Scientists have conducted a series of pioneering experiments demonstrating a new way of making tumour cells far more susceptible to attack with extremely low doses of anti-cancer drugs. The development offers hope that the gruesome side effects of chemotherapy, suffered by tens of thousands of cancer patients, may at some point become a thing of the past.
In addition to making chemotherapy more effective at eliminating tumour cells from the body, the study suggests that it is also possible to lower dosage levels to a point where toxic side effects from the drugs are unlikely to occur.
The breakthrough was made possible with a revolutionary medical technique called RNA interference, which allows scientists to "silence" certain genes in a pioneering development first highlighted by The Independent in 2002.
In one of the experiments, for instance, the scientists found that lung cancer tumour cells can be made to be 10,000 times more sensitive to the anti-cancer drug Taxol - an unprecedented improvement in the power of the treatment.
Taxol - also known as paclitaxel - is also used to treat ovarian cancer and advanced breast cancer. Side effects include fatigue, nausea, numbness and bone marrow depletion leading to lowered immunity and vulnerability to infections.
However, the scientists who conducted the study emphasised that further research in the laboratory and on animals will be needed before the first clinical trials on cancer patients can begin in no less than three to five years time. "There's nothing here that is immediately useful to those individuals with cancer," said Michael White, professor of cell biology at the University of Texas Southwestern Medical Centre in Dallas.
"We're still at the beginning, but this sort of approach is very fast and very effective. It shortens the discovery process, which makes the development process so much quicker."
The scientists grew cells from human lung cancers in the test tube and tested the ability of anti-cancer drugs such as Taxol to attack them after treatment with RNA-interference (RNA-i).
The RNA-i technique in this experiment was designed to "silence" or switch off certain genes in the tumour that appear to be turned on as part of the cancerous process. This made the cells dramatically more susceptible to the anti-cancer drugs.
Since its initial development over the past 10 years, RNA-i has proved to be one of the most exciting areas of biomedical research with prospects of its being used to treat conditions as varied as inherited disorders, blindness, viral infections and now improving the efficacy and safety of cancer therapy.
In the latest experiment with RNA-i, scientists screened a total of more than 21,000 genes and found that 87 can influence a tumour cell's sensitivity to chemotherapy, and that six in particular were strongly linked with Taxol sensitivity, according to the study published in the journal Nature.
When some of the genes were silenced by RNA-i they became a thousand times more sensitive to Taxol. When other genes were silenced, sensitivity to the drug rose ten-thousandfold.
Professor White said: "Chemotherapy is a very blunt instrument. It makes people sick, and its effects are very inconsistent. Identifying genes that make chemotherapy drugs more potent at lower doses is a first step toward alleviating these effects in patients."
The study attempted to investigate why some cancer patients fail to respond to chemotherapy, and why some develop severe side effects from the treatment. "The cells in tissue culture mimic the effects you see in people," Professor White explained.
Nearly 85,000 different molecules of RNA - a substance similar to the DNA genetic blueprint - were used in the study to screen a cell's genes by targeting those that could be silenced. The process gradually switches them off, much like an electric dimmer switch.
Professor White said: "The idea of the screen was to be able to take advantage of the new generation of technology to silence any gene we want.
"That's the power of a genome-wide screen - you go in without any expectation and let the data tell you what's important."
The scientists have already started trials on laboratory animals with cancer to see if the RNA-i approach can be used to make them more sensitive to lower doses of chemotherapy drugs.
Professor White said: "We're conducting animal studies based on lung cancer and ovarian cancer models. These experiments are not difficult and basically they have been shown to work but we still need to have the data published in a peer-reviewed way." Although it could still take between three and five years for clinical trials with existing anti-cancer drugs, it will take 10 years or longer to develop new drugs that are able to work alongside RNA-i, he said.
The scientists also tested the RNA-i approach using other anti-cancer drugs, such as gemcitabine and vinorelbine, but they did not see the dramatic effects that they recorded with paclitaxel.
"Our studies using additional drugs indicate that the genes we uncovered are highly specific for paclitaxel," said Angelique Whitehurst, a researcher at the University of Texas and lead author of the study. The findings indicated that it was not just the effect of silencing certain genes that had the observed effect on the cancer cells, but the interaction of the gene-silencing approach with paclitaxel that was responsible, Professor White said. "Being able to do this in human cells, and being able to do it fast, this is very powerful," he added.
'Chemotherapy was an awful experience'
Christine Davies, breast cancer survivor, 60
Christine Davies, from Cheltenham, was diagnosed with breast cancer in May 1992. After seven months of chemotherapy she was finally given the all-clear.
"Chemotherapy was just the most awful experience; I know some people manage OK but I think I was a particularly bad case. From the first dose onwards, I wondered how I was going to cope. My daughter was only 10 years old and my husband, a teacher, was working away from home every week in London.
"My diary entry from the day I had my first dose reads: 'First lot of chemo. What a bolt from the blue.' I was sick at midnight, then at 4am, then again at 6am.
"The worst thing was the muscle spasm - my throat completely froze up and I could hardly talk. It's hard to imagine it now but I remember I just couldn't get my tongue in my mouth. I was standing at the sink with my daughter behind me and all I could think of was how I could stop her from seeing what was wrong. I got in such a state - it was so frightening that I had to call the doctor, who told me to take Valium to relax the muscles in my mouth.
"I had five lots of chemo in all, from September through to March the next year. They put me on a cocktail of different drugs. The third time was dreadful; I was sick for the first time at 11pm, then eight or nine times more until getting up at 5.15 in the morning. The drugs also gave me pains in my joints, particularly my hips. And I couldn't eat at all - my daughter says the only thing she remembers me being able to swallow were these awful boiled sweets that afterwards made me feel sick just because of the association with the chemo. There were times when I was terribly ill, followed by periods in between doses when just not to be feeling ill made me really happy. My daughter had her 11th birthday; we had a lovely party with all the family. Then came the next dose and I would be back in bed, on my own, feeling so low I couldn't face seeing anyone. The day before the last dose I wrote in my diary that I couldn't explain 'how much I'm dreading it'. That one turned out to be the most debilitating of all and made me sick for two whole days.
"If there were a way to lessen the side effects, to diminish the sickness and nausea, I would think it would transform the experience. For me that was what made it so awful and what, in comparison, made radiotherapy perfectly bearable. When you feel so sick like that your body just can't do anything."
The first line of defence
What is it?
Chemotherapy is the use of a combination of anti-cancer drugs to destroy cancer cells
When was it discovered?
In 1909, by Paul Ehrlich, who used an arsenic compound, arsphenamine to treat syphilis.
How does it work?
The drugs stop the cancerous cells from dividing, and therefore reproducing themselves
When is it used?
Before an operation to shrink a cancer, or after to clear any remaining cancerous cells
Common side-effects
Tiredness, nausea and a greater risk of developing a second form of cancer.
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