Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.2.1.31 (beta-glucuronidase)
7,680 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have tested a new type of immunoliposomes which may effectively mediate the targeting of enzymes to be used for site-specific prodrug activation (immuno-enzymosomes). The enzyme beta-glucuronidase, capable of activating the prodrug epirubicin-glucuronide (epi-glu), was coupled to the external surface of immunoliposomes directed towards ovarian cancer cells. A significant increase in cytotoxicity of the prodrug epi-glu was shown when the in vitro cultured cancer cells were pretreated with these immuno-enzymosomes.
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PMID:A new application for liposomes in cancer therapy. Immunoliposomes bearing enzymes (immuno-enzymosomes) for site-specific activation of prodrugs. 828 16

The prodrug N-[4-(daunorubicin-N-carbonyl-oxymethyl)phenyl] O-beta-glucuronyl carbamate (DNR-GA3) was synthesized for specific activation by human beta-glucuronidase, released in necrotic areas of tumour lesions. In vitro, DNR-GA3 was 18 times less toxic than daunorubicin (DNR) and the prodrug was completely activated to the parent drug by human beta-glucuronidase. The maximum tolerated dose of DNR-GA3 in nude mice bearing s.c. human ovarian cancer xenografts was 6-10 times higher than that of DNR. The prodrug was cleared more rapidly from the circulation (elimination t1/2 = 20 min) than the parent drug (elimination t1/2 = 720 min). The anti-tumour effects of DNR-GA3 and DNR were investigated in four different human ovarian cancer xenografts OVCAR-3, FMa, A2780 and MRI-H-207 at a mean tumour size between 100 and 200 mm3. In three out of four of these tumour lines, the prodrug given i.v. at the maximum tolerated dose ranging from 150 to 250 mg kg(-1) resulted in a maximum tumour growth inhibition from 82% to 95%. The standard treatment with DNR at a dose of 8 mg kg(-1) given i.v. weekly x 2 resulted only in a maximum tumour growth inhibition from 40% to 47%. Tumour line FMa did not respond to DNR, nor to DNR-GA3. Treatment with DNR-GA3 was also given to mice with larger tumours that would contain more necrosis (mean size 300-950 mm3). The specific growth delay by DNR-GA3 was extended from 2.1 to 4.4 in OVCAR-3 xenografts and from 4.4 to 6.0 in MRI-H-207 xenografts. Our data indicate that DNR-GA3 is more effective than DNR and may be especially of use for treatment of tumours with areas of necrosis.
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PMID:The efficacy of the anthracycline prodrug daunorubicin-GA3 in human ovarian cancer xenografts. 986 70

N-[4-daunorubicin-N-carbonyl (oxymethyl)phenyl] O-beta-glucuronyl carbamate (DNR-GA3) is a glucuronide prodrug of daunorubicin (DNR) which induced a better tumor growth delay than DNR when studied at equitoxic doses in three human ovarian cancer xenografts. These results suggested that the prodrug DNR-GA3 was selectively activated by human beta-glucuronidase present in tumor tissue. We determined the pharmacokinetics and distribution of DNR-GA3 in nude mice bearing human ovarian cancer xenografts (OVCAR-3, FMa, A2780, and MRI-H-207). Administration of DNR at 10 mg/kg i.v. (maximum tolerated dose) to OVCAR-3-bearing mice resulted in a peak plasma concentration of the drug of 12.18 microM (t = 1 min). DNR-GA3 at 100 mg/kg i.v. (approximately 50% of the maximum tolerated dose [MTD]) resulted in a peak plasma concentration of DNR that was 28-fold lower than that after DNR itself; in normal tissues, prodrug injection resulted in 5- to 23-fold lower DNR concentrations. DNR showed a relatively poor uptake into OVCAR-3 tumors with a peak concentration of 2.05 nmol x g(-1) after injection. In the same xenograft, DNR-GA3 resulted in a significantly higher DNR peak concentration of 3.45 nmol x g(-1) (P < 0.05). The higher area under the curve of DNR in tumor tissue after DNR-GA3 than after DNR itself would be the result of prodrug activation by beta-glucuronidase. In this respect, a considerably higher beta-glucuronidase activity was found in tumor tissue when compared to plasma. The specific activation of DNR-GA3 by beta-glucuronidase at the tumor site relative to normal organs leads to a more tumor-selective therapy, resulting in greater efficacy without increased toxicity.
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PMID:Distribution and pharmacokinetics of the prodrug daunorubicin-GA3 in nude mice bearing human ovarian cancer xenografts. 1003 53

