β-Glucuronidase and the Hydrolysis of Glucuronides

Levvy, G. A.; Conchie, J.

doi:10.1016/b978-0-12-395501-2.50010-4

Cited by 55 publications

(35 citation statements)

References 210 publications

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“…In this regard, as early as 1966 Connors and Whisson (Connors and Whisson, 1966) have shown that glucuronide prodrugs can be activated in tumours by β-glucuronidase. β-Glucuronidase is present extracellularly in necrotic tumour areas found in tumours larger than 3 mm diameter (Bosslet et al, 1995;Schumacher et al, 1996), whereas in normal tissues it is present only intracellularly inside lysosomes and microsomes (Levvy and Conchie, 1966). A clinical trial of aniline mustard was performed in patients with advanced cancer (Young et al, 1976).…”

Section: Discussionmentioning

confidence: 99%

A novel doxorubicin-glucuronide prodrug DOX-GA3 for tumour-selective chemotherapy: distribution and efficacy in experimental human ovarian cancer

et al. 2001

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Doxorubicin (DOX) is an anticancer agent with a wide spectrum of activity. Cumulative dose-related cardiotoxicity, however, is a major side-effect of DOX, in addition to the acute toxicities, such as myelosuppression, nausea and vomiting. The success of DOX, and its limitations in clinical use, have directed research endeavours for the development of analogues of DOX with an improved therapeutic index. Among these are iododoxorubicin, AD-32 and epidoxorubicin (Weiss, 1992). Iododoxorubicin was noted to be promising in phase I trials, but in phase II trials the response rate was too low to warrant further development. AD-32 has greater anti-tumour activity, and less cardiotoxicity, than DOX, but drug formulation and solubility problems prevented its further clinical development. Of the available analogues, only epidoxorubicin appears to have a reduced cardiotoxicity with retention of antitumour activity and is in use in current cancer chemotherapy.Another way to improve the selectivity and efficacy of chemotherapy is the use of non-toxic prodrugs that are preferentially converted into active anticancer agents at the tumour site (Sinhababu and Thakker, 1996). N-L-leucyl-DOX is a prodrug of DOX, to be activated by tumour peptidases (Deprez-de Campeneere et al, 1982). In human ovarian cancer xenografts, N-L-leucyl-DOX was more effective than DOX . Clinical studies on N-L-leucyl-DOX, however, have indicated premature activation of the prodrug in the circulation, because of which the selectivity of the prodrug would be reduced . Elevated enzyme levels in tumour tissue have been reported for β-glucuronidase (Connors and Whisson, 1966). Bosslet et al (1995) and Schumacher et al (1996) have shown that this enzyme is released in the extracellular space as a result of necrosis in tumours. The enzyme can only be detected in very low concentrations in the circulation (Fishman, 1970). Therefore, β-glucuronidase may be exploited for the specific activation of glucuronide prodrugs in tumour tissue.We have developed glucuronide derivatives of anthracyclines and showed that these prodrugs, such as epirubicin-glucuronide (Haisma et al, 1992) and daunorubicin-glucuronides (Leenders et al, 1995;Houba et al, 1996), are relatively non-toxic in vitro and can be activated by β-glucuronidase to yield the active anthracycline. Treatment with the glucuronide prodrug daunorubicin-GA3 (DNR-GA3) induced a better tumour growth delay than daunorubicin (DNR) when studied at equitoxic doses in 3 human ovarian cancer xenografts which were sensitive to DNR (Houba et al, 1998). Comparison of the distribution and pharmacokinetics of DNR and DNR-GA3 demonstrated that the prodrug DNR-GA3 was selectively activated by human β-glucuronidase present in the tumours and resulted in a higher DNR AUC in tumours and lower A novel doxorubicin-glucuronide prodrug DOX-GA3 for tumour-selective chemotherapy: distribution and efficacy in experimental human ovarian cancer Summary The doxorubicin (DOX) prodrug N-[4-doxorubicin-N-carbonyl (oxymethyl) phenyl] O-β-glucuro...

