Stopping Gut Microbe SideSteps Cancer Drug’s Side Effect

Blocking a bacterial enzyme alleviates a dangerous side effect of a colon cancer drug in mice, according to a multi-institutional research team (Science 2010, 330, 831). Irinotecan is one of just three drugs available to treat colon cancer, but it causes severe diarrhea that limits the doses patients can handle. Gut bacteria snip a sugar group off an irinotecan metabolite to generate a molecule that’s thought to cause diarrhea. So Matthew R. Redinbo of the University of North Carolina, Chapel Hill; Sridhar Mani of Albert Einstein College of Medicine; and colleagues found a way to stop the sugar cleavage while not killing the bacteria, which are essential for good health. The researchers solved the X-ray crystal structure of the sugar-cleaving enzyme produced in Escherichia coli and learned that it contains a loop not seen in its mammalian version. With that knowledge, they developed selective enzyme inhibitors that reduced diarrhea in mice treated with irinotecan. The team hopes that the findings can be translated to humans and that the concept of tweaking gut bacteria’s activities can be applied more broadly to drug development.