Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.1 (cytosine deaminase)
 747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the concept that in vivo transfer of the Escherichia coli cytosine deaminase gene will confer sensitivity of a solid tumor to the prodrug 5-fluorocytosine (5FC), we constructed an adenovirus vector (AdCMV.CD) carrying the cytosine deaminase gene driven by the cytomegalovirus (CMV) promoter, infected HT29 colon carcinoma cells in vitro and in vivo, and evaluated cell growth over time. AdCMV.CD produced a functional cytosine deaminase protein in HT29 cells in vitro as evidenced by the ability of lysates from the infected cells to convert [3H]5FC to its active metabolite 5-fluorouracil (5FU). The AdCMV.CD vector effectively suppressed HT29 cell growth in vitro in the presence of 5FC in a dose-dependent manner. Infection with AdCMV.CD, when as few as 10% of cells expressed the cytosine deaminase gene, was associated with a bystander effect when combined with 5FC in cell mixing studies. Further, this bystander effect was not dependent on cell-to-cell contact as demonstrated by suppression of [3H]thymidine incorporation in HT29 cells when supernatant from AdCMV.CD-infected cells treated with 5FC was transferred cells. Consistent with these in vitro observations, when AdCMV.CD was directly injected into established subcutaneous HT29 tumors in nude mice receiving 5FC, there was a four-fold reduction in tumor size at day 15 compared to controls, and a five-fold reduction at day 28. These observations suggest that adenovirus-mediated gene transfer of the E. coli cytosine deaminase gene and concomitant administration of 5FC may have potential as a strategy for local control of the growth of tumor cells susceptible to 5FU.
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PMID:In vivo adenovirus-mediated gene transfer of the Escherichia coli cytosine deaminase gene to human colon carcinoma-derived tumors induces chemosensitivity to 5-fluorocytosine. 757 18

A human colorectal carcinoma cell line, WiDr, was genetically engineered to express the nonmammalian enzyme, cytosine deaminase (CD). Expression of CD in WiDr cells (WiDr/CD) did not alter the growth rate of these cells when grown in vitro or as solid tumor xenografts in nude mice. However, expression of CD did increase the sensitivity of these cells to the nontoxic prodrug, 5-fluorocytosine (FCyt), decreasing the 50% inhibitory concentration for FCyt from 26,000 microM in parental WiDr cells to 27 microM in WiDr/CD cells. The increase in sensitivity to FCyt in WiDr/CD cells was the result of the CD-mediated conversion of FCyt to 5-fluorouracil (FUra) and subsequent FUra anabolites. The half-life of the prodrug, FCyt, was determined to be approximately 40 min in nude mice. A single i.p. injection of 500 mg FCyt/kg body weight resulted in a transient FCyt plasma level of approximately 4000 microM while osmotic minipumps or constant tail vein infusions of FCyt achieved continual FCyt plasma levels of 5 microM and 50 microM, respectively, with no overt signs of toxicity. Significant antitumor effects were observed in nude mice bearing tumors derived from WiDr/CD cells when these animals were given 500 mg FCyt/kg i.p. for 10 consecutive days. These antitumor effects were demonstrated by decreases in tumor growth rate, tumor size, tumor weight, and thymidine incorporation into tumor DNA. This antitumor effect was significant but less profound if FCyt was administered by constant tail vein infusion. WiDr and WiDr/CD cells were very sensitive to FUra in vitro (50% inhibitory concentration approximately 5 microM). However, no significant antitumor effects were observed in nude mice bearing tumors derived from either WiDr or WiDr/CD cells when these animals were treated with various doses of FUra. Taken collectively, these data indicate that nontoxic plasma levels of FCyt can be attained which can produce profound antitumor effects on tumors engineered to express CD and that these antitumor effects are significantly better than those that can be achieved using FUra. These positive data support the continued development of a gene therapy approach to colorectal carcinoma involving the selective expression of CD in colorectal tumors with subsequent administration of FCyt.
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PMID:In vivo antitumor activity of 5-fluorocytosine on human colorectal carcinoma cells genetically modified to express cytosine deaminase. 840 37

Genetic modification for cancer treatment has involved the introduction of chemotherapy protection and sensitization genes into normal and tumor cells, respectively, for the purpose of improving the outcome of conventional approaches to the treatment of solid tumor neoplasms. This paper will review the use of multidrug resistance-1 retroviral vectors and cytosine deaminase adenoviral prodrug activation vectors for this purpose.
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PMID:Results of retroviral and adenoviral approaches to cancer gene therapy. 1101 68

