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【medical-news】消化道研究结果标明了新型抗癌方
Public release date: 1-Feb-2007
Gut research yields new anti-cancer approach
Attacking treatment-resistant tumors via cell skeletons
Researchers believe they have discovered by chance a new way to fight colorectal cancer, and potentially cancers of the esophagus, liver and skin. Early work shows that a group of compounds called peroxisome proliferator-activated receptor-gamma (PPARgamma) inhibitors may have an unexpected cancer-fighting effect, according to research published today in the journal International Cancer Research. Furthermore, the new studies suggest that PPARgamma inhibitors act through some of the same mechanisms as the blockbuster chemotherapy Taxol, but with key differences.
While studying whether compounds known to affect PPARgamma could play a role in inflammatory bowel diseases, a team at the University of Rochester Medical Center found that medium-to-high doses of PPARgamma inhibitor killed colorectal cancer cell lines. Despite the compound's class name, the anti-cancer effect has nothing to do with the ability of the compounds to inhibit PPARgamma function. Researchers believe that PPARgamma inhibitors instead attack the "skeletons" of cancer cells that enable them to reproduce, grow and spread. Better solutions are needed because, according to the American Cancer Society, colorectal cancer remains the no. 2 cause of cancer death for men, and the no. 3 cause of cancer death for women.
"This is the first observation of a small molecule dramatically reducing levels of the proteins called tubulins, the building blocks of cancer cell skeletons," said Katherine L. Schaefer, Ph.D., a research assistant professor within the Department of Medicine, Gastroenterology and Hepatology Division, at the University of Rochester Medical Center, and first author of the paper. "Because cells that line the colon are similar to those in the liver, esophagus and skin, we see potential for a new way to treat those cancers as well."
In the study that led to the discovery of the anti-cancer effect, researchers were looking for new ways to reduce inflammation seen in Crohn's disease and ulcerative colitis, bowel diseases that cause pain and diarrhea. Specifically, they were comparing the effect on inflammation of encouraging the action of the PPARgamma protein (with activator compounds) against discouraging it (with inhibitors). The team conducted these experiments using colorectal cancer cells as study models because they arise from normal gut cells and share some of their qualities (e.g. normal inflammatory signals). Unlike normal gut cells, however, cancer cells do not die when removed from the gut wall. Living on in the absence of normal survival signals makes cancer cells dangerous in the body, but useful as cell lines for study.
While comparing PPARgamma activators and inhibitors, Schaefer noted with frustration that her cancer cells were dying before she could complete her experiments. Retracing her steps, she found that she had used too much inhibitor. The team, led by Lawrence J. Saubermann, M.D., associate professor of Medicine at the Medical Center, realized they had come across a potentially new therapeutic effect, and launched experiments to confirm it.
Study Details
In the newly published study, researchers observed the effects of three compounds known from the literature to inhibit PPARgamma, T0070907, GW9662 and BADGE, on the ability of colorectal tumor cells to survive. High doses (10-100 霱) of all three interfered with colorectal cancer cell growth, reduced the cells' ability to spread through the bloodstream to cause new tumors elsewhere (metastasize) and caused cells to self-destruct, generally within 24 hours. Further experiments showed that high-dose PPARgamma inhibition destroyed cancer cell microtubules, protein structures that form part of the skeleton of cells.
Beyond providing structural support and shape to cells, microtubules expand and shrink to generate the force needed for cells to divide, a basic process in tumor growth. Microtubules are made of two related proteins, alpha and beta tubulin, which pair up to form a chain and then wind into a helix. The current studies found that high-dose PPARgamma inhibitors reduced levels of alpha and beta tubulin by 60 to 70 percent. Also described in the publication are studies where PPARgamma inhibitors killed tumor cells in mice without causing significant toxicity. That provides at least the hope that the drug class may not be prohibitively toxic in humans, the researchers said. More formal toxicity studies are underway.
While PPARgamma inhibitors reduce tubulin levels, older anti-microtubule drug classes; Vinca alkaloids, taxanes (including Taxol) and epithiolones; interfere with microtubule dynamics. To play their role in tumor growth, microtubules must remain flexible. Taxol, for example, "freezes" tubulin subunits, making the cell skeleton rigid and unable to make the shape changes necessary for cell division. Brought to the market by Bristol-Myers Squibb in 1993, Taxol had annual sales of $1.6 billion at its peak in 2000.
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作者:admin@医学,生命科学 2011-03-14 05:12
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