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Chemical Compound Review

Tirazone     10-hydroxy-7-oxido-8,10- diaza-7...

Synonyms: TIRAPAZAMINE, CHEMBL50882, AG-E-87014, Win-59075, QC-4587, ...
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Disease relevance of SR 4233

  • Moreover, the in vivo administration of the hypoxic cytotoxic agent tirapazamine exhibited selective toxicity to the primitive stem cell subset [1].
  • Tirapazamine (TPZ) is a bioreductive agent that forms a toxic-free radical in hypoxia [2].
  • The addition of hyperthermia to treatment with SR-4233 increased the killing of dim cells by about 5-fold but of bright cells by only 2-fold [3].
  • Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003 [4].
  • Stably transfected clones of MDA231 human breast cancer cells overexpressing human CYPRED immunoreactive protein and catalytic activity showed enhanced sensitivity to the aerobic cytotoxicity of tirapazamine, a bioreductive drug known to be activated by CYPRED; however, no sensitization to the cytotoxic effects of doxorubicin was observed [5].
  • Whereas RT delayed tumor growth regardless of the level of hypoxia, an additive beneficial therapeutic effect of tirapazamine to RT was observed only in hypoxic tumors (aGD, 12.9 d) but not in normoxic tumors (aGD, 6.0 d) [6].

High impact information on SR 4233


Chemical compound and disease context of SR 4233

  • PURPOSE: A phase II study was conducted to evaluate the safety and efficacy of tirapazamine combined with cisplatin for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) [10].
  • Synergistic interaction between tirapazamine and cyclophosphamide in human breast cancer xenografts [11].
  • Under identical circumstances, there was no effect of the hypoxic cell radiosensitizer SR 2508, showing that SR 4233 with intermittent hypoxia was superior to a protocol which sensitized the hypoxic cells to doses of 2.5 Gy per fraction [12].
  • The dose enhancement ratios for SR 4233 and RSU 1069 were 8.8 and 8.5, respectively, showing that these agents had an equivalent and substantial enhancement of their cytotoxicity when combined with hypobaric hypoxia [13].
  • The contribution of H2O2 to the observed aerobic cytotoxicity of SR-4233 is minimal however, since toxicity is only slightly reduced in the presence of exogenous catalase and antioxidants such as vitamin E. The level of PC stimulation by SR-4233 suggests that the rate of electron addition to the drug is independent of O2 concentration [14].

Biological context of SR 4233

  • Tirapazamine-induced cytotoxicity and DNA damage in transplanted tumors: relationship to tumor hypoxia [15].
  • Tirapazamine pharmacokinetics were linear with respect to increasing dose with a mean maximum plasma concentration (Cmax) of 5.97 +/- 2.25 microg/mL and an area under the concentration-time curve (AUC) of 811.4 +/- 311.9 microg/mL.min at 260 mg/m2 [16].
  • The proportion of comets with tail moments </= 20 (i.e., with damage comparable to that produced by about 10 Gy) correlated with cell survival irrespective of cell type, dose of tirapazamine, time of treatment, or position of cell in the spheroid [17].
  • SR 4233 produced lower initial but similar final (after 6 h of repair) numbers of chromosome breaks compared to gamma-rays at equitoxic doses [18].
  • Using the technique of pulsed field gel electrophoresis, we found that the kinetics of rejoining of DNA double-strand breaks in CHO cells after treatment with SR 4233 was concentration dependent, varying from 95% (less than 50 microM) to 10% (200 microM) by 24 h [18].

Anatomical context of SR 4233


Associations of SR 4233 with other chemical compounds

  • The combination of tirapazamine, cisplatin, and radiotherapy resulted in remarkably good and durable clinical responses in patients with very advanced head and neck cancers [9].
  • Using this concept of a "threshold" for DNA damage, cell survival could be predicted for exposure to 4NQO, tirapazamine, nitrogen mustard, RSU 1069, and actinomycin D and was largely independent of cell type [23].
  • CONCLUSION: Dose levels 3 (carboplatin AUC of 6, 225 mg/m(2) paclitaxel, and 330 mg/m(2) tirapazamine) and 2 (carboplatin AUC 6, 225 mg/m(2) paclitaxel, and 260 mg/m(2) tirapazamine) are the maximum tolerated doses for chemotherapy naive and patients treated previously, respectively [24].
  • A lower degree of potentiation was seen with the clinically used agent mitomycin C (6- to 7-fold) and the EO9 analogs, EO7 and EO2, that are poorer substrates for DT-diaphorase (5- to 8-fold and 2- to 3-fold potentiation, respectively), and there was no potentiation or protection with menadione and tirapazamine [25].
  • Using a high-speed micellar electrokinetic chromatography (MEKC) separation, resolution of the investigational antineoplastic SR 4233 from its main metabolite SR 4317 was achieved in less than 60 s [26].

