NEWS

Taxing the Taxanes: Overused Or Undersold?

Mike Miller

Since taxanes were first touted as the anticancer drugs of the 1990s, their use has become widespread in both advanced breast and ovarian cancers as well as in clinical trials for other cancers.

At the most recent meeting of the Chemotherapy Foundation in New York, at least half of the chemotherapeutic interventions described against solid tumors used one kind of taxane or another. The current research paradigm is whether taxanes are showing real efficacy in clinical trials and physician practice or whether they will be replaced by angiogenesis inhibitors or other promising agents.

Researchers hope that by focusing on the mechanism of action of taxanes they can learn how to use that mechanism to attack cancer. Taxanes are the first class of drugs that have shown action as a anti-microtubule action since vinca alkaloids were introduced 20 years earlier.

Defining Mechanisms

Roger Cohen, M.D., University of Virginia Cancer Center, Charlottesville, Va., showed that in combination with vinorelbine, taxol helped to stabilize polymerized microtubules. Although vinorelbine blocked de novo polymerization, Cohen hypothesized "that the two drugs seem to act at different sites of the mitotic spindle but that other mechanisms could be working as well."

A definitive mechanistic action for the taxanes, which could make their use more widespread and effective, has not yet been found.

Christopher Logothetis, M.D., University of Texas M. D. Anderson Cancer Center, Houston, said that although the use of taxanes with other drugs has established efficacy in improving the quality of life of patients with metastatic prostate cancer, deciding which regimen to use has been problematic because no chemotherapy regimen gives a lasting response.



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Dr. Christopher Logothetis

 
Additionally, he noted, there is still uncertainty about how these chemotherapies work in early disease, which would be an ideal use if practical.

Daniel Petrylak, M.D., Columbia Presbyterian Medical Center, New York, found additive or greater antitubular effects against metastatic prostate cancer by adding taxotere to estramustine. Petrylak speculated that "we were not even certain that estramustine was necessary in this regimen but ultimately decided that taxotere can be active on its own and its synergistic effect is even more beneficial."

So if one taxane is good, how good are two in combination? Jacob Lokich, M.D., Cancer Center of Boston, conducted a phase I trial using two taxanes in combination. Lokich found that taxol and taxotere are both myelosuppressive, but that they have other differing toxicities and a lack of complete cross-resistance in experimental systems. In examining the preliminary results from his trial, Lokich noted that when both taxanes are administered together, the taxane effect is increased by two-thirds. Lokich also suggested that responses may be achieved in patients who are resistant to one taxane but sensitive to an alternate taxane.

Taxanes have seen their greatest use in advanced breast and ovarian cancers but Gary Schwartz, M.D., Memorial Sloan-Kettering Cancer Center, New York, said that, "despite many advances in cancer therapy, high rates of treatment failure in solid tumors like GI tract cancers necessitate new approaches." In gastric cancers, Schwartz has been using cyclin dependent kinase inhibition to arrest the cell cycle and induce apoptosis with some success.

Schwartz found that adding taxol to the CDK inhibitor flavopiridol aids in promoting apoptosis but is highly dependent on the day administered and the order of administration. He also found that taxol could aid the apoptotic actions of some of the platinum drugs, reaffirming taxol's beneficial combinatorial efficacy.

Incremental Steps

Ted Trimble, M.D., Division of Cancer Treatment and Diagnosis, National Cancer Institute, who has worked primarily with taxanes against gynecological cancers, said that "we're getting a better understanding of how to most effectively use the taxanes, but, as with most drugs, we're taking many little steps in advancing our knowledge."



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Dr. Ted Trimble

 
As significant as the taxanes have been against many cancers, researchers such as Logothetis are pinning their hopes for the 21st century on "gene therapies because we now have molecular markers like p53 for diseases such as prostate cancer that we can target directly." John Marshall, M.D., at Georgetown University's Lombardi Cancer Center, Washington, D.C., was even more pointed when he wrapped up the meeting by saying that "the days of treating breast, colon, and other cancers with chemotherapies like Taxol may soon be over. We'll be treating markers for each cancer and individualizing treatment."



             
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