Paclitaxel anticancer Report

Discovery of Paclitaxel Anti-cancer activity :

Paclitaxel's antitumor activity was discovered in the 1960s during a large-scale plant-screening program sponsored by the National Cancer Institute (NCI).

35,000 plant species were screened for anticancer activity. The U.S. Forest service collected Pacific yew tree (Taxus brevifolia, picture see above) bark and shipped it to the NCI for study.

Drs. Monroe Wall and M.D. Wani of Research Triangle Institute, North Carolina subsequently find that an extract of the Yew Tree bark has antitumor activity. That compound was named "Paclitaxel" or "Taxol".     

Paclitaxel prevents cell division by promoting disassembly of microtubules - skeletal structures that assemble and divide throughout the life of a cell.
A large number of microtubules are formed at the start of cell division, and as cell division comes to an end, these microtubules are normally broken down. However, paclitaxel prevents microtubules from breaking down. In the presence of this drug, cancer cells, which attempt to divide frequently, become so clogged with microtubules that they cease to grow and divide.

In 1983, NCI began conducting clinical trials of paclitaxel's safety and its effectiveness against various types of cancer.

Demand for paclitaxel increased in 1989 after the investigators at The Johns Hopkins Oncology Center reported that the drug produced partial or complete responses (shrinking or disappearance of the tumor) in 30 percent of previously treated patients with advanced ovarian cancer. it was clear that ovarian cancer patients with few other options benefited from the treatment.

In December 1992, FDA approved the use of paclitaxel for refractory (treatment-resistant) ovarian cancer.

Subsequently, clinical trials using paclitaxel for the treatment of advanced breast cancer demonstrated that the drug is effective against this disease.

In April 1994, FDA approved the use of paclitaxel for breast cancer that has recurred within 6 months after the completion of initial chemotherapy and for metastatic breast cancer that is not responding to combination chemotherapy.

March 1997, FDA designated Taxol as Orphan Drug for treatment of AIDS-related Kaposi's sarcoma.

April 1998, FDA gave an additional approval for Paclitaxel injections, for first-line therapy for the treatment of advanced carcinoma of the ovary in combination with cisplatin.

June 1998, BMS received an NDA 20-262/S-024 for a Taxol indication: in combination with Cisplatin, for the first-line treatment of non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or
radiation therapy

Researchers continue to look for new and better ways to use Paclitaxel in the treatment of cancer. They are studying Paclitaxel's effectiveness when used to treat breast and ovarian cancer earlier in the course of these diseases and when used in combination with other drugs.

Trials to test the effectiveness of Paclitaxel against many other types of cancer, including leukemia, lymphoma, and cancers of the lung, head and neck, and colon, also are in progress. In addition, researchers are investigating ways to overcome some patients' resistance to Paclitaxel and are trying to develop methods for using the drug in patients who have impaired organ function To date, 180 clinical trials have been condusted, researchers have found the drug to be active in lung, head and neck, bladder, esophageal, and germ cell cancers. 　

Early research using Paclitaxel was limited by a restricted supply due to several difficulties in obtaining the drug. The concentration of the compound in yew bark is low, and Paclitaxel extraction is complex and expensive. The Pacific yew is a limited resource, it grows very slow and is located in old-growth forests that are the habitat of the endangered spotted owl.

As demand for paclitaxel increased, researchers have been exploring new ways to increase the availability of Paclitaxel.

Since January 1991, Bristol-Myers Squibb has been selected by NIH as the CRADA (Cooperative Research and Development Agreement) partner for Taxol. (This agreement was valid until Dec. 1997.)

Bristol-Myers Squibb produces Paxlitaxel Injection (Taxol, Registered Trademark) via a semi-synthesis process from Taxus baccata, the Europe Yew tree.

To use cell culture or fungi fermentation techniques to produce Taxol are also on processing.

Total synthesis of Paclitaxel was achieved in 1994. However it is unlikely to be applied in the commercial production of Paclitaxol.

There have been many research reports on the constitutions of othet yew tree species worldwide.

Scientists in US, China, Japan, Taiwan and other countries have done detailed research on Taxus chinensisi (Chinese yew) as the new resource of Paclitaxel. There are four Chinese yew species growing on the territory of China. Scientists proved that all of them contain Paclitaxel at a similar level as the Taxus brevifolia.

Scientists have isolated and identified 110 taxanes from Chinese yews, and 36 of them were new taxanes. in vitro and in vivo studies proved that Paclitaxel is the most active anti-cancer compound among all these yew tree taxanes.

9TOP Natural Pharamaceutical Co., incorporates with Chinese academic institutions , developed a new production line to extract pure Paclitaxel from planted 3-5 years young Taxus chinensis. With the large field of planted young Taxus chinensis, which contains Paclitaxel as high as 0.015 - 0.02%, and the new manufacturing technology, 9TOP Natural Pharmaceutical ensured the reliable new resource of high quality Natural Paclitaxel with very competitive cost.

