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Chemical Compound Review

Tretazicar     5-(aziridin-1-yl)-2,4- dinitro-benzamide

Synonyms: Lopac-C-2235, CHEMBL23330, CCRIS 1631, AG-E-59971, C2235_SIGMA, ...
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Disease relevance of CCRIS 1631

  • Mutant libraries were generated for each of these residues and clones screened for their ability to sensitize E. coli to CB1954 [1].
  • Using an adenovirus vector, we introduced the F124K NTR mutant into human SK-OV-3 ovarian carcinoma cells and showed it to be approximately 5-fold more potent in sensitizing the cells to CB1954 at the clinically relevant prodrug concentration of 1 micro M than was the WT enzyme [1].
  • The high level of nitroreductase expression observed at 1 to 5 x 10(11) virus particles mandates further studies in patients with inoperable tumors who will receive CTL102 and CB1954 [2].
  • Virus-directed enzyme prodrug therapy utilizing the bacterial enzyme nitroreductase delivered by a replication-defective adenovirus vector to activate the prodrug CB1954 is a promising strategy currently undergoing clinical trials in patients with a range of cancers [3].
  • Virus directed enzyme prodrug therapy for ovarian and pancreatic cancer using retrovirally delivered E. coli nitroreductase and CB1954 [4].

High impact information on CCRIS 1631

  • Enhanced mutant NTRs such as F124K should improve the efficacy of the NTR/CB1954 combination in cancer gene therapy [1].
  • Amino acid substitutions at six positions conferred markedly greater sensitivity to CB1954 than did the WT enzyme; the best mutants, at residue F124, resulted in approximately 5-fold improvement [1].
  • The objective of this study was to develop a physiologically relevant tissue culture model for quantifying bystander effects and to validate the model using as an example the activation of dinitrobenzamide prodrugs (e.g., CB 1954) by Escherichia coli aerobic nitroreductase (NTR) [5].
  • In particular, 1-carbamoylmethyl-3-carbamoyl-1,4dihydropyridine was shown to be a co-substrate for NQO2 with greater stability than NRH, with the ability to enter cells and potentiate the cytotoxicity of CB 1954 [6].
  • Bioactivation of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) by human NAD(P)H quinone oxidoreductase 2: a novel co-substrate-mediated antitumor prodrug therapy [6].

Chemical compound and disease context of CCRIS 1631


Biological context of CCRIS 1631

  • Placing the nitroreductase gene under the control of the telomerase gene promoters sensitized cancer cells in tissue culture to the pro-drug CB1954 and promoter activity was predictive of sensitization to the pro-drug (2-20-fold sensitization), with cell death restricted to lines exhibiting high levels of promoter activity [11].
  • Computer modeling based on our results suggests that CB1954 is situated in the active site, with the aziridinyl group pointing toward Tyr155 and the amide group placed near a hydrophobic pocket next to Tyr128 [12].
  • In vitro, the AUC required to achieve the IC50 for CB1954, in NTR-expressing cancer cells, ranges from 10-50 microM/h. Thus, CB1954 is well tolerated at a dose of 24 mg/m2, and sufficient serum/peritoneal levels are achieved for an enzyme-prodrug approach to be feasible [13].
  • Gene-directed enzyme prodrug therapy: quantitative bystander cytotoxicity and DNA damage induced by CB1954 in cells expressing bacterial nitroreductase [14].
  • Enhanced efficacy of Escherichia coli nitroreductase/CB1954 prodrug activation gene therapy using an E1B-55K-deleted oncolytic adenovirus vector [15].

Anatomical context of CCRIS 1631

  • There is a very large (100-3000-fold) increase in CB 1954 cytotoxicity toward either NQO2-transfected rodent or nontransfected human tumor cell lines in the presence of NRH [6].
  • Infection with adenoviral telomerase-NTR constructs in a panel of seven cancer cell lines resulted in up to 18-fold sensitization to the prodrug CB1954, an effect that was retained in two drug-resistant ovarian lines [16].
  • Unlike the Tcf-NTR virus, the CMV-NTR virus expresses NTR in human lung fibroblasts and sensitizes these normal cells to CB1954 [17].
  • Upon CB1954 treatment, transgenic mice show extensive cell depletion in thymus and spleen (14-16% of normal cell numbers), whereas all other tissues are unaffected by prodrug administration [18].
  • The astrocytes expressing NTR were selectively ablated after administration of the prodrug CB1954, resulting in motor discoordination [19].