Immuno-enzymosomes have been proposed for the targeting of enzymes to cancer cells to achieve site specific activation of anticancer prodrugs. Previously, we reported that the enzyme beta-glucuronidase (GUS), capable of activating anthracycline-glucuronide prodrugs, can be coupled to the surface of inmunoliposomes directed against human ovarian cancer cells (OVCAR-3). This study aimed at the design of an immuno-enzymosome formulation with maximum enzyme targeting capability. By purification of the commercially available enzyme beta-glucuronidase (GUS), a 2-fold increase in the enzyme specific activity and a 4-fold increase in the enzymatic activity of immuno-enzymosomes was achieved. As a result, upon incubation with human ovarian cancer cells (OVCAR-3), cell-associated enzymatic activity increased correspondingly. The optimized immuno-enzymosomes were shown to bind to the target cells in a specific fashion. Above a GUS/Fab' molar ratio of 0.5, impairment of the target cell binding ability of the immuno-enzymosomes was observed. This was likely due to a steric hindrance effect mediated by the presence of large amounts of bulky GUS molecules on the liposome surface. Nevertheless, increasing the GUS density on the surface of the immuno-enzymosomes to levels by far exceeding the GUS/Fab' molar ratio of 0.5, yielded a considerably improved enzyme targeting capability.
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PMID:Design of immuno-enzymosomes with maximum enzyme targeting capability: effect of the enzyme density on the enzyme targeting capability and cell binding properties. 1040 77

The doxorubicin (DOX) prodrug N-[4-doxorubicin-N-carbonyl (oxymethyl) phenyl] O-beta-glucuronyl carbamate (DOX-GA3) was synthesised for specific activation by human beta-glucuronidase, which is released in necrotic areas of tumour lesions. This novel prodrug was completely activated to the parent drug by human beta-glucuronidase with V(max)= 25.0 micromol x min(-1) x mg(-1) and K(m) = 1100 microM. The pharmacokinetics and distribution of DOX-GA3 in nude mice bearing human ovarian cancer xenografts (OVCAR-3) were determined and compared with DOX. Administration of DOX at 8 mg x kg(-1) i.v. (maximum tolerated dose, MTD) to OVCAR-3-bearing mice resulted in a peak plasma concentration of the drug of 16.4 microM (t = 1 min). A 7.6-times lower peak plasma concentration of DOX was measured after injection of DOX-GA3 at 250 mg x kg(-1) i.v. (50% of MTD). In normal tissues the prodrug showed peak DOX concentrations that were up to 5-fold (heart) lower than those found after DOX administration. DOX-GA3 activation by beta-glucuronidase in the tumour yielded an almost 5-fold higher DOX peak concentration of 9.57 nmol x g(-1) (P< 0.05) than the peak concentration of only 2.14 nmol x g(-1) observed after DOX. As a consequence, the area under the curve of DOX calculated in tumour tissue after DOX-GA3 (13.1 micromol x min(-1) x g(-1)) was 10-fold higher than after DOX (1.31 micromol x min(-1) x g(-1)). The anti-tumour effects of DOX-GA3 and DOX were compared at equitoxic doses in OVCAR-3 xenografts at a mean tumour size of 125 mm(3). The prodrug given i.v. at 500 mg x kg(-1) weekly x 2 resulted in a maximum tumour growth inhibition of 87%, while the standard treatment with DOX at a dose of 8 mg x kg(-1) i.v. weekly x 2 resulted in a maximum tumour growth inhibition of only 56%. Treatment with DOX-GA3 was also given to mice with larger tumours containing more necrosis. For tumours with a mean size of 400 mm(3) the specific growth delay by DOX-GA3 increased from 2.7 to 3.9. Our data indicate that DOX-GA3 is more effective than DOX and suggest that the prodrug will be specifically advantageous for treatment of advanced disease.
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PMID:A novel doxorubicin-glucuronide prodrug DOX-GA3 for tumour-selective chemotherapy: distribution and efficacy in experimental human ovarian cancer. 1120 53

