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Gene Review

codA  -  cytosine deaminase

Escherichia coli O157:H7 str. EDL933

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Disease relevance of codA

  • Localization of the codA gene on the Escherichia coli chromosome [1].
  • In the present study, the highly GC rich codA gene encoding for choline oxidase was cloned from genomic DNA of Arthrobacter globiformis strain ATCC 8010 and expressed to high yields in Escherichia coli strain Rosetta(DE3)pLysS [2].
  • We analyzed the efficacy of using cytosine deaminase-bearing cancer cells as an autologous tumor vaccine in a rat model that mimics liver metastasis from colon carcinoma [3].
  • In contrast, 70% of 5-FC was converted into the cytotoxic agent 5-FU when MCF-7 breast cancer cells (BCCs) were exposed to the same Ad.CMV-CD vector followed by 5-FC for 48 hours [4].
  • Ad.CMV-CD is a replication incompetent adenoviral vector carrying a cytomegalovirus (CMV)-driven transcription unit of the cytosine deaminase (CD) gene [4].

High impact information on codA


Chemical compound and disease context of codA


Biological context of codA


Anatomical context of codA

  • To test if the CD adenoviral vector sensitizes breast cancer cells to 5-FC, we exposed primary explants of normal human mammary epithelial cells (HMECs) and the established breast cancer cell (BCC) lines MCF-7 and MDA-MB-453 to the Ad.CMV-CD for 90 minutes [4].
  • Furthermore, increased infiltrating CD4(+) and CD8(+) T cells and necrosis within tumors were found in mice receiving combination therapy of Ad-hTERT-CD and etoposide compared with those treated with either treatment alone [16].
  • To determine if this paradigm holds in normal humans, a first-generation Ad vector (Ad(GV)CD.10, an E1(-)E3(-) Ad serotype 5-based vector coding for the Escherichia coli cytosine deaminase gene) was sprayed locally in escalating doses (8 x 10(8)-8 x 10(10) particle units (pu), n = 2/group) into the lung airway epithelium of six normal individuals [17].
  • Several double-/triple-gene constructs expressing HSV-1-tk, gfp, and E. coli cd were engineered based on gene fusion or the use of an internal ribosome entry site (IRES) [18].
  • 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) [19].

Associations of codA with chemical compounds

  • Derepression of codA expression was induced by starvation for either uracil or cytosine nucleotides [8].
  • Intrahepatic injection of CD+ cells followed by 5-fluorocytosine treatment rendered the treated animals resistant to challenge with wild-type tumor cells, with no (zero of seven) treated animals developing wild-type tumors in contrast to all (four of four) control animals [3].
  • The CD transcription unit in this vector catalyzes the deamination of the nontoxic pro-drug, 5-fluorocytosine (5-FC), thus converting it to the cytotoxic drug 5-fluorouracil (5-FU) [4].
  • Transduction of the CD gene made C6 cells become highly sensitive to the anti-fungi drug 5-fluorocytosine (5FC) [20].
  • Alanine-scanning mutagenesis reveals a cytosine deaminase mutant with altered substrate preference [21].

Analytical, diagnostic and therapeutic context of codA

  • These observations suggest that adenovirus-mediated gene transfer of the Escherichia coli cytosine deaminase gene followed by exposure to the nontoxic pro-drug 5-FC may be a potential strategy to selectively reduce the level of contaminating BCCs in collections of hematopoietic cells used for autografts in breast cancer patients [4].
  • To test if the conditions were damaging for the hematopoietic reconstituting cells, marrow cells collected from 5-FU-treated male donor mice were incubated with the cytosine deaminase adenoviral vector and then exposed to 5-FC either for 4 days in vitro before transplantation or for 14 days immediately after transplantation in vivo [4].
  • CONCLUSION: The results of this study, the first targeted gene therapy for breast cancer and the first to use the cytosine deaminase system in human subjects, are encouraging for the development of genetic prodrug activation therapies that exploit the transcriptional profile of cancer cells [22].
  • Moreover, CD mRNA was expressed exclusively in MKN45 tumor xenografts after infection with AdCEA-CD, despite the fact that an adenovirus-mediated transfer of CD DNA was detected in all tissues tested [15].
  • The authors compared the extent, duration, and pattern of transgene (luc) expression in vivo after portal venous, intraperitoneal, or intravenous virus administration and survival after treatment with the vv containing CD followed by the prodrug 5-fluorocytosine (5-FC) in a murine model of disseminated liver metastases from colon cancer [23].


