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Discovery blocks cancer drug's toxic side effect
Date:11/4/2010

sugar off the inactivated cancer drug, essentially reactivating it. The revived drug then causes tissue damage, which triggers the diarrhea seen as a side effect in the vast majority of patients who receive it, with up to 30 percent suffering severe diarrhea.

In a manner of speaking, we cured the bacterias sweet tooth without damaging the microbes or intestines and, in the process, the toxic side effect was alleviated, Redinbo said.

Instead of changing the makeup of the drug itself, Redinbo decided to take a new tack. Working with researchers at North Carolina Central University in Durham and the Albert Einstein College of Medicine in New York, the UNC team looked for chemical compounds that would latch on to and block the action of the beta glucuronidase enzymes. From a database of more than 10,000 compounds, they narrowed the field to four prime candidates, then tested them in the laboratory on several types of bacterial cells.

The result: all four compounds worked the enzymes remained dormant and the cells were unscathed. Scientists also tested one of the inhibitors in mice. Again, it proved successful animals treated with CPT-11 that also received the compound had significantly less diarrhea than those that only received the cancer drug.

With further development, this approach could improve anticancer drug efficacy and tolerance, Redinbo said. In general, though, this also shows that specific bacterial proteins can be selectively targeted without killing these health-promoting microbial symbiotes.

Study co-author, Sridhar Mani, M.D., professor of medicine and genetics at Einstein, said the severe diarrhea caused by CPT-11 can sharply limit the dosage that cancer patients can receive. Our tests showed conclusively that the inhibitor identified by our UNC colleagues prevented diarrhea in mice that were also receiving CPT-11. Were hopeful that clinical trials will show that administering this inhibitor when pati
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Contact: Dianne Shaw
dgs@med.unc.edu
919-966-5905
University of North Carolina School of Medicine
Source:Eurekalert

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