Using a combination of a targeted cancer-fighting agent called DFMO and a low dose of an anti-inflammatory drug, UC Irvine researchers have reduced the risk of reoccurring colorectal polyps, an early sign of colon cancer, by as much as 95 percent with fewer toxic side effects.

The study marks a breakthrough in the effort to combat colon cancer, the third leading cause of cancer in men and fourth in women, according to Dr. Frank L. Meyskens Jr., the Daniel G. Aldrich Chair at UC Irvine and director of its Chao Family Comprehensive Cancer Center.

“There is a great hope that we will be able to prevent colon cancer effectively using this method,” said Meyskens, who led the clinical trial effort to test this drug combination. He presented his findings at the American Association for Cancer Research annual meeting in San Diego.

In earlier studies, Meyskens had established a safe and well-tolerated dose of DFMO (difluoromethylornithine) that was 1/50 of what would typically be used to treat advanced cancers. By combining this reduced dose of DFMO with a non-steroidal, anti-inflammatory drug called sulindac, researchers believed they could improve treatment and decrease the reoccurrence of potentially cancerous colon polyps with reduced toxic side effects.

DFMO is the basis of the drug eflornithine, which was initially developed as a cancer medication and is no longer manufactured commercially for that purpose. Sulindac is sold commercially as Clinoril and is used to treat arthritis and other inflammatory conditions.

The researchers enrolled 375 patients who had a history of at least one colorectal polyp, or adenoma, within the previous five years. Patients were randomly assigned to either a combination of 500 mg of daily DFMO and 150 mg of sulindac or placebos. Patients were followed for three years, and adenoma recurrence was measured by colonoscopy. Among the results:

* Overall risk for recurrent adenoma: 41.1 percent in placebo group to 12.3 percent in treated patients, a 79 percent reduction

* Risk for recurrent advanced adenomas: 8.5 percent in placebo group to 0.7 in treated patients, a 92 percent reduction

* Risk for adenomas larger than one centimeter: 7 percent in the placebo group to 0.7 percent in the treatment group, a 90 percent reduction.

* Rate of repeating adenoma among patients who had previously had more than one adenoma: 13.2 percent in the placebo group to with 0.7 percent in the treatment group, a 95 percent reduction.

The rate of reduction was so pronounced that the trial’s independent data and safety monitoring board stopped the trial early.

An analysis of side effects and toxicity found no difference between the treatment and placebo groups. There also was no difference in side effects requiring an overnight hospitalization, gastrointestinal side effects or cardiovascular side effects between the two groups.

“What we have shown here is that there is value in testing these agents at lower doses and in combination to determine if we can achieve the same effect without the damaging side effects,” Meyskens said.

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Increased consumption of teas rich in catechins is associated with reduced risk of stomach, colon and other gastrointestinal cancers. However, the effects of digestion on the anticancer activity of tea catechins have largely been ignored. A study by nutrition researchers at The Ohio State University and Purdue University found that the digestive process could both alter the structure of the tea catechins and their anticancer activity.

Fabiola Gutierrez Orozco, a graduate student in the laboratory of Dr. Joshua Bomser, The Ohio State University, presented study results on April 7 at Experimental Biology 2008 in San Diego. Other co-authors of the study are Dr. Marti Cenky of Ohio State; Dr. Mario G. Ferruzzi and Rodney Green, a graduate student in the Ferruzzi laboratory, of Purdue University. The presentation at Experimental Biology is part of the scientific program of the American Society for Nutrition.

Using a model simulating gastric and small-intestinal digestion, the researchers treated gastric cancer cells and colon cancer cell lines with digested and undigested (parent) extracts of green, tea, black tea, and a combination of the most active tea catechins (EGCG/EGC). In colon cells, digestion of both the green tea extracts and the catechin combination significantly reduced anticancer activity compared to undigested parent extracts. Black tea, on the other hand, showed the same anticancer activity for both parent and digested extracts.

Digestion and the type of tea made a difference in terms of anticancer activity. In addition, the anticancer activity of the tea extracts differed between gastric and colon cancer cell lines. In gastric cancer cells, the undigested extracts were 50 percent less effective than in colon cancer cells.

What does the new study show us?

First, says Dr. Bomser, it points out that better understanding the impact of digestion on tea could lead to changes in how we formulate products in order to protect and enhance their anticancer activity. It also could change how we prepare tea now. In a study from Dr. Ferruzzi’s laboratory published last November, for example, he found that adding citrus (such as lemon juice) or ascorbic acid to green tea protected the catechins from digestive degradation. Lemon juice caused 80 percent of tea’s catechins to remain available for the body to absorb.

Second, say the researchers, some of the digestive changes may impact anti-cancer activities. Work in Dr. Ferruzzi’s laboratory has shown that digestion can alter the structure of polyphenols, degrading and destroying some while forming others. His laboratory is currently identifying these new compounds and testing their own anticancer activity.

Third, the findings of digestive impact on tea catechins are likely also true for other bioactive compounds in foods. Dr. Bomser points out that the active compound in broccoli, for example, is not released until chewing and the digestive process begins. How do we formulate food to prevent degradation and perhaps enhance anti-cancer activity?

