Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.1.4 (deaminase)
 5,113 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various 2'-azido- and 2'-aminoarabinofuranosyl purine and pyrimidine nucleosides have been synthesized. Among these, the derivatives of cytosine and of adenine inhibit the growth of some tumor cell lines in vitro and in vivo. 2'-Azidoarabinofuranosyl cytosine also interferes with the replication of herpes simplex virus types I and II. Whereas 2'-azidoara-C is resistant to deamination by a partially purified CdR deaminase from KB cells, the adenine derivatives are substrates for aminohydrolases partially purified from calf and mouse intestines. Both azido- and aminoara-C are phosphorylated by partially purified CdR kinases from leukemia L1210 and from human AML blast cells. The accumulated data encourage exploration of the clinical utility of the more potent of these analogues.
Recent Results Cancer Res 1980
PMID:Synthesis, biologic effects, and biochemical properties of some 2'-azido- and 2'-amino-2'-deoxyarabinofuranosyl pyrimidines and purines. 744 52

The activities and isoenzyme pattern of cobalt-activated acylase and of aminoacylase I were estimated in carcinomas of bronchi, lung, thorax, stomach, colon and uterus. In all cancer tissues the activity of cobalt-activated acylase was markedly increased as compared with the normal tissue. Alterations of the isoenzyme pattern of cobalt-activated acylase were found in the carcinoma of stomach and of uterus, with the increased expression of the form-1 of the enzyme. No regularity in the aminoacylase I changes in tumor tissues has been observed.
 ...
PMID:Cobalt-activated acylase and aminoacylase I in human malignant tumors. 745 52

We have previously demonstrated that the RCK gene involved in t(11;14)(q23;q32) and the more centromeric MLL/ALL1 gene involved in t(4;11)(q21;q23) and t(11;19)(q23;p13) are localized on different adjacent NotI fragments by using pulsed-field gel electrophoresis (PFGE) analysis with the yeast artificial chromosome (YAC) clone yB22B2. The PFGE analysis using the YACs of YTY17 containing the prophobilinogen deaminase (PBGD), CBL2 and THY1 genes and yB22B2 allowed the following ordering of genes and breakpoints from CD3 to THY1 on 11q23: cent-CD3-ALL/MLL1-RCK-PBGD-CBL2-THY1, and the establishment of a long-range restriction map covering these genes. In addition, we showed that the FLI1 region involved in the t(11;22)(q24;q12) in Ewing's sarcoma was more telomeric region that the THY1 gene by analyzing somatic cell hybrids carrying the 11q- and/or 14q+ chromosome of the t(11;14)(q23;q32) translocation, and by PFGE analysis of the YAC clone YTY17.
Genes Chromosomes Cancer 1993 Nov
PMID:Long-range mapping of the 11q23 region involved in chromosome aberrations in human tumors by pulsed-field gel electrophoresis with a yeast artificial chromosome. 750 24

Current treatments for metastatic malignant disease are often ineffective. One of the most promising of the selective genetic strategies against cancer is VDEPT (virally directed enzyme prodrug therapy). This uses a viral vector to carry a prodrug-activating enzyme gene into both tumour and normal cells. By linking the foreign gene downstream of tumour-specific transcription units, tumour-specific expression of the foreign enzyme gene can be achieved. We have developed a genetic therapy strategy using VDEPT against cancers that overexpress the oncogene ERBB2. This occurs in approximately one-third of breast and pancreatic tumours (and in a smaller proportion of other tumours) and involves transcriptional up-regulation of the ERBB2 gene with or without gene amplification. We have constructed a chimeric minigene consisting of the proximal ERBB2 promoter linked to the gene encoding cytosine deaminase, an enzyme that can deaminate the prodrug 5-fluorocytosine (5-FC) to form cytotoxic 5-fluorouracil (5-FU). We have constructed a double-copy recombinant retrovirus to deliver the enzyme gene under the control of the ERBB2 promoter into a panel of ERBB2 expression-positive (ERBB2+) and -negative (ERBB2-) pancreatic and breast cell lines. Cytosine deaminase activity was high in ERBB2+ transduced cells but was not detected in ERBB2- transduced cells. Significant cell death was observed in ERBB2+ transduced cells treated with 5-FC whereas ERBB2- cells were not affected. Hence we present a novel gene therapy strategy that is potentially tumour-specific and could be used against a range of tumour types that overexpress the ERBB2 oncogene.
 ...
PMID:Gene therapy for cancer using tumour-specific prodrug activation. 758 78