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Section: Discussionmentioning

confidence: 99%

A novel doxorubicin-glucuronide prodrug DOX-GA3 for tumour-selective chemotherapy: distribution and efficacy in experimental human ovarian cancer

et al. 2001

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Section: Dietary D-glucarate Effects On the Biomarkers Of Inflammatiomentioning

confidence: 99%

“…GA is a natural, apparently non-toxic compound produced in small amounts by mammals, including humans, as well as by certain plants (29). GA is an end product of the D-glucuronic acid pathway in mammals (29). The oxidation of D-glucuronic acid or its lactone results in products that hydrolyze spontaneously in aqueous solution to yield the potent βG inhibitor, D-glucaro-1,4-lactone (1,4-GL), non-inhibitory D-glucaro-1,4-lactone -glucaro-6,3-lactone (6,3-GL) and GA, all of which are excreted in urine (30).…”

Section: Dietary D-glucarate Effects On the Biomarkers Of Inflammatiomentioning

confidence: 99%

Dietary D-glucarate effects on the biomarkers of inflammation during early post-initiation stages of benzo[a]pyrene-induced lung tumorigenesis in A/J mice

Zoltaszek

Kowalczyk

et al. 2010

Oncol Lett

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Abstract. Previous studies showed that dietary calcium D-glucarate (CG) inhibited benzo[a]pyrene (B[a]P)-inducedA/J mouse lung tumorigenesis, suppressing cell proliferation and chronic inflammation and inducing apoptosis during late post-initiation stages. The present study aimed to investigate changes in the homeostasis of cytokines in blood serum, as well as alterations in biomarkers of inflammation and apoptosis in lung tissue caused by dietary CG during early post-initiation stages of B[a]P-induced lung tumorigenesis. Two doses of 3 mg of B[a]P were given intragastrically to A/J mice 2 weeks apart. CG administration in the AIN-93G diet (2 and 4%, w/w) commenced at 2 weeks following the second dose of B[a]P. The levels of interleukin (IL)-6, IL-10 and tumor necrosis factor α (TNFα) in blood serum were investigated by FCAP array analysis. Two weeks after the second dose of B[a]P, approximately 8-and 28-fold increases of TNFα and IL-6, respectively, occurred in the blood serum and an approximately 16% decrease of IL-10 levels compared to the untreated control group was noted. At 4 weeks after the second dose of B[a]P and after 2 weeks of CG administration in the diet, the 2 and 4% CG diets significantly reduced the levels of IL-6 and TNFα (by 70 and 33%, respectively). In a dose-related manner, the diets also increased the level of antiinflammatory cytokine IL-10 compared to the B[a]P group. At 6 weeks after the second dose of B[a]P, the cytokine levels in the serum continued to show a decrease in the CG-treated groups. These events are accompanied by an increased level of cleaved caspase-9 product with a molecular weight of 37 kDa. In conclusion, dietary D-glucarate decreases the level of proinflammatory cytokines, increases the level of the anti-inflammatory cytokine IL-10 during early post-initiation stages of B[a]P-induced lung tumorigenesis in A/J mice and affects apoptotic induction.

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“…It has even been suggested that Dupuytren's contracture, which occurs frequently in epileptic patients, may be the result of a hormonal disturbance caused by hepatic enzyme induction (Lancet, 1972b). D-glucaric acid is an end product of Dglucuronic acid metabolism in the liver, and is excreted normally in the urine (Levvy & Conchie, 1966). Anticonvulsant drugs can increase the excretion of this substance 100-fold or more (Latham, Millbank, Richens & Rowe, 1973) and this is presumed to be by induction of enzymes on the D-glucaric acid pathway (Hunter, Maxwell, Carrella, Stewart & Williams, 1971).…”

mentioning

confidence: 99%

The Clinical Consequences of Chronic Hepatic Enzyme Induction by Anticonvulsant Drugs

Richens

1974

Brit J Clinical Pharma

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β-Glucuronidase and the Hydrolysis of Glucuronides

Cited by 55 publications

References 210 publications

A novel doxorubicin-glucuronide prodrug DOX-GA3 for tumour-selective chemotherapy: distribution and efficacy in experimental human ovarian cancer

A novel doxorubicin-glucuronide prodrug DOX-GA3 for tumour-selective chemotherapy: distribution and efficacy in experimental human ovarian cancer

Dietary D-glucarate effects on the biomarkers of inflammation during early post-initiation stages of benzo[a]pyrene-induced lung tumorigenesis in A/J mice

The Clinical Consequences of Chronic Hepatic Enzyme Induction by Anticonvulsant Drugs

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