Irinotecan (CPT-11) is a key component of the chemotherapy regimen used to treat colorectal cancer. However, its dose is limited by severe diarrhea. To get around that problem, researchers at the Lineberger Comprehensive Cancer Center at the University of North Carolina in Chapel Hill and colleagues focused on the source of the toxicity, the beneficial bacteria in the patients' gut.
Irinotecan is a prodrug that is converted to its active form in vivo. As the body clears the drug, it is converted back to an inactive form in the liver.
Unfortunately, the commensal bacteria in the patients' intestines reactivate the compound, causing severe diarrhea. In the November 5 issue of Science, the investigators reported that they can mitigate the toxicity in mice by inhibiting the bacterial b-glucuronidase enzymes.
The team identified potent and selective inhibitors of the bacterial enzymes that do not affect the mammalian form of the enzyme. Animals treated with an inhibitors and irinotecan had less diarrhea and less bloody diarrhea than animals treated with irinotecan alone.
Moreover, when the researchers examined the colon tissue from the treated animals, they found that the inhibitor reduced epithelial damaged caused by the chemotherapy agent. And the inhibitors did not harm the bacterial community, which is important for the patient's overall health.
The researchers hypothesize that if they can prevent or reduce diarrhea in patients, they may be able to increase the irinotecan dose and, thereby increase its efficacy.
Whether or not that approach will pan out will take more work, of course, but the early results are promising and show just how productive thinking out of the box can be.