The researchers isolated CPT as the biologically active compound in C. acuminata, and extensive animal antitumor studies were conducted on CPT and its analogs. CPT sodium salt, which is, in contrast to CPT, water-soluble and therefore easily administered intravenously, was chosen by NCI for clinical trials in the early 1970s. CPT sodium salt is only 10 percent as active as CPT. The trials, however, were terminated due to observation of severe bladder toxicity. In China, positive results were reported: up to 1,000 patients with no prior antitumor treatment were treated and positive results were reported in gastric cancer, intestinal cancer, head and neck tumors, and bladder carcinoma. Results were more promising in China because the previously treated American patients had drug-resistant forms of cancer.

In 1985 it was discovered that CPT inhibited topoisomerase I (T-I), an enzyme which has been implicated in various DNA transactions including replication, transcription, and recombination. Pharmacia & Upjohn's irinotecan (CPT-11, Camptosar(TM)) has also been approved by the FDA.

Topoisomerase I is found in all cells, healthy or cancerous. One form of T-I inhibition has some selectivity for cancer cells only because cancer cells are dividing much more rapidly than most normal cells (except gut epithelium = nausea/vomiting/diarrhea, hair follicles = hair loss in treatment), and so cancer cells are affected more rapidly. [Topo I is the conventional abbreviation for topoisomerase I, T-I is a neologism. It is certainly found in cancer cells but also in any cell which is replicating...the basis for action is that rapidly growing cells will be affected the most.

CPT and some of its analogs are currently in clinical trial, and are showing promise against a variety of tumors which have not yielded to other treatments. One of the analogs, topotecan, developed by SmithKline Beecham, has recently been approved by the FDA for general use in the treatment of ovarian cancer. Pharmacia & Upjohn's Camptosar(TM) has also been approved by the FDA. -- John Beutler, Ph.D.]

Taxol is isolated from the Pacific yew tree (Taxus brevifolia Nutt., Taxaceae) and was discovered at RTI in 1966. Before the study of the Pacific yew tree was assigned to RTI, bark, twigs, leaves, and fruit of the tree were initially screened for antitumor activity under a collaborative program between NCI and the U.S. Department of Agriculture (USDA). This screening showed that samples of the stembark exerted cytotoxic activity. At RTI, the secondary metabolite named taxol was isolated through bioactivity-guided fractionation. Taxol has been used in clinical settings since 1988 for the treatment of women with advanced ovarian cancer. There have been numerous cases of partial or complete remission. The drug and an analog, taxotere, have also been reported to be effective in cases of breast, lung, and prostate cancer. Studies have shown that taxol exerts its antitumor activity by binding to tubulin, the principle protein involved in mitosis, thereby inhibiting cell division.

Producing taxol from the stembark of the Pacific yew, a non-renewable source, led initially to shortages of the drug and decimation of wild yew populations. In order to obtain adequate quantities, measures have since been taken to produce taxol from other Taxus species, and to produce synthetic or semisynthetic taxol. The needles of the European yew (T. baccata) and other Taxus species have been found to yield intermediate compounds called baccatins, which are readily converted to taxol and taxotere. These needles are considered a renewable source of these drugs, since harvesting the needles does not harm the tree in the way that harvesting the stem bark does. Taxomyces andreanae, a fungus discovered growing on the bark of a single Pacific yew tree in an undisturbed growth forest in Montana, has also been found to be a renewable source of these drugs: the fungus not only contains taxol, but actually produces it.

[Wall, M. E. and M. C. Wani. 1996. Camptothecin and taxol: from discovery to clinic. Journal of Ethnopharmacology, Vol. 51,239-254.

Webb. G., Fungus and Taxol, HerbalGram 38, 19.]

Article copyright American Botanical Council.

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By Ginger Webb