Cytidine (CR) deaminase was purified 47,000-fold to homogeneity from human placenta. The molecular mass of CR deaminase was estimated to be 48.7 kDa by gel filtration and 16.1 kDa by sodium dodecyl sulfate polyacrylamide gel electrophoresis, suggesting that it contains three or four identical subunits. We determined the amino acid sequence of several peptide fragments and designed 5'-primers to amplify, by the polymerase chain reaction, a specific 364-base pair DNA fragment using human liver complementary DNA (cDNA) as the template. This DNA fragment, which contains the codons of one peptide, was used as a probe to screen a cDNA library from human liver. We isolated and sequenced a cDNA clone of 910 base pairs that contained a 5' nontranslated region, a 438-base pair coding region, and a 3' nontranslated region with a polyadenylated tail. The translated region of the clone contained a deduced sequence of 146 amino acids, with a predicted molecular mass of 16.2 kDa and the sequences of our peptides. The cDNA was ligated in pGEX vector and expressed in Escherichia coli. The expressed protein had a high CR deaminase activity and molecular mass of 16.3 kDa. These data demonstrate clearly that the open reading frame of our cDNA clone codes for a functional human CR deaminase. Polymerase chain reaction amplifications of gene-specific DNA fragments from human/rodent hybrid cells indicate the localization of CR deaminase gene to human chromosome 1. The cDNA for CR deaminase will be a useful molecular probe to investigate the importance of this enzyme in chemotherapy.
Cancer Res 1994 Oct 15
PMID:Human cytidine deaminase: purification of enzyme, cloning, and expression of its complementary DNA. 792 72

2-Chlorodeoxyadenosine (CdA) is a deaminase-resistant purine analogue which has shown clinical activity against various haematological tumours, and is currently undergoing phase II trials. In the present study, the semiautomated fluorometric microculture cytotoxicity assay (FMCA) was used for in vitro evaluation of CdA activity in cell suspensions from both haematological and solid tumours. A total of 133 samples from various diagnoses were successfully tested with continuous drug exposure. CdA showed high in vitro activity against samples from chronic and acute lymphocytic leukaemia and acute myelocytic leukaemia, but little or no response was observed in the solid tumour groups. Cross-resistance analysis with standard drugs revealed the following rank order of correlation coefficients: cytosine arabinoside (AraC) > daunorubicin > doxorubicin > vincristine > prednisolone > 4-hydroperoxycyclophosphamide > etoposide > cisplatin. The high correlation between CdA and AraC was maintained even if the analysis was based only on the haematological tumours. The results indicate that CdA is differentially active against haematological tumours with little or no activity against solid tumours. CdA also appears highly cross resistant with AraC. If this disease-specific information is substantiated in further clinical trials and extended to other phase I-II drugs, non-clonogenic drug resistance assays such as the FMCA may become useful in new drug evaluation, and in targeting specific diagnoses and patients for phase II trials.
Eur J Cancer 1994
PMID:In vitro activity of 2-chlorodeoxyadenosine (CdA) in primary cultures of human haematological and solid tumours. 794 67

Cytosine deaminase (CD) is a microbial enzyme that can convert the antifungal agent 5-fluorocytosine (5-FC) into the antitumor agent, 5-fluorouracil (5-FU). The enzyme was chemically conjugated to the L6 monoclonal antibody, forming a conjugate that bound to antigens on the H2981 lung adenocarcinoma. Detailed studies were undertaken to determine the extent to which L6-CD generated 5-FU in tumor-bearing mice. Very high tumor:blood ratios of L6-CD (42:1) in vivo were obtained by injecting the conjugate followed 24 h later by an antiidiotypic antibody that could bind to circulating L6-CD but not to L6-CD that was bound to H2981 cells. As a result, significantly more 5-FC could be administered (> 800 mg/kg) than 5-FU (90 mg/kg). L6-CD converted 5-FC into 5-FU such that the L6-CD/antiidiotypic monoclonal antibody/5-FC combination resulted in 17 times more intratumoral 5-FU compared to systemic 5-FU administration. The conversion was antigen dependent since much lower intratumoral 5-FU levels were obtained in H3719 tumors that failed to localize L6-CD. The conversion of 5-FC into 5-FU was low in blood, kidneys, and liver. This demonstrates that a major increase in intratumoral drug concentrations can be attained with an monoclonal antibody-enzyme conjugate in combination with an anticancer prodrug compared to systemic drug therapy.
Cancer Res 1994 May 15
PMID:Intratumoral generation of 5-fluorouracil mediated by an antibody-cytosine deaminase conjugate in combination with 5-fluorocytosine. 816 3