A glucuronide doxorubicin prodrug N-[4-doxorubicin-N-carbonyl (oxymethyl) phenyl] O-beta-glucuronyl carbamate (DOX-GA3) has been developed to improve the antitumor effects of doxorubicin (DOX). The prodrug was originally designed to be activated into drug by human beta-glucuronidase (GUS) released from tumor cells in necrotic areas of tumor lesions. The aim of this study was to further improve the antitumor effects of DOX-GA3 by means of antibody-directed enzyme prodrug therapy (ADEPT). We thus investigated if the administration of an enzyme-immunoconjugate prepared from the pancarcinoma Ep-CAM specific monoclonal antibody (MAb) 323/A3 and beta-glucuronidase would result in improved antitumor effects because of additional enzyme localization in tumor tissue. In vitro, the prodrug DOX-GA3 was found to be 12-times less toxic than the parent drug DOX in a human ovarian cancer cell line. Immunospecific and complete activation of the prodrug took place when the cells were pretreated with 323/A3-beta-glucuronidase conjugate. In nude mice bearing s.c. human ovarian cancer xenografts (FMa) the maximum tolerated dose (MTD) of DOX-GA3 (500 mg/kg weekly x 2) was much higher when compared with that of DOX (8 mg/kg weekly x 2). In mice bearing well-established FMa xenografts, the standard treatment of DOX at the MTD (8 mg/kg weekly x 2) resulted in a tumor growth inhibition of 67%. Treatment with DOX-GA3 at a single dose of 500 mg/kg resulted in a better tumor growth inhibition of 87%. The combination of DOX-GA3 (500 mg/kg) with 323/A3-mGUS conjugate and anti-GUS MAb 105, to clear circulating conjugate, improved the antitumor effect even further to 98%. At the lower dose of 250 mg/kg DOX-GA3 tumor growth inhibition (34%) was not better than that of DOX. The combination, however, of DOX-GA3 at 250 mg/kg and 323/A3-mGUS conjugate plus MAb 105 again greatly improved the antitumor effect (growth inhibition of 93%). DOX given at 8 mg/kg weekly x 2 did not result in tumor regressions. As a result of ADEPT, the number of regressions of tumors improved from 0 out of 12 to 9 out of 11 at a dose of 250 mg/kg DOX-GA3. At the higher prodrug dose (500 mg/kg) the number of regressions improved from 2 out of 12 to 9 out of 10 as a result from the addition of enzyme-immunoconjugate. Our studies show that the efficacy of the widely used anti-cancer agent DOX may be improved by using the prodrug DOX-GA3, in combination with the tumor-specific enzyme-immunoconjugate 323/A3-mGUS and a conjugate clearing antibody.
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PMID:Pronounced antitumor efficacy of doxorubicin when given as the prodrug DOX-GA3 in combination with a monoclonal antibody beta-glucuronidase conjugate. 1125 80

Tumor-specific activation of the glucuronide prodrug of doxorubicin, N-[4-doxorubicin-N-carbonyl(oxymethyl)phenyl]-O-beta-glucuronyl carbamate (DOX-GA3), by beta-glucuronidase present in necrotic tumor areas might be improved after transduction of tumor cells to secrete a targeted form of beta-glucuronidase. To that end, we constructed an adenovirus vector, designated Ad/C28-GUSh, encoding human beta-glucuronidase fused to a human single-chain Fv (scFv) against the epithelial cell adhesion molecule (EpCAM), C28, and preceded by a signal sequence for secretion. Antibody specificity and enzyme activity were retained in the fusion protein secreted by tumor cells infected with Ad/C28-GUSh. Diffusion of fusion protein from transduced tumor cells within MCF-7 multicellular spheroids was visualized by immunohistochemistry. Treatment of spheroids with Ad/C28-GUSh and DOX-GA3 resulted in growth inhibition comparable to treatment with doxorubicin alone. Treatment of well-established FMa human ovarian cancer xenografts with intravenous injection of DOX-GA3 (500 mg/kg) resulted in a tumor volume-doubling time of 23.8 days compared to 8.0 days for phosphate-buffered saline (PBS)-treated mice. Intratumoral administration of Ad/C28-GUSh before DOX-GA3 enhanced the growth inhibition and increased the tumor volume-doubling time to 43.1 days (p < 0.01), while virus alone had no effect. Thus, we have successfully shown that an adenovirus vector encoding a secreted, targeted form of human beta-glucuronidase can further improve DOX-GA3 monotherapy.
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PMID:Pronounced antitumor efficacy by extracellular activation of a doxorubicin-glucuronide prodrug after adenoviral vector-mediated expression of a human antibody-enzyme fusion protein. 1501 32

