Researchers trying to minimise side effects of chemotherapy

August 7th, 2008 - 12:27 pm ICT by IANS  

London, Aug 7 (IANS) Researchers are trying to determine exactly how chemotherapy kills malignant tumours in order to minimise their side effects and test efficacy of safer agents. Stephen Taylor and Karen Gascoigne of Manchester University’s Faculty of Life Sciences have taken a new systematic approach to studying anti-mitotic drugs, used extensively in breast or ovarian cancer in Britain.

This class of drugs, which includes the agent taxol, has been used clinically for many years because they are highly effective. However, as in all chemotherapy, there are side effects.

In the case of taxol it can lead to permanent nerve damage and loss of sensation in fingers.

Little is known about how anti-mitotic drugs work, because many studies were population-based approaches that were indirect and led to vague and confusing interpretations.

Taylor said that “to bypass the neurotoxicity, new anti-mitotics are being generated. Early clinical studies show that these drugs do not result in significant neurotoxicity. The big question now is whether they will have anti-tumour effects.

“To help determine this, we need to know which types of tumours are likely to be sensitive to these new agents, and which ones are likely to be resistant. This would allow clinicians to better design the clinical trials, that is you only recruit patients who are likely to respond.”

In addition, if the drugs show promise, then it would pave the way for patient stratification in the future, again allowing oncologists to identify which patients are likely to benefit from these drugs in advance of treatment.

“To predict which types of tumours are likely to respond, we first need to know how anti-mitotic drugs work, both the classical drugs and these new agents,” Taylor said.

He and Gascoigne, whose findings have shown how different tumours respond to the anti-mitotic drugs - targeting the mitotic spindle (the structure that separates the chromosomes during cell division) - revealed that the variation in cell behaviour was far greater than previously recognised.

They used a high throughput automated time-lapse light microscopy approach to systematically analyse over 10,000 single cells from 15 cell lines in response to three different classes of anti-mitotic drugs. This revealed the large variation in cell behaviour with cells within any given line exhibiting multiple fates.

“We embarked on a fresh, more direct approach that is actually quite simple. Basically, we just watched the cells using time-lapse microscopy; this allowed us to track the behaviour of individual cells and determine their fate when exposed to different anti-mitotic drugs,” Taylor said.

“The first thing we realised was that the picture was much more complicated than we originally thought; the range of different behaviours was profound. Not only did cells from different cell lines behave differently, but cells within the same line also behaved differently.

“The level of complexity was at first overwhelming. However, as we slowly made our way through the data, patterns began to emerge. This allowed us to formulate a new hypothesis. We were then able to design more experiments to test this hypothesis.

“In essence, it turns out that when cells are exposed to these drugs they arrest in mitosis. Then a race starts between two competing cellular signalling networks. One network is trying to kill the cell, the other is trying to cause the cell to exit mitosis and thus allow the cell to survive. The winner of the race decides the fate of the cell; death or survival.

“What we want to do now is figure out how we can help the cell death pathway win the race more often; this would hopefully mean that the anti-mitotic drugs would be better at killing cancer cells.”

The findings have been published in Cancer Cell this month.

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