Deoxycytidine kinase (dCK) and deaminase (dCDA) are both key enzymes in the activation and inactivation, respectively, of several deoxycytidine antimetabolites. We determined the total dCK and dCDA activities using standard assays, in 28 human solid tumours grown as xenografts in nude mice, and four corresponding cell lines. dCK activities in colon tumours varied from 11 to 12 nmol/h/mg protein, in ovarian tumours from 3 to 10 nmol/h/mg protein, in soft tissue sarcomas from 2 to 7 nmol/h/mg protein and in squamous cell carcinomas of the head and neck about 45-fold, between 0.4 and 18 nmol/h/mg protein. The dCDA activities showed a larger variation, from 243 to 483, 14 to 1231, 3 to 7 and 1 to 222 nmol/h/mg protein, respectively. The ratios of dCK vs. dCDA activities in these tumours varied from 0.025 to 0.046, 0.004 to 0.240, 0.581 to 1.123 and from 0.012 to 4.227, respectively. In four cell lines (A2780, OVCAR-3, WiDr and UM-SCC-14C), sources for some of the above mentioned tumours, a different pattern in dCK and dCDA was observed than in the corresponding tumours. The variation in dCDA activities was in a smaller range (20-fold) than in the tumours (40-fold). In all cell lines dCK activity was higher than dCDA activity, in contrast to the corresponding tumours, in which the reverse pattern was observed. Previously, some of the tumours were tested for sensitivity to the deoxycytidine analogues 5-aza-deoxycytidine and 2',2'-difluorodeoxycytidine. In the sensitive tumours, both the highest and lowest dCK activity was observed, indicating that dCK activity in solid tumours is high enough to activate deoxycytidine analogues.
Eur J Cancer 1993
PMID:Deoxycytidine kinase and deoxycytidine deaminase activities in human tumour xenografts. 829 52

Cytosine deaminase (EC 3.5.4.1), a non-mammalian enzyme, catalyzes the deamination of cytosine and 5-fluorocytosine to form uracil and 5-fluorouracil, respectively. Eukaryotic cells have been genetically modified with a bacterial cytosine deaminase gene to express a functional enzyme. When the genetically modified cells are combined with 5-fluorocytosine, it creates a potent negative selection system, which may have important applications in cancer gene therapy. In this paper, we introduce a novel positive selection method based upon the expression of the cytosine deaminase gene. This method utilizes inhibitors in the pyrimidine de novo synthesis pathway to create a condition in which cells are dependent on the conversion of pyrimidine supplements to uracil by cytosine deaminase. Thus, only cells expressing the cytosine deaminase gene can be rescued in a positive selection medium.
 ...
PMID:Cytosine deaminase gene as a positive selection marker. 863 98

To ascertain whether concomitant expression of Escherichia coli deaminase (CD) and herpes simplex virus type-1 thymidine kinase (HSV-1 TK) could mediate greater levels of cytotoxicity beyond that observed with either suicide gene alone, 9L gliosarcoma cells were transduced with a retrovirus encoding a CD/HSV-1 TK fusion gene. The resultant CD/HSV-1 TK fusion protein (CDglyTK) was found to be bifunctional via CD and HSV-1 TK enzymatic assays, and conferred upon cells prodrug sensitivities equivalent to or better than that observed for each enzyme independently (ganciclovir [GCV] and bromovinyldeoxyuridine [BVdU] for HSV-1 TK and 5-fluorocytosine [5-FC] for CD). Simultaneous treatment of CDglyTK-expressing cells with prodrugs specific for HSV-1 TK and CD (GCV/5-FC or BVdU/5-FC) resulted in slight synergistic toxicity, two- to three-fold greater than that expected if the cytotoxic effects of each prodrug were purely additive. More importantly, co-treatment with HSV-1 TK- and CD-specific prodrugs was found to increase greatly the radiosensitivity of CDglyTK-expressing cells. Sensitivity enhancement ratios of 2.44 (GCV/5-FC) and 3.90 (BVdU/5-FC) were achieved. The results suggest that double suicide gene therapy, using a bifunctional CD/HSV-1 TK fusion gene, coupled with radiotherapy may provide a highly efficient means of selectively treating cancer.
 ...
PMID:Glioma cells transduced with an Escherichia coli CD/HSV-1 TK fusion gene exhibit enhanced metabolic suicide and radiosensitivity. 898 97


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>