Alleviating cancer drug toxicity by inhibiting a bacterial enzyme.

Publication Type:

Journal Article

Source:

Science (New York, N.Y.), Volume 330, Issue 6005, p.831-5 (2010)

Keywords:

Animalsdigestive disease, digestive deseases Antineoplastic Agents, Phytogenicdigestive disease, digestive deseases Bacteria, Anaerobicdigestive disease, digestive deseases Camptothecindigestive disease, digestive deseases Cell Line, Tumordigestive disease, digestive deseases Colondigestive disease, digestive deseases Crystallography, X-Raydigestive disease, digestive deseases Diarrheadigestive disease, digestive deseases Drug Evaluation, Preclinicaldigestive disease, digestive deseases Enzyme Inhibitorsdigestive disease, digestive deseases Escherichia colidigestive disease, digestive deseases Escherichia coli Proteinsdigestive disease, digestive deseases Femaledigestive disease, digestive deseases Glucuronidasedigestive disease, digestive deseases Humansdigestive disease, digestive deseases Intestinal Mucosadigestive disease, digestive deseases Micedigestive disease, digestive deseases Mice, Inbred BALB Cdigestive disease, digestive deseases Models, Moleculardigestive disease, digestive deseases Prodrugsdigestive disease, digestive deseases Protein Conformation

Abstract:

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.