Editors' ChoiceCancer

Drugging Bugs to Make Chemotherapy Safer

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Science Translational Medicine  17 Nov 2010:
Vol. 2, Issue 58, pp. 58ec177
DOI: 10.1126/scitranslmed.3001903

Some of our best known drugs have come from tree bark—the pain-killer aspirin, the antimalarial drug quinine, and the breast cancer drug tamoxifen. Another tree bark–derived drug, irinotecan, improves survival for patients with colorectal and other cancers. Yet irinotecan has common, dose-limiting toxicities, including diarrhea and colitis. Irinotecan inactivation in the liver by the addition of glucuronide groups, which increase water solubility and aid excretion into the gut, could prevent these side effects; however, β-glucuronidase enzymes present in normal gut bacterial flora convert irinotecan back to its active metabolitic state. Although antibiotics can be used to eradicate these bacteria, the bacterial flora performs essential roles in normal human physiological processes. Now, Wallace et al. report that the use of specific inhibitors of bacterial β-glucuronidases can prevent irinotecan-induced diarrhea without killing these bacteria.

The authors first screened a chemical library to identify inhibitors of bacterial β-glucuronidases. They then focused on four compounds for further study and demonstrated that each inhibited bacterial β-glucuronidases without killing the bacteria. Mammalian β-glucuronidases lack the bacterial β-glucuronidase motif bound by these inhibitors and hence were unaffected by these inhibitors; this specificity should allow for treatment with minimal side effects in patients. Lastly, the authors examined the effects of β-glucuronidase inhibitors on the safety of mice undergoing irinotecan treatment. Mice treated with irinotecan alone experienced severe diarrhea and colitis, which necessitated euthanasia. On the other hand, mice treated with irinotecan plus a β-glucuronidase inhibitor had a much lower incidence of diarrhea and no evidence of colitis.

These new findings show that bacterial β-glucuronidase inhibitors have great potential to improve the safety of irinotecan-containing chemotherapy regimens. The next question is whether these results extend to the treatment of human cancer patients, and, if so, whether this strategy will allow for further dose escalation of irinotecan so that patient outcomes can be improved without compromising safety.

B. D. Wallace et al., Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science 330, 831–835 (2010). [Abstract]

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