  1. Localization of the codA gene on the Escherichia coli chromosome. Austin, E.A., Huber, B.E. J. Bacteriol. (1993) [Pubmed]
  2. Cloning, sequence analysis, and purification of choline oxidase from Arthrobacter globiformis: a bacterial enzyme involved in osmotic stress tolerance. Fan, F., Ghanem, M., Gadda, G. Arch. Biochem. Biophys. (2004) [Pubmed]
  3. Cytosine deaminase/5-fluorocytosine-based vaccination against liver tumors: evidence of distant bystander effect. Pierrefite-Carle, V., Baqué, P., Gavelli, A., Mala, M., Chazal, M., Gugenheim, J., Bourgeon, A., Milano, G., Staccini, P., Rossi, B. J. Natl. Cancer Inst. (1999) [Pubmed]
  4. Cytosine deaminase adenoviral vector and 5-fluorocytosine selectively reduce breast cancer cells 1 million-fold when they contaminate hematopoietic cells: a potential purging method for autologous transplantation. Garcia-Sanchez, F., Pizzorno, G., Fu, S.Q., Nanakorn, T., Krause, D.S., Liang, J., Adams, E., Leffert, J.J., Yin, L.H., Cooperberg, M.R., Hanania, E., Wang, W.L., Won, J.H., Peng, X.Y., Cote, R., Brown, R., Burtness, B., Giles, R., Crystal, R., Deisseroth, A.B. Blood (1998) [Pubmed]
  5. Synergistic anticancer effects of ganciclovir/thymidine kinase and 5-fluorocytosine/cytosine deaminase gene therapies. Aghi, M., Kramm, C.M., Chou, T.C., Breakefield, X.O., Chiocca, E.A. J. Natl. Cancer Inst. (1998) [Pubmed]
  6. Transfer of the bacterial gene for cytosine deaminase to mammalian cells confers lethal sensitivity to 5-fluorocytosine: a negative selection system. Mullen, C.A., Kilstrup, M., Blaese, R.M. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  7. Genetic evidence for a repressor of synthesis of cytosine deaminase and purine biosynthesis enzymes in Escherichia coli. Kilstrup, M., Meng, L.M., Neuhard, J., Nygaard, P. J. Bacteriol. (1989) [Pubmed]
  8. Pyrimidine, purine and nitrogen control of cytosine deaminase synthesis in Escherichia coli K 12. Involvement of the glnLG and purR genes in the regulation of codA expression. Andersen, L., Kilstrup, M., Neuhard, J. Arch. Microbiol. (1989) [Pubmed]
  9. Concomitant expression of E. coli cytosine deaminase and uracil phosphoribosyltransferase improves the cytotoxicity of 5-fluorocytosine. Tiraby, M., Cazaux, C., Baron, M., Drocourt, D., Reynes, J.P., Tiraby, G. FEMS Microbiol. Lett. (1998) [Pubmed]
  10. Killing Epstein-Barr virus-positive B lymphocytes by gene therapy: comparing the efficacy of cytosine deaminase and herpes simplex virus thymidine kinase. Rogers, R.P., Ge, J.Q., Holley-Guthrie, E., Hoganson, D.K., Comstock, K.E., Olsen, J.C., Kenney, S. Hum. Gene Ther. (1996) [Pubmed]
  11. Provision of positive and negative selections in retroviral vectors containing the cytosine deaminase gene. Shiau, A.L., Yang, H.M., Wu, P., Wu, C.L. Gene Ther. (1998) [Pubmed]
