An intriguing clue as to why some tumours respond less well than others to an important class of anti-cancer drugs has been uncovered by scientists at the University's MRC Cancer Cell Unit.

Taxol and similar drugs target the process of cell division and are used for treating a number of late stage cancers, including breast and ovarian tumours. But researchers have found that high levels of a molecule called AURORA-A within cancer cells could make Taxol less effective.

Their discovery - revealed in a laboratory study published this week - will now be tested in cancer patients. If confirmed, it could be used to devise a test to predict the effectiveness of Taxol-type drugs, allowing treatments to be planned for the individual patient. The research could also pave the way for future cancer therapies.

Drug resistance is one of the biggest problems facing cancer doctors. Supplementary drugs aimed at increasing the effectiveness of chemotherapy could save many lives - but first scientists need to identify the key mechanisms of drug resistance and find ways of overcoming them.

In the new study headed by Professor Ashok Venkitaraman, Cancer Research UK and MRC sponsored scientists working at the MRC Cancer Cell Unit, University of Cambridge, looked at the role of the AURORA-A molecule. AURORA-A is found at higher than normal levels in up to half of breast and bowel tumours, as well as in many other kinds of cancer.

Researchers genetically engineered cervical cancer cells with the gene for AURORA-A in order to increase levels of the molecule. When treated with Taxol, only about half as many engineered cells were killed by the drug as non- engineered cells.

Professor Venkitaraman said:

"High amounts of AURORA-A seemed to make cancer cells less sensitive to treatment. Testing tumours for the molecule might help us to predict how effective Taxol treatment is likely to be. Of course, our findings will need to be confirmed in cancer patients before it is clear that such a test will work."

"Our work raises the additional possibility that new drugs which inactivate the molecule could boost the response of cancer cells to treatment."

Scientists also investigated precisely how the molecule might effect the response of cancer cells to Taxol treatment. Normally, a cell can only divide if it has correctly shared out all its genes, ensuring each new cell receives a complete set. If there is a problem with the process of sharing out genes, an alarm will be triggered and the cell will not divide. Drugs like Taxol work by attacking the system responsible for sharing out genes and so triggering the alarm, sending cancer cells to their deaths.

But in the study, cells with high amounts of AURORA-A seemed to over-ride the alarm and continue to divide, even when their genes were not correctly shared out. This ability to ignore the alarm could make them resistant to Taxol-type drugs.

Sir Paul Nurse, Chief Executive of Cancer Research UK, said:

"This study gives us a better understanding of the molecular basis of drug resistance and opens up real opportunities for overcoming the problem.

"Taxol is a valuable drug for many patients with late-stage cancer, so finding ways of improving its effectiveness would be an important development."

The paper is published in Cancer Cell Vol. 3(1) p51-62(2003).

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