Chapter 32. Taxol: From Discovery to Therapeutic Use

Publisher Summary This chapter discusses the discovery, development, clinical status, approaches to supply, and structure–activity relationships in the taxol area. Taxol provides both a novel chemotype and a novel mechanism, stabilization of microtubules, for cancer therapy. However, the clinical development of taxol has been difficult because of poor solubility, supply problems, and hypersensitivity reactions. The chapter describes the first review in new anti-cancer drugs, drug combinations, and chemotherapy strategies series on taxol an agent first reported in 1971 that has been found beneficial in the treatment of refractory ovarian, breast, and other cancers and was recently approved for marketing. There are three levels of assays that have been used in structure–activity relationship (SAR) studies: at the biochemical level, using assays for either polymerization of tubulin or inhibition of depolymerization of microtubules; at the cellular level, measuring cytotoxicity to tumor cell lines, such as KB, J774.2 macrophages, P388 leukemia, or B16 melanoma; and at the organism level, examining growth inhibition of either mouse tumors or human tumor xenografts. The reported yield of taxol from Wall's original isolation from Pacific yew bark was 0.02%, although typical yields on large scale collections are below 0.01%. One large tree yields enough drugs for one treatment for one patient. The chapter discusses the two clinical trials on multiple schedules of administration and refractory and advanced ovarian cancer, respectively. In the early 1970s, taxol was not considered to be a viable development candidate. Taxol caused the regression of the MX-I human mammary tumor and showed moderate activity with growth inhibition of 7040% of the LX-1 lung tumor and the CX-1 colon tumor, the only other human tumors in the experiment. The anti-tumor activity of taxol in experimental models indicates that taxol has better activity against solid tumors than against leukemias. Recent combination studies of taxol with cisplatin, doxorubicin, etoposide, and cyclophosphamide have not shown superiority to the single agents. Taxol resistant Chinese hamster ovary cell lines, with specific tubulin mutations, have been characterized, while the Tax-I8 cell mutant is taxol-dependent.