  12. Cytosine deaminase as a negative selective marker for Arabidopsis. Perera, R.J., Linard, C.G., Signer, E.R. Plant Mol. Biol. (1993) [Pubmed]
  13. Characterization of the Escherichia coli codBA operon encoding cytosine permease and cytosine deaminase. Danielsen, S., Kilstrup, M., Barilla, K., Jochimsen, B., Neuhard, J. Mol. Microbiol. (1992) [Pubmed]
  14. Adenoviral-mediated transfer of a heat-inducible double suicide gene into prostate carcinoma cells. Blackburn, R.V., Galoforo, S.S., Corry, P.M., Lee, Y.J. Cancer Res. (1998) [Pubmed]
  15. In vivo selective gene expression and therapy mediated by adenoviral vectors for human carcinoembryonic antigen-producing gastric carcinoma. Lan, K.H., Kanai, F., Shiratori, Y., Ohashi, M., Tanaka, T., Okudaira, T., Yoshida, Y., Hamada, H., Omata, M. Cancer Res. (1997) [Pubmed]
  16. Low-Dose Etoposide Enhances Telomerase-Dependent Adenovirus-Mediated Cytosine Deaminase Gene Therapy through Augmentation of Adenoviral Infection and Transgene Expression in a Syngeneic Bladder Tumor Model. Shieh, G.S., Shiau, A.L., Yo, Y.T., Lin, P.R., Chang, C.C., Tzai, T.S., Wu, C.L. Cancer Res. (2006) [Pubmed]
  17. Host responses and persistence of vector genome following intrabronchial administration of an E1(-)E3(-) adenovirus gene transfer vector to normal individuals. Harvey, B.G., Hackett, N.R., Ely, S., Crystal, R.G. Mol. Ther. (2001) [Pubmed]
  18. Improved herpes simplex virus type 1 amplicon vectors for proportional coexpression of positron emission tomography marker and therapeutic genes. Jacobs, A.H., Winkeler, A., Hartung, M., Slack, M., Dittmar, C., Kummer, C., Knoess, C., Galldiks, N., Vollmar, S., Wienhard, K., Heiss, W.D. Hum. Gene Ther. (2003) [Pubmed]
  19. In vivo adenovirus-mediated gene transfer of the Escherichia coli cytosine deaminase gene to human colon carcinoma-derived tumors induces chemosensitivity to 5-fluorocytosine. Hirschowitz, E.A., Ohwada, A., Pascal, W.R., Russi, T.J., Crystal, R.G. Hum. Gene Ther. (1995) [Pubmed]
  20. Transduction of cytosine deaminase gene makes rat glioma cells highly sensitive to 5-fluorocytosine. Ge, K., Xu, L., Zheng, Z., Xu, D., Sun, L., Liu, X. Int. J. Cancer (1997) [Pubmed]
  21. Alanine-scanning mutagenesis reveals a cytosine deaminase mutant with altered substrate preference. Mahan, S.D., Ireton, G.C., Stoddard, B.L., Black, M.E. Biochemistry (2004) [Pubmed]
  22. Genetic prodrug activation therapy for breast cancer: A phase I clinical trial of erbB-2-directed suicide gene expression. Pandha, H.S., Martin, L.A., Rigg, A., Hurst, H.C., Stamp, G.W., Sikora, K., Lemoine, N.R. J. Clin. Oncol. (1999) [Pubmed]
  23. Regional versus systemic delivery of recombinant vaccinia virus as suicide gene therapy for murine liver metastases. Gnant, M.F., Puhlmann, M., Bartlett, D.L., Alexander, H.R. Ann. Surg. (1999) [Pubmed]
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