Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The VSports app下载. gov means it’s official. Federal government websites often end in . gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely V体育官网. .

. 2010 Nov 5;330(6005):831-5.
doi: 10.1126/science.1191175.

Alleviating cancer drug toxicity by inhibiting a bacterial enzyme (VSports手机版)

Bret D Wallace  1 , Hongwei Wang, Kimberly T Lane, John E Scott, Jillian Orans, Ja Seol Koo, Madhukumar Venkatesh, Christian Jobin, Li-An Yeh, Sridhar Mani, Matthew R Redinbo
Affiliations

Alleviating cancer drug toxicity by inhibiting a bacterial enzyme

"V体育平台登录" Bret D Wallace et al. Science. .

Abstract (V体育官网入口)

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 VSports手机版. 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. .

PubMed Disclaimer

"V体育平台登录" Figures

Fig. 1
Fig. 1
CPT-11 metabolism and E. coli β-glucuronidase. (A) Intravenously administered CPT-11 is activated by carboxylesterases (CE) to SN-38, an antineoplastic topoisomerase I poison. Liver SN-38 is inactivated via glucuronidation to SN-38G by UDP-glucuronosyltransferase (UGT) enzymes and sent to the intestines. β-Glucuronidases (β-glucs) in the symbiotic GI bacteria remove the glucuronide as a carbon source, and active SN-38 in the intestinal lumen generates dose-limiting diarrhea. (B) Crystal structure of the E. coli β-glucuronidase tetramer at 2.5 Å resolution. (C) Four selective bacterial β-glucuronidase inhibitors identified via high-throughput screening.
Fig. 2
Fig. 2
Potent β-glucuronidase inhibitors. (A) Crystal structures of Inhibitors 2 and 3 bound to the active site of E. coli β-glucuronidase. (B) Inhibitors are observed to stack cooperatively between monomers in the E. coli β-glucuronidase tetramer. Amino acid abbreviations: D, Asp; E, Glu; F, Phe; G, Gly; L, Leu; M, Met; R, Arg; S, Ser; Y, Tyr.
Fig. 3
Fig. 3
Inhibitor selectivity for bacterial β-glucuronidase. (A) The 360–376 loop forms direct contact with the bound inhibitors in the E. coli β-glucuronidase structure. This loop is missing from the structure of human β-glucuronidase; thus, it is labeled the “bacterial loop.” (B) Elimination of the “bacterial loop” from E. coli β-glucuronidase produces an enzyme insensitive to inhibitor efficacy. (C) β-Glucuronidase inhibition in living E. coli cells grown under both aerobic and anaerobic conditions. (D) β-Glucuronidase inhibition in two obligate anaerobic bacteria. Error bars represent SD; N = 3.
Fig. 4
Fig. 4
Alleviation of CPT-11 toxicity in mice. (A) CPT-11 produced bloody diarrhea starting after 8 days and peaking at 10 days, whereas oral administration of Inhibitor 1 with CPT-11 reduced the incidence of bloody diarrhea. Vehicle and Inhibitor 1 alone caused no bloody diarrhea. By day 8 to 11, mice in the CPT-11 group began to suffer from severe lethargy and lack of movement; by day 11, all mice in that group were euthanized according to AIC protocol 20070715. (B) Histologic score of the distal and proximal colon of animals in the four treatment groups. Error bars represent SD; N = 12. (C) Tissue histology of colons taken from mice from each treatment group show healthy glandular structure for both vehicle and Inhibitor 1 but highly disrupted tissues in the CPT-11 group. In contrast, Inhibitor 1 provided in combination with CPT-11 protects the colon from damage.
See this image and copyright information in PMC

Comment in (V体育ios版)

"VSports最新版本" References

    1. Hsiang YH, Hertzberg R, Hecht S, Liu LF. J Biol Chem. 1985;260:14873. - V体育2025版 - PubMed
    1. Redinbo MR, Champoux JJ, Hol WG. Curr Opin Struct Biol. 1999;9:29. - PubMed
    1. Pizzolato JF, Saltz LB. Lancet. 2003;361:2235. - V体育ios版 - PubMed
    1. Pommier Y. Nat Rev Cancer. 2006;6:789. - "V体育官网入口" PubMed
    1. Smith NF, Figg WD, Sparreboom A. Toxicol In Vitro. 2006;20:163. - V体育平台登录 - PubMed

Publication types (VSports最新版本)

MeSH terms

Substances