The National Cancer Institute (NCI) found that yew samples showed activity against 9KB cancer-cell tissue culture. NCI sent a subsample to Monroe Wall, Ph.D., a medicinal chemist working under contract to NCI at Research Triangle Institute in North Carolina.
Wall's group found that a crude extract of the yew bark was effective in both the cancer-cell tissue system and against a mouse leukemia. They worked to isolate the primary active principle of Taxol.
Wall asked NCI to give the yew material special priority for research. He isolated the active principle and named it Taxol.
NCI checked the activity of all parts of the Pacific yew. They now knew three things - the structure of Taxol, its success in cancer screens, and something about how it worked against cancer.
Wall, with Mansukh Wani (at Research Triangle Institute) and Andrew McPhail (of Duke University), published the structure of the Taxol molecule, a complex diterpene with an unusual oxetane ring and an ester side chain.
Taxol began to show results against a recently developed B16 mouse melanoma system. During the 1970s, cytotoxicity tests continued with tumor lines in new animal screens, including human tumor xenografts (tissues grafted from one species to another.)
Preclinical work on Taxol began. NCI contacted Susan Horowitz (professor of molecular pharmacology at Albert Einstein College of Medicine in the Bronx), working under an NCI Cancer Research Emphasis Grant, to ask her to investigate how Taxol worked on cancer cells. With graduate student Peter Schiff, she found that Taxol inhibited the replication of human tumor cells. Specifically, Taxol induces tubulin polymerization and inhibits disassembly of microtubules, an activity necessary to complete cell division.
Taxol showed positive results in human cancer xenografts. Taxol showed activity in three systems, including a human breast cancer xenograft developed in the late 1970s.
Horowitz and Schiff published their findings about Taxol's action of freezing microtubules and causing the cell to die.
Toxicology studies began. Scientists looked for a suitable surfactant formulation for administering the insoluble drug.
NCI approved Taxol for filing an Investigational New Drug Application (INDA) with the Federal Drug Administration.
Phase I clinical trials began, testing patients who were not responding to other treatments, determining doses and toxicity, and generating data on dose limits of Taxol.
NCI contracted for collection of 60,000 pounds of dry Pacific yew bark.
Phase II clinical trials showed 30 percent improvement in patients with unresponsive cases of advanced ovarian cancer.
Trials of Taxol progressed for other forms of cancers - breast, cervical, colon, gastric, non-small-cell lung, prostate, head and neck, small-cell lung, and renal. NCI contracted for an additional 60,000 pounds of dry bark.
Phase II trials showed 48 percent tumor shrinkage with metastatic breast cancer patients who had at least one prior chemotherapy regime. (Metastatic refers to cancers which tend to spread from one body part to another.)
The Ohio Agricultural Research and Development Center joined the Research Institute of Pharmaceutical Sciences, the School of Pharmacy of the University of Mississippi, and Zelenka Nursery, Inc., Grand Haven, Michigan, in a contract with the Cooperative State Research Service, USDA, to harvest and deliver critically needed Taxus clippings (100,000 lbs. fresh weight) to the National Cancer Institute by the summer of 1992.
Clinical trials were conducted at 20 centers on a number of different cancers, with some experimenting with combinations of therapies.
Based on the chronology presented in Pacific Yew: Draft Environmental Impact Statement. Appendices. U.S. Departments of Agriculture, Interior, and Health and Human Services. January 1993.