ABSTRACT
Natural products, including their semisynthetically modified or their synthetic analogues, have been valuable and abundant sources or leads for various drugs currently in clinical use. Undoubtedly, new and known naturally occurring substances will continue to play an important role in the future development of novel therapeutic agents. Natural products and related derivatives are also powerful agents for cancer chemotherapy. Examples include plant products such as the vinca alkaloids, camptothecins, derivatives of podophyllotoxin, and antitumor antibiotics such as the anthracyclines, mitomycin C, actinomycin D, bleomycins, and others.1 Taxol (1, Figure 1, NSC 125973, paclitaxel), first isolated in 1971 by Wani et al.2 from the bark of Taxus brevifolia and approved in December 1992 by the FDA for the treatment of drug refractory metastatic ovarian cancer, is yet another example demonstrating the importance of natural products as a source for the development of novel anticancer agents. It is also interesting to note that Taxol acts through a new and unique mechanism of action, promoting the formation and hyperstabilization of microtubules.3 Recently it has been suggested that the antitumor activity of Taxol may be influenced by additional effects. It was observed that Taxol induced the expression of tumor necrosis factor-α and interleukin-1 in macrophages,4–6 caused stimulation of MAP-2 kinase activity, and increased tyrosine phosphorylation.7,8 It was also reported that Taxol blocks processes essential for invasion and metastases in prostate tumor cells (PC-3 ML).9 Because of the multiple functions of microtubules in the regulation of cellular processes, in addition to their role in mitosis, it is conceivable that Taxol may find applications in therapeutic areas other than cancer chemotherapy. The recent 319finding that Taxol inhibits the progression of congenital polycystic kidney disease (PKD) in cpk mice indicates that Taxol may also be usful for the treatment of human PKD.10
