Agent blocks drug’s toxic side effects

UNC-CHAPEL HILL (US) — A debilitating side effect of a widely used but harshly potent treatment for colon cancer could be eliminated if a promising new laboratory discovery bears fruit.

The pre-clinical finding, published in the Nov. 5 issue of the journal Science, relates to the drug CPT-11, or Irinotecan, a chemotherapeutic agent used to fight colon cancer and other solid malignancies.

It is believed to be the first successful targeting of an enzyme in symbiotic bacteria found in the digestive system.

While it has proven a valuable tool for attacking tumors, CPT-11 can also cause severe diarrhea, which limits the dosage that patients can tolerate, curbing the drug’s potential effectiveness.

Researchers have discovered it is possible to target and block the enzyme, beta glucuronidase, which is thought to play a major role in the gastric side effects.

Scientists had to overcome a major hurdle: the culprit enzymes are found in microbes in the gut that play a major role in human health, so eliminating the anticancer drug’s toxicity without making things worse for patients was a real challenge, says Matthew  Redinbo, professor of chemistry at the University of North Carolina at Chapel Hill.

“We need to retain our intestinal bacteria—they help us digest food, make critical vitamins, and protect us from infection.

“This targeted approach stops the one bacterial protein thought to cause the drug’s devastating side effect, but without damaging the beneficial microbes or the intestines.”

The trouble with CPT-11 begins part way through the body’s process of excreting the drug, presumably after it has already killed tumor cells and been rendered inert.

When it reaches the intestines, beta glucuronidase enzymes in the gut bacteria snip a sugar off the inactivated cancer drug, essentially reactivating it, where it causes tissue damage.

It then 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 bacteria’s sweet tooth without damaging the microbes or intestines and, in the process, the toxic side effect was alleviated,” Redinbo says.

Instead of changing the makeup of the drug itself, Redinbo decided to take a new tack and 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 says. “In general, though, this also shows that specific bacterial proteins can be selectively targeted without killing these health-promoting microbial symbiotes.”

“Our tests showed conclusively that the inhibitor identified by our UNC colleagues prevented diarrhea in mice that were also receiving CPT-11,” says study co-author, Sridhar Mani, professor of medicine and genetics at Albert Einstein College of Medicine.

“We’re hopeful that clinical trials will show that administering this inhibitor when patients start taking CPT-11 allows for improvement in the drug’s anti-tumor effect in patients with cancer.”

Researchers at North Carolina Central University also contributed to the study, which was funded by the National Institutes of Health, the Golden Leaf Foundation, and the State of North Carolina.

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