by ecancer reporter Janet Fricker

An innovative strategy that selectively targets an enzyme present gut bacteria has the potential to eradicate the gastric side effects of the drug CPT-11 (also called irinotecan) used to treat colon cancer, reports the journal Science.

 CPT-11,   a chemotherapeutic agent used against colon, lung and brain cancers as well as refractory forms of leukaemia and lymphoma, is known to cause severe diarrhoea in around 30 % of patients, thereby limiting the dose patients can tolerate and the potential effectiveness of the drug.

Problems arise when the inactivated drug is excreted via the biliary ducts into the GI tract, where it serves as a substrate for beta glucuronidase enzymes found in commensal bacteria.  Beta glucuronidase has the effect of removing the glucouronide sugar group, thereby reviving the drug and enabling it to cause the tissue damage that triggers the diarrhoea.

Using antibiotics to reduce GI bacteria levels has been considered as a potential approach, but dismissed since it would also have the drawback of also eliminating commensal bacteria that are critical for digesting food, making vitamins and protecting people from infection.

Researchers led by Matthew Redinbo, from the University of North Carolina at Chapel Hill (US) used structural and chemical biology to identify inhibitors that would selectively block the action of the beta glucuronidase enzymes. The team screened a chemical library of 10,240 compounds, which allowed the field to be narrowed down to four prime candidates.

The investigators showed that the four lead compounds could inhibit beta-glucuronidase enzyme activity in several different types of bacteria. Finally, they examined the ability of one of the compounds to eliminate diarrhoea and intestinal damage in mice.

The mice were divided into four groups, the first received distilled water; the second group the inhibitor and no CPT-11; the third CPT-11 but no inhibitor; and the fourth group CPT-111 and the inhibitor. Results showed that at days 8 to 10, only animals in the third group experienced symptoms of diarrhoea.

 “If successfully translated into humans, leads like those described here could allow dose intensification of CPT-11, enabling studies of whether efficacy could be improved in relevant human cancers by reducing one of the current dose limiting side effects,” wrote the authors, who had been inspired to undertake the study after witnessing the debilitating effects of CPT-11 on a colleague.

Reference

BD Wallace, H Wang KT Lane et al. Alleviating cancer drug toxicity by inhibiting a bacterial enzyme.  Science 5 November 2010: 330, 831-835.