Scientific evidences confirmed that 9TOP Natural Paclitaxel contains 99.0 - 99.5% pure Paclitaxel, the highest quality level of Paclitaxel product.

Clinical trials in China since 1995 have proved the effectiveness and safety of Natural Paclitaxel Injection (which contains Paclitaxel extracted from Taxus chinensis) in cancer treatment.

The Natural Paclitaxel from Taxus chinensis is a invaluable new resource for Paclitaxel.

It ensures the high quality and lower cost of Paclitaxel Injection and related prepartions for patients. It provides the pharmaceutical manufacturers and research laboratories a reliable supply source and lower cost to developing new anti-cancer agents.

Last update 30 Aug.. 1999

Paclitaxel (Taxol-R) is a compound made from the bark of the Pacific yew tree (Taxus brevifolia). It has been approved by the U.S. Food and Drug Administration (FDA) for treating breast and ovarian cancers as well as lung and AIDS-related cancers.
Paclitaxel has a unique way of preventing the growth of cancer cells: it affects cell structures called microtubules, which play an important role in cell functions. In normal cell growth, microtubules are formed when a cell starts dividing. Once the cell stops dividing, the microtubules are broken down or destroyed. Paclitaxel stops the microtubules from breaking down. With paclitaxel, cancer cells become so clogged with microtubules that they cannot grow and divide.
Early Research In 1983 NCI began clinical trials (research studies) that looked at paclitaxel's safety and how well it worked to treat certain cancers. In 1989 NCI-supported researchers at The Johns Hopkins Oncology Center reported that tumors shrank or disappeared in 30 percent of patients who were being given paclitaxel for the treatment of advanced ovarian cancer. Although the responses to paclitaxel were not permanent (they lasted an average of 5 months, some up to 9 months), it was clear that advanced ovarian cancer patients could benefit from the treatment. In December 1992, FDA approved the use of paclitaxel for ovarian cancer that was resistant to treatment (refractory).
Other clinical trials using paclitaxel have shown that the drug is effective in the treatment of advanced breast cancer. In April 1994, FDA approved paclitaxel for treating breast cancers that recur within 6 months after the first round of chemotherapy. It is also approved for breast cancer that has spread (metastatic) and does not respond to combination chemotherapy.
In August 1997, paclitaxel was also approved by the FDA as a treatment for some people with the AIDS-related cancer called Kaposi's sarcoma. Most recently, in June 1998, the FDA approved paclitaxel, in combination with other anticancer drugs, to treat patients with some advanced types of lung cancer.
Like most cancer drugs, paclitaxel has side effects that can be serious. Its most serious effect is damage to the bone marrow; the soft, sponge-like tissue in the center of large bones that produces the blood cells that fight infection. Hair loss and nerve damage are also common side effects of paclitaxel. However, the benefits for many patients with advanced cancers can outweigh the risks associated with this drug.
Current Clinical Trials Researchers continue to look for new and better ways to use paclitaxel to treat cancer. They continue to study paclitaxel for treatment of early breast, ovarian, and lung cancer and it's usefulness when combined with other drugs. For example, preliminary findings from ongoing clinical trials suggest that combining paclitaxel with other anticancer drugs may be an effective treatment for patients with lymph node-positive breast cancer. Other studies are looking at paclitaxel as a treatment for lymphomas, stomach, head and neck, and bladder cancers. In addition, researchers are studying ways to overcome some cancers' resistance to paclitaxel.
Paclitaxel Supplies: Old Problems and New Approaches Early research using paclitaxel was limited due to difficulties in obtaining the drug. The amounts of paclitaxel in yew bark were low, and extracting it remains a complicated and expensive process. In addition, bark collection was restricted because the Pacific yew is a limited resource located in forests that are home to the endangered spotted owl.
As demand for paclitaxel grew, NCI, with the help of industry and other Government agencies, worked to increase the availability of paclitaxel. Bark collection and processing expanded to increase the short-term supply of the drug while NCI encouraged research to find other sources of paclitaxel and related compounds.
One option is to synthesize paclitaxel. Currently, a semi-synthetic form of the drug is being studied. To produce the semi-synthetic drug, a substance from the needles of the yew tree is chemically changed to produce paclitaxel.
Another alternative is docetaxel (Taxotere-R), a substance that is similar to paclitaxel. Docetaxel, like the semi-synthetic paclitaxel, comes from the needles of the yew tree. The drug, developed by the French pharmaceutical firm Rhone-Poulenc Rorer has shown promise in clinical trials. In fact, in May 1996, the FDA approved docetaxel to treat advanced breast cancer that does not respond to other anticancer drugs. The side effects of docetaxel are similar to those related to paclitaxel.
NCI is also working with Rhone-Poulenc Rorer to test the effectiveness of docetaxel for a variety of cancers, such as breast, ovarian, lung, prostate, bladder, head and neck, and cervical cancers. Rhone-Poulenc Rorer is providing docetaxel for the trials that are funded by NCI.
This fact sheet was reviewed on 7/12/99
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