And fourth, say the researchers, the epidemiological findings of protective impact of teas rich in the unstable, easily degraded catechins may indicate that other compounds in tea are responsible, in part, for this anticancer activity. Further research is necessary to identify these compounds and to understand the impact of digestion on their anticancer activity.

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Scientists have for the first time discovered that people with the same cancer susceptibility genes respond differently depending on their race. Their results are published in Nature Genetics* .

The team from the University of Edinburgh has shown that a genetic marker is associated with an increased the risk of colon cancer in Europeans, but not in the Japanese population. But this genetic variant was associated with a similar risk of rectal cancer in both populations.

While dietary differences are already well known to be important, this discovery shows for the first time that genetic factors might explain some of the differences in bowel cancer risk between populations**.

This is one in a series of Cancer Research UK funded studies searching for bowel cancer susceptibility genes. The international collaborative project has the long term aim to find a set of genetic markers that could be used to identify subgroups of the population with an increased risk of bowel cancer.

Lead author, Cancer Research UK’s Professor Malcolm Dunlop based at the Institute of Genetics and Molecular Medicine at the University of Edinburgh, said: “This is the first time that a race-specific effect has been found for a genetic marker. It’s an important step forward in our knowledge of the causes of bowel cancer, bringing us ever closer to a genetic test for those at high risk of the disease.

“It’s important to catch bowel cancer at an early stage when it’s more likely to be treated successfully.”

Prof Dunlop and his team looked at the complete genetic make up of over 33,000 people in seven different countries.

In a parallel study, also published today in Nature Genetics***, a team of researchers led by Professor Richard Houlston based at the Institute of Cancer Research and Professor Ian Tomlinson at Cancer Research UK’s London Research Institute , along with Professor Dunlop and Professor Campbell in Edinburgh, found two new gene variants that increase the risk of bowel cancer.

Cancer Research UK’s director of cancer information, Dr Lesley Walker, said: “Our understanding of the causes of bowel cancer is quickly increasing. We can now begin to explain the some of the difference in rates of the disease between populations through specific genes.

“This international collaboration has helped us appreciate the complexity of the genetics behind bowel cancer. This collaboration will continue to bring knowledge that will eventually allow us to test people with a family history of the disease, catching cancer earlier in those who are at the highest risk or preventing it all together.”

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One day the doctors may be able to detect early stages of colon cancer without a biopsy. They will can use the new technique developed by researchers at the Stanford University School of Medicine.
This imaging technology is one of many new ways of detecting cancers in the body in real time.
The first research is to detect the colon cancer.

Colon cancer is the third most common cancer in men and women, with about 150,000 people diagnosed each year. Although colonoscopy isn’t perfect, it’s currently the best way of finding colon cancers when they are still at the most treatable stage.

If doctors find suspicious growths during a routine colonoscopy, they take a sample, called a biopsy, and send it to a pathology lab to screen for cancer. That step takes time and not all people have ready access to a nearby pathologist. What’s more, doctors biopsy only the cancers that form easily visible growths called polyps. Early stage cancers that remain flat aren’t detected.

The trick to picking up cancer without a biopsy is to find a way of seeing which cells are cancerous while they are still in the body.

The group found a short protein that sticks to colon cells in the early stages of cancer. Before screening a person, they spray that short protein attached to a fluorescent beacon into the colon. The protein then gloms on to any cancerous cells and creates an easily visible fluorescent patch. They then used a miniaturized microscope called Cellvizio GI, developed by Pennsylvania-based Mauna Kea Technologies and loaned to Contag, to peer inside the colon and look for those telltale spots.

Not only did the researchers see fluorescent patches, they could make out the individual cancerous cells. That fine resolution could allow doctors to pick up the earliest possible cancers. Contag said it could also become a useful research tool for studying the small number of cancer stem cells that are thought to establish the eventual tumor.

In the initial trial with 15 patients, the technique detected 82 percent of the polyps that were considered cancerous by a pathologist. Contag said the next step is to work with some of the additional small proteins they’ve found that also attach to cancerous cells. He thinks that a combination of those proteins will make the technique highly accurate.

Once the screen is ready for widespread use, Contag said it could bring accurate cancer detection to people in remote locations who otherwise don’t have access to pathology labs. “A doctor could send a video in real time via the Internet to someone trained to analyze the living cell images,” Contag said. This could help people begin the appropriate therapy when the cancer is still at an early stage.

Contag thinks this technique, developed in part through the cancer imaging program at the Stanford Cancer Center, could also be adapted to detect cancers in the mouth, esophagus and stomach. In addition, real-time screening could be used as a way of assessing whether a chemotherapy regimen is working. Contag said that if a tumor responds to a given chemotherapy, changes in the cells might be visible immediately. That response could allow doctors to switch patients to a new, more effective treatment if the first one results in no improvement. Currently people go through several rounds of chemotherapy before the first screen to find out if the treatment is working, a delay that prevents people from moving on to an effective treatment as soon as possible.

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