We like to think that most of science emanates from brilliant people in white coats sitting around and thinking great and lofty thoughts. Sometimes this is indeed true. But on occasion great discoveries are created from sheer brute force. The discovery of Taxol (paclitaxel) and the taxane class of chemotherapy drugs is an example of this latter process.
At the dawn of the chemotherapy era, in an attempt to find effective chemotherapeutic agents, the National Cancer Institute set up the Cancer Chemotherapy National Service Center in 1955. This was a program whose mandate was to screen every possible chemical, new or old, for its potential efficacy as an anti-cancer drug. In this effort, a panel of cell lines was created and validated against known chemotherapy agents. This then became the testing system against which all other chemicals, new or otherwise, would be screened for efficacy. Basically, any time a new chemical was synthesized or isolated from some source, it would be transported to this screening center and tested for its chemotherapeutic potential.
Starting in about 1958, the Department of Agriculture began collecting specimens from about 1,000 plant species annually for testing in this chemotherapy screening system. In 1962, bark was collected from a Pacific yew tree in a forest in the north of the state of Washington. An extract from this bark was found in 1964 to be cytotoxic in a cell assay. The yew tree’s species name was taxus brevifolia, and so the extract became known as taxol. It was tested in further cancer model systems, including various cancers in rodents, and proved itself efficacious as an anti-cancer agent. However, continued testing of this chemical proved difficult as supplies of the compound required removing the bark from additional yew trees, and this process was very harmful to the trees, which often died as a consequence. The pre-clinical testing was completed in June of 1982 and human trials were then set to begin, but thousands of pounds of bark were necessary in order to extract and isolate sufficient quantities of taxol for the trials. This brought various environmental activist groups and politicians into the picture.
Finally in 1989, the NCI solicited the collaboration of pharmaceutical companies to take over the development of the drug, something that was not routinely done up to that point in time, and which was controversial even after it was undertaken. Bristol Myers Squibb (BMS) was ultimately given first rights to the marketing of the drug in exchange for being responsible for the development of its supply and clinical trials. Consequently, by 1992 there were over 30 academic teams working on the synthesis of taxol, an effort that was ultimately successful in 1994 when two groups ended up in a tie: a group led by K.C. Nicolaou from Scripps Research Institute and a group led by Robert Holton of Florida State University.
By 1992, Taxol (paclitaxel) had demonstrated its effectiveness for the treatment of ovarian cancer and so was approved by the FDA for that indication. Very rapidly thereafter it also became approved and used for breast cancer, lung cancer, esophageal cancer, gastric cancer, and other malignancies as well. As a member of the taxane family of compounds, it is very closely related to Taxotere (docetaxel) and in many circumstances is interchangeable for its use.
Taxanes are not without problems. They can cause myelosuppression, hair loss, nausea and diarrhea, as well as peripheral neuropathy. The latter can be a particularly troublesome and long-lasting issue.
Taxanes kill cancer cells by stabilizing the mitotic spindle, a structure which develops when chromosomes are duplicated during the mitosis process. The stabilization of the mitotic spindle basically interferes with the cancer cell’s ability to replicate. If the cancer cell cannot have an effective mitotic spindle, it cannot reproduce.
The Taxol story has several lessons. I think it highlights how much effort and especially how much time is sometimes necessary to develop an effective agent. Fortuitously, Taxol has been a particularly important and significant contribution to the cancer treatment armamentarium. But pharmaceutical companies argue this point in defense of the high prices. The vast majority of chemicals and drugs do not survive this process.
It also illustrates that effective and important drugs can come from the plant and herb world, and the ancient, or even modern, herbalists and physicians were probably often using primitive and crude versions of effective agents for various purposes. Aspirin and digoxin come quickly to mind for various purposes. I doubt anyone used the bark from the Pacific yew tree, but cannabis seems to be growing in popularity.
Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York. Email: [email protected].
This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.
