The strategy used in their preclinical research—inhibiting an enzyme in bacteria of the digestive tract—could allow patients to receive higher and more effective doses of the drug, known as CPT-11 or Irinotecan.
Sridhar Mani, M.D.The study, spearheaded by scientists at the University of North Carolina at Chapel Hill and involving collaborators at Albert Einstein College of Medicine of Yeshiva University and North Carolina Central University in Durham, is described in the November 5 issue of Science.
While the chemotherapy agent CPT-11 has proven useful in attacking colorectal tumors, it can also cause severe diarrhea – limiting the dosage that patients can tolerate and curbing the drug’s potential effectiveness. The primary cause of the diarrhea is believed to be beta glucuronidase, an enzyme found in bacteria that live in the gastrointestinal tract. After the liver has rendered CPT-11 inert, the drug enters the intestine where it’s reactivated by the beta glucuronidase of the gut bacteria. The revived CPT-11 irritates the intestine and causes severe diarrhea in up to 30 percent of patients who receive it.
To overcome this crippling side effect, the UNC researchers decided to look for compounds that would block the action of beta glucuronidase without eliminating the gut bacteria, which are important for human health.
“We need to retain our intestinal bacteria – they help us digest food, make critical vitamins and protect us from infection,” said Matthew R. Redinbo, Ph.D., who led the UNC research team, and is professor and chair of the chemistry department in the UNC College of Arts and Sciences and a member of the UNC Lineberger Comprehensive Cancer Center. “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.”
Study co-author, Sridhar Mani, M.D., professor of medicine and of 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. 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.”
The research was funded by the National Institutes of Health, the Golden Leaf Foundation and the State of North Carolina.
Other study co-authors were graduate students Bret D. Wallace and Jillian Orans, and postdoctoral fellow Kimberly T. Lane, Ph.D., all from the UNC chemistry department; Ja Seol Koo, M.D., and Christian Jobin, Ph.D., from the medicine department in the UNC School of Medicine; Hongwei Wang, Ph.D. and Madhukumar Venkatesh, Ph.D., from the departments of medicine, oncology and genetics at Albert Einstein College of Medicine; and John E. Scott, Ph.D., and Li-An Yeh, Ph.D., with the Biomanufacturing Research Institute and Technology Enterprise program at N.C. Central University.