Michael Grever, M.D., Former Associate Director, DTP: The story of Taxol is probably the National Cancer Institute in its finest hour. It was actually through the National Cancer Institute that this Natural Products work was supported, and Dr. Monroe Wall and his colleagues were very, very instrumental in finding and identifying this agent.

Susan Band Horwitz, Ph.D., Einstein College of Medicine: Taxol came at the right time. I think that the National Cancer Institute had put a great deal of money and time and effort into actually trying to develop natural products.

Saul Schepartz, Ph.D. Former Deputy Director, DCTD: The Natural Products Program, or Plant Screening Program I should say, began around 1960. And in order to collect various plant samples we had a contract, or what was called I guess a transfer of funds to another federal agency, namely the Department of Agriculture, which collected plants for us, from all over the world. In 1962 as part of their collection in the northwest they collected samples of Taxus brevifolia, the Pacific yew.

Horowitz: And the story goes that Taxol was collected during the summer by a botanist and some college students that were sent out west to California and Oregon. Actually, the first parts of the yew tree were collected at the end of August, just before the college students were going back.

Schepartz: Testing in vitro initially showed that it was a potential interest, particularly the bark.

Horowitz: I received a letter from the National Cancer Institute asking me if I would look at this drug and try to determine its mechanism of action.

Horowitz: It wasn't until I saw the structure of Taxol that I wrote back to them and said this is a compound that I think would be interesting because the structure of the molecule was unusual and unique.

Horowitz: I had a new graduate student who was looking for something to do for his PhD thesis. His name was Peter Schiff (He went on to be chairman of radiation oncology at Columbia, but at that time he was a graduate student.) and we looked at this structure, and I said to Peter, "Well, this is the deal: One month. You can work with this drug for one month and if we think it's interesting, we'll go on. But after one month if we can't move on it, we've got to go and get another thesis project." Well, by the end of the month we knew it was very exciting.

Horowitz: We had added Taxol to hela cells and then we had stained those hela cells to look for microtubules. And the amazing thing was that when we looked under the microscope these cells were just loaded, filled with microtubules. And that was a very unusual thing. I mean, Taxol clearly was a drug that blocked cell mitosis, we learned that very quickly. It was very cytotoxic. We could use it at very low concentrations and kill cells.

Horowitz: But there were other drugs like vinca alkaloids that could have done that. But when we looked under those cells and saw this mass of microtubules, that was unique. And we realized that what the drug was doing was that it was binding to the microtubules, stabilizing them so they could not depolymerize like normal microtubules do, and that this was a unique way that this drug was working.

Horowitz: When the first patient was given Taxol actually had a very, very severe anaphylactic shock and terrible allergic reactions.

Chabner: The compound was very insoluble. And so it had to be dissolved in cremaphore which is a lipid emulsion. And in that form, the cremaphore caused the hypersensitivity responses. So patients had to be pre-treated with steroids and antihistamines. It was a rather complicated and difficult series of clinical trials. Peter Warnick at Einstein was really the person that worked this out. After about three or four years in the clinic, it suddenly became apparent that the drug had activity in ovarian cancer. And at that point, we really took over the problem of manufacturing ... procuring the natural product, manufacturing the drug from it and providing it in sufficient quantity to do all the trials that we wanted to do.

Grever: When we found the activity of the Taxol in patients with far advanced ovarian cancer, it was unfortunate that the supply of Taxol was really truly at crisis level. We had the help of the Natural Products Group within the Developmental Therapeutics Program. And what they explained was that there was approximately an 18 month period from bark to vial. So we realized that we were facing one of the most challenging situations where you have a drug that helps patients with cancer but you just don't have enough of it.

Schepartz: There were so many people interested in it. We would get phone calls from loggers in Oregon saying they had this tree and they were wondering if it could be of help to us. So there was a tremendous interest in trying to do whatever they could to help us develop this drug further. And it was really greatly appreciated.

Grever: As a result of our collaboration with the pharmaceutical industry, we were able to identify a more rapid way of making Taxol available. We also found that Taxol actually could be derived from a renewable source that didn't really require the destruction of the yew tree.

Horowitz: I think one of the important parts of the Taxol story is the fact that it was very multidisciplinary. People like myself, lab people, biochemists, pharmacologists, people in the clinic, oncologists who worked on it, people like Monroe Wall, a medicinal chemist who isolated, determined the structure and, of course, industry, Bristol Myers Squibb was very involved in making the drug available to patients.

Grever: The enormous effort that was put out by the Developmental Therapeutic Program was actually complemented by the clinical developmental strategies that were under the direction of the cancer therapy evaluation program.

Horowitz: You know for many years Taxol was unique in the fact that we didn't have other drugs which stabilized microtubules. For about 15 years Taxol was the only molecule did that. Now we have a number of drugs which have a very similar mechanism of action to Taxol.

Horowitz: Many people probably would just say, "Well these compounds are all like Taxol; why should we bother to study them?" But I think what's important is to say what's different from Taxol. How can we learn new things from these drugs and maybe have new types of therapy from them?

Horowitz: When Taxol was developed, drug companies simply were not interested in developing drugs for malignancies. I mean, there was no indication that this would be profitable. In fact it was Taxol (which we call the first billion dollar drug) that made drug companies realize that there was money to be made in developing drugs for malignancies.

Grever: But if it hadn't been for the Developmental Therapeutics Program the entire spectrum of taxis, I believe, would never have been available for cancer patients. So we believe that this is, the collaboration between the pharmaceutical industry, the Developmental Therapeutics Program, and the Clinical Therapy Evaluation Program probably represents one of the finest hours, where everybody came together to solve a problem for patients with very far advanced malignancy.