Associations of CCRIS 1631 with other chemical compounds

  • One example of suicide gene therapy is the bacterial nitroreductase (NTR) gene, which bioactivates the prodrug CB1954 into an active cytotoxic alkylating agent [16].
  • The results support the possibility of using nitroreductase and CB1954 for 'suicide gene' therapy and in addition suggest that alternative prodrugs, such as nitrofurazone, warrant further investigation in this novel approach [20].
  • While CB 1954 gave both 2- and 4-hydroxylamine metabolites in NTR+ve cells, related analogues with substituted carboxamides gave only a single hydroxylamine metabolite possibly because the steric bulk in the side chain constrains binding within the active site [21].
  • Compound 20 is a much less efficient substrate than CB 1954 for the major aerobic nitroreductase from rat Walker tumor cells, NAD(P)H:quinone oxidoreductase (DT diaphorase) [22].
  • Irrespective of the differences between the various reduced pyridinium derivatives in their ability to act as co-factors for the reduction of menadione by DT diaphorase, all the compounds that showed activity in this assay were equally effective co-factors for the reduction of the nitrobenzamide, CB 1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) [23].

Gene context of CCRIS 1631

  • The human form of NQO1 metabolizes CB 1954 much less efficiently than rat NQO1 [24].
  • The PSA-based nitroreductase virus produced comparable amounts of nitroreductase and sensitization to CB1954 approaching that of the CMV-driven virus [25].
  • Moreover, injection of SW480 xenografts (mutated p53) with Ad.p53R resulted in a clear inhibition of growth in response to the prodrug CB1954 [26].
  • These results agree well with those of the in vitro enzyme assays that show that Q104Y is significantly more active than the wild-type DT-diaphorase in the activation of CB 1954 [27].
  • Our site-directed mutagenesis study has revealed that residue 104 (Tyr in the rat enzyme and Gln in the human enzyme) is an important residue responsible for the catalytic differences between the rat and the human enzymes in the activation of CB 1954 (S. Chen et al., 1997, J. Biol. Chem. 272, 1437-1439) [27].

