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.UNC News Services contact:
Patric Lane | EurekAlert!
Research offers clues for improved influenza vaccine design
09.04.2018 | NIH/National Institute of Allergy and Infectious Diseases
Injecting gene cocktail into mouse pancreas leads to humanlike tumors
06.04.2018 | University of Texas Health Science Center at San Antonio
Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.
Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...
Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.
The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...
Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.
Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...
In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...
In an article that appears in the journal “Review of Modern Physics”, researchers at the Laboratory for Attosecond Physics (LAP) assess the current state of the field of ultrafast physics and consider its implications for future technologies.
Physicists can now control light in both time and space with hitherto unimagined precision. This is particularly true for the ability to generate ultrashort...
13.04.2018 | Event News
12.04.2018 | Event News
09.04.2018 | Event News
19.04.2018 | Materials Sciences
19.04.2018 | Physics and Astronomy
19.04.2018 | Physics and Astronomy