To help define the safety profile of the use of adenovirus (Ad) gene transfer vectors in humans, this report summarizes our experience since April 1993 of the local administration of E1(-)/E3(-) Ad vectors to humans using low (<10(9) particle units) or intermediate (10(9)-10(11) particle units) doses. Included in the study are 90 individuals and 12 controls, with diverse comorbid conditions, including cystic fibrosis, colon cancer metastatic to liver, severe coronary artery disease, and peripheral vascular disease, as well as normals. These individuals received 140 different administrations of vector, with up to seven administrations to a single individual. The vectors used include three different transgenes (human cystic fibrosis transmembrane conductance regulator cDNA, E. coli cytosine deaminase gene, and the human vascular endothelial growth factor 121 cDNA) administered by six different routes (nasal epithelium, bronchial epithelium, percutaneous to solid tumor, intradermal, epicardial injection of the myocardium, and skeletal muscle). The total population was followed for 130.4 patient-years. The study assesses adverse events, common laboratory tests, and long-term follow-up, including incidence of death or development of malignancy. The total group incidence of major adverse events linked to an Ad vector was 0.7%. There were no deaths attributable to the Ad vectors per se, and the incidence of malignancy was within that expected for the population. Overall, the observations are consistent with the concept that local administration of low and intermediate doses of Ad vectors appears to be well tolerated.
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PMID:Safety of local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of morbid conditions. 1177 12

To evaluate whether in vitro and in vivo transferring of Escherichia coli cytosine deaminase gene to a solid tumor will confer the sensitivity to the prodrug 5-fluorocytosine (5FC) on these cells, we constructed two replication-defective adenovirus vector in which the cytosine deaminase gene was driven by CAG promoter (Adex1CACD) and AFP gene 5'-flanking region (Adex1AFPCD), respectively. By transferring these two vectors to SMMC7721AFP(-) and HepG2 human hepatocellular carcinoma (HCC) cells in vitro, we found that Adex1CACD vector could effectively suppress SMMC7721AFP(-) and HepG2 cells growing in the presence of 5FC even if the infected cell is less to 20%, while Adex1AFPCD vector only conferred HepG2 cells sensitivity to 5FC. When Adex1CACD was directly injected into established subcutaneous SMMC7721AFP(-) tumors in nude mice receiving 5FC, the tumor growth was inhibited significantly, which was consistent with those in vitro results. Furthermore, the Adex1AFPCD plus 5FC suppressed SMMC7721AFP(+) tumor growth in vivo, but not SMMC7721AFP(-) tumor. The results suggested that the CAG promoter-controlled CD gene could effectively mediate the growth inhibition in different kinds of HCC combined with administration of 5FC, and the AFP promoter-controlled CD gene could only suppress the HCCs expressing high levels of AFP. Therefore, adenovirus-mediated tumor-specific gene transfer may be a potential strategy for local control of tumor growth.
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PMID:Adenovirus-mediated tissue-specific cytosine deaminase gene therapy for human hepatocellular carcinoma with different AFP expression levels. 1241 26

A fundamental obstacle in systemic therapy for metastatic breast cancer patients is specific targeting of therapy directly to a solid tumor. Hypoxic or necrotic regions are characteristic of solid tumors in many murine and human tumors, including the majority of primary tumors of the breast. A strain of anaerobic bacteria such as Bifidobacterium or Clostridium selectively localizes to and proliferates in solid tumors after systemic application. Another approach uses attenuated Salmonella strains that need tumor-specific nutrients to selectively proliferate and is a potential gene delivery system. We constructed a plasmid, pBLES100-S-eCD, which included the cytosine deaminase gene. Transfected Bifidobacterium longum produced cytosine deaminase in the hypoxic tumor. Enzyme/pro-drug therapy was confirmed to be effective for systemic administration.
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PMID:Genetically engineered bifidobacterium as a drug delivery system for systemic therapy of metastatic breast cancer patients. 1651 59

A fundamental obstacle in systemic therapy for metastatic breast cancer patients is specific targeting of therapy directly to a solid tumor. Hypoxic or necrotic regions are characteristic of solid tumors in many murine and human tumors, including the majority of primary tumors of the breast. A strain of anaerobic bacteria such as Bifidobacterium or Clostridium selectively localizes to and proliferates in solid tumors after systemic application. Another approach uses attenuated Salmonella strains that need tumor-specific nutrients to selectively proliferate and is a potential gene delivery system. We constructed a plasmid, pBLES100-S-eCD, which included the cytosine deaminase gene. Transfected Bifidobacterium longum produced cytosine deaminase in the hypoxic tumor. Enzyme/pro-drug therapy was confirmed to be effective for systemic administration.
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PMID:[Anaerobic bacteria as a gene delivery system for breast cancer therapy]. 1854 Mar 73