Anticancer agent - ixabepilone
The epothilones are a class of natural products that were first isolated in a fermentation broth of the myxobacterium Sorangium cellulosum. They were found to have a similar mechanism of action to the taxane drugs, as they bind to tubilin, stabilising microtubules and thus preventing cells from dividing.
The epothilones are a class of natural products that were first isolated in a fermentation broth of the myxobacterium Sorangium cellulosum. They were found to have a similar mechanism of action to the taxane drugs, as they bind to tubilin, stabilising microtubules and thus preventing cells from dividing.
They are less structurally complex than taxanes, and have the additional advantage of better water solubility.
Initial investigations on some of the naturally occurring molecules showed that they had only modest antitumour activity because they are not particularly metabolically stable and their pharmacokinetics are not good. Ixabepilone is a synthetic epothilone analogue developed by Bristol-Myers Squibb that is more stable in vivo, and is showing promise as a drug.1
Numerous clinical trials have been carried out. For example, a multicentre Phase II trial was carried out in 126 patients who had metastatic breast cancer that was resistant to anthracyclines, capectabine and taxanes.2 Subjects were given 40mg/m2 by intravenous infusion over three hours every 21 days. There was an objective response rate of 18.3%, with half of the patients achieving stable disease, and a median overall survival of 8.6 months. Side-effects included neutropoenia and peripheral neuropathy.
In another Phase II trial, 23 patients with metastatic breast cancer who had not previously been treated with taxanes were given doses of 6mg/m2 by intravenous infusion for five days every three weeks.3 Six of the patients achieved stable disease, and there was a partial response rate of 57%. The duration of response and time to progression were both five and a half months. Again, the most common side-effect was neutropoenia, with other problems including fatigue, anorexia and motor neuropathy, but this time none of the subjects experienced sensory neuropathy.
The drug has also been investigated in combination with trastuzumab and carboplatin in patients with HER2+ breast cancer, and this gave good results.4 A total of 3.5% of the patients achieved a complete response, nearly 40% a partial response, and a further 23% achieved stable disease.
The drug has now been approved by the FDA for the treatment of resistant, refractory metastatic or locally advanced breast cancer. Trials continue in breast cancer, and it is also being investigated as a possible treatment for other forms of cancer.