( ated proteins alpha and beta tubulin ...)Gut research yields new anti-cancer approach

ated 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.

Unfortunately, Taxol and other standard, anti-tubulin drugs failed in colorectal cancer clinical trials. Gut tumor cells have evolved to include "efflux" proteins that recognize standard chemotherapies as foreign, and "pump them out" of tumor cells. Even for breast and lung cancer, the tumor types for which Taxol is most used, nearly 100 percent of these tumors eventually become resistant, said Alok A. Khorana, M.D., assistant professor of Medicine at the Medical Center. In cells with more drug efflux pumps, Taxol is not effective (e.g. pancreas, liver and colon), he said.

High-dose PPARgamma inhibitors may overcome the limits of current treatment because the profile of molecules likely to be pumped out by drug efflux proteins is known, and at least one of the PPARgamma inhibitors does not match it. In addition, PPARgamma inhibitors do not bind to the standard tubulin-binding site that renders Taxol useless when binding s
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Source:University of Rochester Medical Center

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