The scientists were the first to use what are known as "small interfering RNAs" to block the spread of human colorectal cancer cells implanted in laboratory mice. Small interfering RNAs (siRNAs), first described in 2001, are tiny bits of genetic material that can prevent the translation of genes into proteins -- including specific proteins involved in biochemical reactions that promote cancer and other diseases.
According to the federal Centers for Disease Control and Prevention, colorectal cancer is the country's second leading cancer killer. In 2002, the most recent year for which statistics are available, 70,651 men and 68,883 women were diagnosed with the colorectal cancer in the United States; 28,471 men and 28,132 women died from the disease.
"What's exciting about this is that by using siRNAs we were able to selectively block components of the PI3K pathway, a biochemical pathway that is activated in a number of cancers, and suppress the spread of colon cancer in experimental animals," said UTMB professor of surgery B. Mark Evers, senior author of a paper on the research published in the June issue of Annals of Surgery. "Over the last couple of years people have talked a lot about cell-culture studies of siRNAs, but only a handful of labs have pushed it to animal models, which we need to do before going on to clinical trials."
To study the effects of siRNAs targeted against the PI3K pathway in mice, the researchers used a well-established technique in which human colorectal cancer cells were implanted into the spleens of genetically engineered immune-deficient "nude" mice. They then injected siRNAs designed to prevent the production of two specific PI3K proteins into the mice. The result was a major reduction in the spread of colorectal cancer to the liver.
Evers and the paper's other authors -- UTMB research fellows Piotr Rychahou and Lindsey Jackson and pathology professor Srinivasan Rajaraman -- also conducted a detailed analysis of the PI3K pathway's components and did experiments to determine how their siRNAs would affect colorectal cancer cell cultures. Scientists have already developed chemical inhibitors to attack the pathway (some of which are now in clinical trials), but toxic side effects limit their use.
"When we treat with siRNA and then follow the treatment with standard chemotherapeutic agents, we can markedly increase the rate at which cancer cells are killed," Evers said. "Since we have not seen any toxicity with these siRNAs in our mice, we think we can potentially also use them as a way to sensitize tumors and launch a combined attack that will allow us to achieve much better results with reduced side effects."
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Annals of Surgery