Alleviating cancer drug toxicity by inhibiting a bacterial enzyme
- Wallace B.D.; Wang H.; Lane K.T.; Scott J.E.; Orans J.; Koo J.S.; Venkatesh M.; Jobin C.; Yeh L.-A.; Mani S.; Redinbo M.R.
- Issue Date
- Science, v.330, no.6005, pp.831 - 835
- Journal Title
- Start Page
- End Page
- The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial β-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial β-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial β-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11-induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy.
- Files in This Item
- There are no files associated with this item.
- Appears in
- 2. Clinical Science > Department of Gastroenterology and Hepatology > 1. Journal Articles
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.