trying to avoid spending any. Law suits were later filed against them stating that they were attempting to keep lower priced generics off the market. By 1966 Holton and FSU had ended the partnership and all royalties were split fifty-fifty. Holton and a partner then started their own business. They continued research and development of many of the analogs that Bristol had turned down. The revenues were basically turned over to FSU. (Holton was working for a salary of one dollar a year).
The generic name of Taxol is Paclitaxel. It is given as a clear fluid through a canulla, which is similar to an IV, over a twenty four hour period. Treatment is usually given in a hospital every three weeks. There are side effects associated with Taxol including nausea, vomiting, upset stomach, loss of appetite, muscle and joint pain, mouth sores, and hair loss. More severe but rarely seen effects seen consisted of internal bleeding, respiratory complications, and bone marrow depression. Despite these, Taxol is still considered the best available form of cancer treatment today, and work is still being done towards developing its analogs.