Anticancer agent - patupilone

The anticancer drug paclitaxel works by stabilising microtubules. These are protein polymers that play crucial roles in a number of cellular processes such as mitosis.

Drugs like paclitaxel polymerise the microtubules, causing cell cycle arrest and, ultimately, cell death. However, resistance can develop, and a new microtubule stabilising agent, patupilone, which is substantially more potent than paclitaxel and retains activity in some cell lines that have developed resistance, is being investigated by Novartis.

Patupilone is a naturally occurring compound, first isolated from the culture broth of the myxobacterium Sorangium cellulosum. The macrocyclic molecule is otherwise known as epothilone B, and along with several other, non-natural, epothilone compounds, it is undergoing trials as an anticancer agent.

As well as trials looking at its effectiveness in combination with capecitabine, carboplatin, estramustine and gemcitabine, Phase II studies as a single agent have also been carried out.¹ For example, in 32 patients with ovarian cancer that was both platinum and taxane resistant, a response rate of 25% was observed at a dose level of 2.5mg/m², given three times over 15 days. The main side-effect is diarrhoea, compared with taxanes where the dose limiting toxicity is neutropoenia.

A similar dosing schedule in 20 patients with hormone refractory prostate cancer gave a response rate of 20%.² Most of these patients had received at least one course of chemotherapy in the past.

In 47 patients with non-small cell lung cancer, about a quarter of whom had previously been treated with taxane drugs, the response rate was 11%, which is similar to the response rate seen with docetaxel.³ Lower response rates were seen in several other cancers, including kidney, gastric and colorectal, plus neuroendocrine cancer in which no response at all was observed.