Analytical, diagnostic and therapeutic context of CCRIS 1631


  1. Generation of Escherichia coli nitroreductase mutants conferring improved cell sensitization to the prodrug CB1954. Grove, J.I., Lovering, A.L., Guise, C., Race, P.R., Wrighton, C.J., White, S.A., Hyde, E.I., Searle, P.F. Cancer Res. (2003) [Pubmed]
  2. Virus-directed enzyme prodrug therapy: intratumoral administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer. Palmer, D.H., Mautner, V., Mirza, D., Oliff, S., Gerritsen, W., van der Sijp, J.R., Hubscher, S., Reynolds, G., Bonney, S., Rajaratnam, R., Hull, D., Horne, M., Ellis, J., Mountain, A., Hill, S., Harris, P.A., Searle, P.F., Young, L.S., James, N.D., Kerr, D.J. J. Clin. Oncol. (2004) [Pubmed]
  3. Inhibition of NF-kappaB enhances the cytotoxicity of virus-directed enzyme prodrug therapy and oncolytic adenovirus cancer gene therapy. Palmer, D.H., Chen, M.J., Searle, P.F., Kerr, D.J., Young, L.S. Gene Ther. (2005) [Pubmed]
  4. Virus directed enzyme prodrug therapy for ovarian and pancreatic cancer using retrovirally delivered E. coli nitroreductase and CB1954. McNeish, I.A., Green, N.K., Gilligan, M.G., Ford, M.J., Mautner, V., Young, L.S., Kerr, D.J., Searle, P.F. Gene Ther. (1998) [Pubmed]
  5. Quantitation of bystander effects in nitroreductase suicide gene therapy using three-dimensional cell cultures. Wilson, W.R., Pullen, S.M., Hogg, A., Helsby, N.A., Hicks, K.O., Denny, W.A. Cancer Res. (2002) [Pubmed]
  6. Bioactivation of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) by human NAD(P)H quinone oxidoreductase 2: a novel co-substrate-mediated antitumor prodrug therapy. Knox, R.J., Jenkins, T.C., Hobbs, S.M., Chen, S., Melton, R.G., Burke, P.J. Cancer Res. (2000) [Pubmed]
  7. The bioactivation of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB1954)--I. Purification and properties of a nitroreductase enzyme from Escherichia coli--a potential enzyme for antibody-directed enzyme prodrug therapy (ADEPT). Anlezark, G.M., Melton, R.G., Sherwood, R.F., Coles, B., Friedlos, F., Knox, R.J. Biochem. Pharmacol. (1992) [Pubmed]
  8. Virtual cofactors for an Escherichia coli nitroreductase enzyme: relevance to reductively activated prodrugs in antibody directed enzyme prodrug therapy (ADEPT). Knox, R.J., Friedlos, F., Jarman, M., Davies, L.C., Goddard, P., Anlezark, G.M., Melton, R.G., Sherwood, R.F. Biochem. Pharmacol. (1995) [Pubmed]
  9. Nitroreductase: a prodrug-activating enzyme for cancer gene therapy. Searle, P.F., Chen, M.J., Hu, L., Race, P.R., Lovering, A.L., Grove, J.I., Guise, C., Jaberipour, M., James, N.D., Mautner, V., Young, L.S., Kerr, D.J., Mountain, A., White, S.A., Hyde, E.I. Clin. Exp. Pharmacol. Physiol. (2004) [Pubmed]
  10. Role of redox cycling and activation by DT-diaphorase in the cytotoxicity of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB-1954) and its analogs. Miŝkiniene, V., Sergediene, E., Nemeikaite, A., Segura-Aguilar, J., Cenas, N. Cancer Lett. (1999) [Pubmed]
  11. Telomerase-specific suicide gene therapy vectors expressing bacterial nitroreductase sensitize human cancer cells to the pro-drug CB1954. Plumb, J.A., Bilsland, A., Kakani, R., Zhao, J., Glasspool, R.M., Knox, R.J., Evans, T.R., Keith, W.N. Oncogene (2001) [Pubmed]
  12. Molecular characterization of binding of substrates and inhibitors to DT-diaphorase: combined approach involving site-directed mutagenesis, inhibitor-binding analysis, and computer modeling. Chen, S., Wu, K., Zhang, D., Sherman, M., Knox, R., Yang, C.S. Mol. Pharmacol. (1999) [Pubmed]
  13. Virus-directed, enzyme prodrug therapy with nitroimidazole reductase: a phase I and pharmacokinetic study of its prodrug, CB1954. Chung-Faye, G., Palmer, D., Anderson, D., Clark, J., Downes, M., Baddeley, J., Hussain, S., Murray, P.I., Searle, P., Seymour, L., Harris, P.A., Ferry, D., Kerr, D.J. Clin. Cancer Res. (2001) [Pubmed]
  14. Gene-directed enzyme prodrug therapy: quantitative bystander cytotoxicity and DNA damage induced by CB1954 in cells expressing bacterial nitroreductase. Friedlos, F., Court, S., Ford, M., Denny, W.A., Springer, C. Gene Ther. (1998) [Pubmed]
