side effects are also reported for paclitaxel.
Taxol did display interesting activities against various cell models of cancer and was moderately active in different models of leukemia. However, its solubility in aqueous media is very low. The initial overall interest in the compound was low, also as its availability was very limited. This changed quickly after new in vivo models were introduced at NCI in the early 1970s, and Taxol was found to be strongly active in a mouse model of melanoma. The pharmacological activity finally led to its nomination as a development candidate in 1977, triggering further examination.
In the same year, Susan Band Horwitz (Albert Einstein College of Medicine, Yeshiva University) was contacted by the NCI and was asked to explore the effects of Taxol [41]. She performed some initial experiments and observed that Taxol was capable of stopping replication of HeLa cells even at nanomolar concentrations due to its ability to induce mitotic arrest. Furthermore, she discovered a completely new phenotype. Cells treated with Taxol would be filled with stable microtubule bundles. In later research, it was determined that Taxol efficiently stabilizes microtubules, thus arresting cell cycle [42]. This new mechanism created a tremendous interest in Taxol. However, access to the compound was very limited. In fact, the bark of an estimated 3000 trees is needed to allow isolation of 1 kg of Taxol. Given that the tree will inevitably die after its bark is harvested and the pacific yew is a slow‐growing species, the development process was slowed down significantly.
The intriguing complexity of the carbon backbone and its substitution pattern and the obvious need for alternative sources other than bark led to many academic groups pursuing synthetic approaches. Taxol's structure was elucidated by nuclear magnetic resonance (NMR) spectroscopy in 1971 by Wani [39], Holton [43], and Nicolaou [44] who reported the first two successful synthetic approaches to this challenging molecule, which may have marked a hallmark of natural product chemistry as this challenging molecule stimulated the whole field of natural product scientists. Other elegant syntheses were reported by Danishefsky [45], Wender [46], Kuwajima [47], Mukaiyama [48], and Takahashi [49], among others. However, the required complexity of the developed synthetic approaches limited their practical utility.
The first material for preclinical and clinical studies was still obtained from harvesting yew trees. Finally, in 1984 Taxol entered clinical phase 1 and phase 2 for ovarian cancer, which was initiated in 1985. Clinical profiling was delayed again by limited supply of the compound, but the first results were published by William McGuire (John Hopkins Center, New York) [50]. An initial response rate of 30 % was reported in women with cancer previously not responding to treatment. The increasing compound demands made further clinical profiling almost impossible. In addition, concerns about the environmental impact sparked public debate [51]. Specifically, it was discussed if it was appropriate to risk extinction of species to support clinical trials, which, if eventually successful, could potentially save some individuals. In 1987, NCI estimated that 60 000 lb of bark would have to be collected to support the requests for phase 2 studies, with another 60 000 lb required in 1989.
Previously, 6500 lb of bark had sufficed for supporting research for 10 years and only 2000 lb of bark were needed to provide the required amounts of Taxol from the period 1962 to 1966. In 1989, 27 years after its discovery, no suitable route to access larger compounds quantities was within reach, and no patents protecting the compound were issued. The NCI decided to transfer the project to a pharmaceutical company for resolution of the remaining development issues and commercialization. At this time not too many companies were interested in cancer chemotherapy, as research costs were high and the expected chances of actually developing an effective drug were regarded as very small. Furthermore, in 1988 chemotherapy accounted for less than 3 % of the global drug market, compared with more than 17 % for cardiovascular drugs. Consequently, only four companies applied. The NCI finally decided to transfer rights to development under a cooperative research and development agreement to Bristol Meyers Squibb (BMS) in 1991. The contractual terms, which were granted to BMS, were very favorable; BMS received not only a market exclusivity for (the non‐patented) Taxol but also an orphan drug status, the right to use all NCI‐derived clinical data for applying for additional indications beyond ovarian cancer and, in a separate agreement with the Bureau of Land Management and the Forest Service, the right of first refusal on all products obtained from yew trees grown on public land [52]. This exclusivity spurred a public debate on granting a monopoly for plants on public land to a private enterprise and for giving exclusivity for a new cancer treatment based on data obtained by public funding. Also, concerns rose that yew trees could be harvested to the point of species extinction, as a result, the Pacific Yew Act was passed in 1992, which regulated yew harvesting to ensure careful management of remaining pacific yew resources and to provide sufficient supply of Taxol in the future. In 1992, BMS secured the name “Taxol” as a trademark – despite its utilization for more than 20 years – and created the new generic name “paclitaxel” for the drug.
The shortcomings of compound supply were finally resolved by combining results from different academic laboratories. Greene, Potier, and coworkers discovered that needles of the English Yew (Taxus baccata) contained large amounts (up to 0.1 %) of 10‐deacetyl baccatin III. They developed a method to selectively silylate the hydroxyl group at C‐7, followed by acetylation of the hydroxyl group at C‐10 with enantiomerically pure results (Figure 1.8) [53]. Holton at Florida State University developed an effective β‐lactam opening procedure. As he filed patent applications on this process, licensing by BMS, resulted in royalty payments of more than US$ 400 million to Florida State University.
Today, Taxol is a widely examined cancer treatment, with a total of 3875 studies on paclitaxel listed on clinicaltrials.gov on 1 March 2020. It is approved in the United States for the treatment of breast, pancreatic, ovarian, Kaposi's sarcoma, and non‐small‐cell lung cancers.
One limitation of Taxol is its very poor aqueous solubility of less than 0.01 mg/mL. The used formulation for clinical use as an intravenous injection is composed of a 1 : 1 mixture of cremophor EL (polyethoxylated castor oil) and ethanol, diluted with dextrose solutions or brine [54]. Cremophor, however, is not regarded as an ideal vehicle for human use, as it can create hypersensitivity, alter endothelial and cardiac muscle function and induce several other side effects. Furthermore, the concentration of cremophor that has to be used is unusually high.
Figure 1.8 Semisynthetic approaches to Taxol.
Source: Based on Denis et al. [53].
Neil Desai, a chemical engineer, and Patrick Soon‐Shiong, surgeon and entrepreneur, met at a NCI organized conference on Taxol in 1992 and reasoned that it should be possible to derive a formulation, which was be better tolerated after application. After an intense optimization effort, they discovered that paclitaxel bound to albumin and formulated as nanoparticles can be a safer alternative which significantly improves the handling, solubility, and side effect profile of Taxol.
The compound, termed Abraxane™, could be dosed providing about 50 % higher paclitaxel amounts and still displayed better tolerability. Clinical studies reported improved response rates accompanied with improved tolerability [55]. This kind of innovation can be rather seen as an incremental one, but the specific approach can help utilizing the full potential of a given treatment. Abraxis, the company that was founded to drive the development of the reformulation platform and specifically Abraxane, was sold to Celgene in 2010 for US$ 2.9 billion.
Paclitaxel represents a perfect example for the impact of different contributions from individual researchers on the overall success of a drug. Here, isolation, structure elucidation, structure–activity relationship (SAR), access routes, and galenic aspects were tackled by a large number of scientists, contributing