Eleven new metabolites, butanolides 1-6, lignan derivatives 7-9, sesquiterpene 10, and 3',4'-seco-flavane derivative 11, have been isolated from an ethanol extract of Machilus wangchiana. Twenty known compounds, including ginkgolides A and B (16 and 17), were also isolated. Their structures and absolute configurations were determined by spectroscopic and chemical methods. Compounds 7, 8a, 8b, 9, 11, (+)-guaiacin (12), meso-dihydroguaiaretic acid (13), and hamabiwalactone A (15) showed potent in vitro activities against the release of beta-glucuronidase in rat polymorphonuclear leukocytes (PMNs) induced by platelet-activating factor (PAF), with 42.5-75.6% inhibition at 10(-5) M. Compounds 8, 8a, 8b, 9, and 11 reduced dl-galactosamine (GalN)-induced hepatocyte (WB-F344 cells) damage with 39.4 +/- 6.3% to 53.6 +/- 3.5% inhibition at 10(-4) M. Isomahubannolide-23 (14) was cytotoxic against human stomach cancer (BGC-823) and ovarian cancer (A2780) cell lines, with IC(50) values of 0.13 and 2.66 muM, respectively.
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PMID:Chemical constituents of the bark of Machilus wangchiana and their biological activities. 1991 29

To search for the chemical constituents possessing anti-inflammatory or cytotoxic activities from plants, Morus wittiorum was investigated for the first time. The stem bark of M. wittiorum was extracted with 95% EtOH. The EtOH extract was fractionationed on silica gel by eluting with petroleum ehter, CHCl3 and EtOAc successively. The further isolation and purification of the EtOAc fraction of 95% EtOH extract was performed by various column chromatography such as silica gel, Sephadex LH-20, RP-C18 column chromatography and so on. The structures of compounds were determined on the basis of spectral analysis such as NMR, MS etc. As a result, nine compounds were isolated including six flavonoids and three stilbenoids and elucidated as quercetin (1), 5, 7, 3', 4'-tetrahydroxy-3-methoxyflavone (2), norartocarpanone (3), dihydrokaempferol (4), euchrenone a7 (5), morachalcone A (6), resveratrol (7), oxyresveratrol (8), 4'-prenyloxyresveratrol (9). Compounds 1-9 were isolated from this plant for the first time, among which compounds 1-8 were evaluated for their anti-inflammatory and cytotoxic activities, respectively. Wherein compounds 6 and 8 showed inhibition to the release of beta-glucuronidase from rat polymorphonuclear leukocyte (PMNs) induced by platelet activating factor (PAF) at a concentration of 10(-5) mol x L(-1). The inhibitory ratios were 76.8%, 94.2% individually. Compounds 2 and 8 exhibited selective cytotoxicity agaist human ovarian cancer (A2780) and human gastric cancer (BGC-823) with IC50 values as 0.66, 1.31 micromol x L(-1) individually.
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PMID:[Phenolic constituents from stem bark of Morus wittiorum and their anti-inflammation and cytotoxicity]. 2124 22

Twenty-one compounds were isolated from an ethanol extract of Machilus wangchiana by a combination of various chromatographic techniques including column chromatography over silica gel and Sephadex LH-20 and reversed-phase HPLC. Their structures were identified by spectroscopic data analysis including optical rotation, UV, IR, MS, and NMR data. The compounds are categorized as eight butanolides (1-8), eight lignans (9-16), and five terpenoids (17-21). Compound 16 is a new natural product with an uncommon heptanorlignan skeleton. Meanwhile, the unique Ginkgo biloba (maidenhair) metabolites ginkgolides A (19) and ginkgolides B (20) were obtained from this material. In the preliminary assays, compound 5 showed selective inhibitory activities against human stomach cancer cells (BGC-823) and ovary cancer cells (A2780) with IC50 values of 0.13 x 10(-6) and 2.66 x 10(-6) mol x L(-1), respectively. Compounds 8 and 9, at 1 x 10(-5) mol x L(-1), showed inhibitory activities against the release of beta-glucuronidase of the polymorphous nuclear leukocytes induced by platelet activating factor (PAF), with inhibition rates of 60.0% and 54.2%.
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PMID:[Chemical constituents from Machilus wangchiana]. 2318 36


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