  15. Enhanced efficacy of Escherichia coli nitroreductase/CB1954 prodrug activation gene therapy using an E1B-55K-deleted oncolytic adenovirus vector. Chen, M.J., Green, N.K., Reynolds, G.M., Flavell, J.R., Mautner, V., Kerr, D.J., Young, L.S., Searle, P.F. Gene Ther. (2004) [Pubmed]
  16. Selective ablation of human cancer cells by telomerase-specific adenoviral suicide gene therapy vectors expressing bacterial nitroreductase. Bilsland, A.E., Anderson, C.J., Fletcher-Monaghan, A.J., McGregor, F., Evans, T.R., Ganly, I., Knox, R.J., Plumb, J.A., Keith, W.N. Oncogene (2003) [Pubmed]
  17. Late expression of nitroreductase in an oncolytic adenovirus sensitizes colon cancer cells to the prodrug CB1954. Lukashev, A.N., Fuerer, C., Chen, M.J., Searle, P., Iggo, R. Hum. Gene Ther. (2005) [Pubmed]
  18. The expression of bacterial nitroreductase in transgenic mice results in specific cell killing by the prodrug CB1954. Drabek, D., Guy, J., Craig, R., Grosveld, F. Gene Ther. (1997) [Pubmed]
  19. Inducible ablation of astrocytes shows that these cells are required for neuronal survival in the adult brain. Cui, W., Allen, N.D., Skynner, M., Gusterson, B., Clark, A.J. Glia (2001) [Pubmed]
  20. Investigation of alternative prodrugs for use with E. coli nitroreductase in 'suicide gene' approaches to cancer therapy. Bailey, S.M., Knox, R.J., Hobbs, S.M., Jenkins, T.C., Mauger, A.B., Melton, R.G., Burke, P.J., Connors, T.A., Hart, I.R. Gene Ther. (1996) [Pubmed]
  21. Aziridinyldinitrobenzamides: synthesis and structure-activity relationships for activation by E. coli nitroreductase. Helsby, N.A., Atwell, G.J., Yang, S., Palmer, B.D., Anderson, R.F., Pullen, S.M., Ferry, D.M., Hogg, A., Wilson, W.R., Denny, W.A. J. Med. Chem. (2004) [Pubmed]
  22. Hypoxia-selective antitumor agents. 5. Synthesis of water-soluble nitroaniline mustards with selective cytotoxicity for hypoxic mammalian cells. Palmer, B.D., Wilson, W.R., Cliffe, S., Denny, W.A. J. Med. Chem. (1992) [Pubmed]
  23. Identification of novel reduced pyridinium derivatives as synthetic co-factors for the enzyme DT diaphorase (NAD(P)H dehydrogenase (quinone), EC Friedlos, F., Jarman, M., Davies, L.C., Boland, M.P., Knox, R.J. Biochem. Pharmacol. (1992) [Pubmed]
  24. CB 1954: from the Walker tumor to NQO2 and VDEPT. Knox, R.J., Burke, P.J., Chen, S., Kerr, D.J. Curr. Pharm. Des. (2003) [Pubmed]
  25. Prostate-specific antigen promoter/enhancer driven gene therapy for prostate cancer: construction and testing of a tissue-specific adenovirus vector. Latham, J.P., Searle, P.F., Mautner, V., James, N.D. Cancer Res. (2000) [Pubmed]
  26. Tumour-specific therapeutic adenovirus vectors: repression of transgene expression in healthy cells by endogenous p53. Lipinski, K.S., Djeha, A.H., Krausz, E., Lane, D.P., Searle, P.F., Mountain, A., Wrighton, C.J. Gene Ther. (2001) [Pubmed]
  27. Demonstration of the activation of prodrug CB 1954 using human DT-diaphorase mutant Q104Y-transfected MDA-MB-231 cells and mouse xenograft model. Wu, K., Eng, E., Knox, R., Chen, S. Arch. Biochem. Biophys. (2001) [Pubmed]
  28. Appropriate subcellular localisation of prodrug-activating enzymes has important consequences for suicide gene therapy. Spooner, R.A., Maycroft, K.A., Paterson, H., Friedlos, F., Springer, C.J., Marais, R. Int. J. Cancer (2001) [Pubmed]
  29. Towards gene therapy in prosthesis loosening: efficient killing of interface cells by gene-directed enzyme prodrug therapy with nitroreductase and the prodrug CB1954. de Poorter, J.J., Tolboom, T.C., Rabelink, M.J., Pieterman, E., Hoeben, R.C., Nelissen, R.G., Huizinga, T.W. The journal of gene medicine. (2005) [Pubmed]
  30. Chemopotentiation by CB 1954: the importance of postincubations and the possible involvement of poly(ADP-ribosylation). Walling, J.M., Stratford, I.J., Stephens, M.A. Int. J. Radiat. Oncol. Biol. Phys. (1984) [Pubmed]
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