Revolution in cancer treatment

[Al-khiyal]

Scientists discover technique for pain-free, highly effective chemotherapy - the latest milestone in a miraculous medical journey:

Cancer treatment could be on the brink of a revolution following a study showing that it may be possible significantly to improve the effectiveness of chemotherapy drugs without causing side effects.

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.

Revolution in cancer treatment

[Al-khiyal]

There is barely an area of biomedical science that has not been touched by the revolutionary technique of RNA-interference (RNA-i), an area of research which won last year's Nobel Prize in medicine because of its importance in modern molecular biology.

RNA-i allows scientists to target a gene with exquisite accuracy by giving them a precise molecular tool for gradually turning down a gene's activity, much like a dimmer switch of an electric light bulb.

RNA-i seems to be one of nature's ways of controlling gene activity and it appears to be ubiquitous among all living cells. Scientists discovered RNA-i in petunia plants in the 1990s, but have since found that it occurs in almost every organism studied, from fungi to fruit flies, from mouse to man.

It is possible that the process of controlling gene activity using RNA-i evolved as a primitive form of defence against the lethal genes of invading viruses, before the evolution of sophisticated immune systems in higher animals.

However, it became apparent that scientists could exploit the phenomenon to target specific genes that they wanted to control. For example, they could use it to shut off the vital genes for an invading virus such as HIV - and there are plans for at least one clinical trial to do just that.

Another idea was to use RNA-i to switch off the genes in a human cell that are essential for the growth of a cancer. If these "oncogenes" are turned off or silenced, the cancer should die. Again, clinical trials are being planned.

A further approach is to turn off the genes that are involved in stimulating the growth of new blood vessels. If this can be done in the eye, for instance, you might have a cure for macular degeneration - when new blood-vessel growth blocks vision in the retina.

One other line of research is to use RNA-i to switch off damaged genes responsible for inherited genetic disorders, such as Huntington's disease. Suddenly it was possible to talk about potential cures for previously untreatable illnesses.

There appears to be no limit to the range of disorders that can be addressed with RNA-i. Now, as the latest study in Nature has shown, the technique may even be used as a method of improving the efficacy and safety of existing - as well as future - anti-cancer drugs.

One of the beauties of the RNA-i approach is that it is relatively easy for scientists to make the necessary drugs. In effect, they are just small strands of the RNA molecule, which can be synthesised automatically by machine. Each strand is about 22 units long - tiny compared with the 3 billion units that make up the entire DNA molecule of the human genome.

Each of these "short-interfering" strands of RNA can be targeted specifically to work against a particular gene, which is one of the reasons why the technique is so attractive. It means there is less chance of cross-reactions or unintended side effects.

However, one of the biggest problems with RNA-i is what is called "delivery" - how do you make sure that the synthetic RNA molecules actually get inside the cells that matter? That is the real problem with using RNA-i on patients. Solve that, and you have a potential treatment for many of the most intractable illnesses known to man.

Two American scientists, Andrew Fire and Craig Mello, won the 2006 Nobel Prize in medicine or physiology for their pioneering research into RNA-i, published in 1998. They worked on nematode worms and, some years later, other scientists found that the phenomenon also occurred in human cells - paving the way for clinical treatments for disorders ranging from heart disease to cancer.

In its citation, the Nobel Assembly said RNA-i promised to be one of the most exciting developments in medical science. "RNA interference is already being widely used in basic science as a method to study the function of genes and it may lead to novel therapies in the future," it said.

RNA-i: Discovered in a petunia, found in flies and now causing a medical revolution

[amalgamate]

two questions come to mind: 1) what is the phenotypic attribute of this gene (in what phisical ways does it affect the body) and 2.)would this gene, that'd be turned off by the RNA-i in cancer cells, be also turned off in normal cells when used in the body? and if it does, what are the possible the side-affects?


ok so that's 3 questions- whatever!