Gene context of SR 4233


Analytical, diagnostic and therapeutic context of SR 4233


  1. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Parmar, K., Mauch, P., Vergilio, J.A., Sackstein, R., Down, J.D. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  2. Antagonism of buthionine sulfoximine cytotoxicity for human neuroblastoma cell lines by hypoxia is reversed by the bioreductive agent tirapazamine. Yang, B., Keshelava, N., Anderson, C.P., Reynolds, C.P. Cancer Res. (2003) [Pubmed]
  3. Interaction of SR-4233 with hyperthermia and radiation in the FSaIIC murine fibrosarcoma tumor system in vitro and in vivo. Herman, T.S., Teicher, B.A., Coleman, C.N. Cancer Res. (1990) [Pubmed]
  4. Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003. Williamson, S.K., Crowley, J.J., Lara, P.N., McCoy, J., Lau, D.H., Tucker, R.W., Mills, G.M., Gandara, D.R. J. Clin. Oncol. (2005) [Pubmed]
  5. Human NADPH-cytochrome p450 reductase overexpression does not enhance the aerobic cytotoxicity of doxorubicin in human breast cancer cell lines. Ramji, S., Lee, C., Inaba, T., Patterson, A.V., Riddick, D.S. Cancer Res. (2003) [Pubmed]
  6. Pretreatment 18F-FAZA PET predicts success of hypoxia-directed radiochemotherapy using tirapazamine. Beck, R., Röper, B., Carlsen, J.M., Huisman, M.C., Lebschi, J.A., Andratschke, N., Picchio, M., Souvatzoglou, M., Machulla, H.J., Piert, M. J. Nucl. Med. (2007) [Pubmed]
  7. Low-dose metronomic daily cyclophosphamide and weekly tirapazamine: a well-tolerated combination regimen with enhanced efficacy that exploits tumor hypoxia. Emmenegger, U., Morton, G.C., Francia, G., Shaked, Y., Franco, M., Weinerman, A., Man, S., Kerbel, R.S. Cancer Res. (2006) [Pubmed]
  8. Phosphorylated histone H2AX in spheroids, tumors, and tissues of mice exposed to etoposide and 3-amino-1,2,4-benzotriazine-1,3-dioxide. Olive, P.L., Banáth, J.P., Sinnott, L.T. Cancer Res. (2004) [Pubmed]
  9. Phase I trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients with advanced head and neck cancer. Rischin, D., Peters, L., Hicks, R., Hughes, P., Fisher, R., Hart, R., Sexton, M., D'Costa, I., von Roemeling, R. J. Clin. Oncol. (2001) [Pubmed]
  10. Tirapazamine with cisplatin in patients with advanced non-small-cell lung cancer: a phase II study. Treat, J., Johnson, E., Langer, C., Belani, C., Haynes, B., Greenberg, R., Rodriquez, R., Drobins, P., Miller, W., Meehan, L., McKeon, A., Devin, J., von Roemeling, R., Viallet, J. J. Clin. Oncol. (1998) [Pubmed]
  11. Synergistic interaction between tirapazamine and cyclophosphamide in human breast cancer xenografts. Langmuir, V.K., Rooker, J.A., Osen, M., Mendonca, H.L., Laderoute, K.R. Cancer Res. (1994) [Pubmed]
  12. Tumor hypoxia can be exploited to preferentially sensitize tumors to fractionated irradiation. Brown, J.M., Lemmon, M.J. Int. J. Radiat. Oncol. Biol. Phys. (1991) [Pubmed]
  13. Hypobaric hypoxia: a method for testing bioreductive drugs in vivo. McAleer, J.J., McKeown, S.R., MacManus, M.P., Lappin, T.R., Bridges, J.M. Int. J. Radiat. Oncol. Biol. Phys. (1992) [Pubmed]
  14. Bioreductive metabolism of SR-4233 (WIN 59075) by whole cell suspensions under aerobic and hypoxic conditions: role of the pentose cycle and implications for the mechanism of cytotoxicity observed in air. Tuttle, S.W., Hazard, L., Koch, C.J., Mitchell, J.B., Coleman, C.N., Biaglow, J.E. Int. J. Radiat. Oncol. Biol. Phys. (1994) [Pubmed]
  15. Tirapazamine-induced cytotoxicity and DNA damage in transplanted tumors: relationship to tumor hypoxia. Siim, B.G., Menke, D.R., Dorie, M.J., Brown, J.M. Cancer Res. (1997) [Pubmed]
  16. Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors. Johnson, C.A., Kilpatrick, D., von Roemeling, R., Langer, C., Graham, M.A., Greenslade, D., Kennedy, G., Keenan, E., O'Dwyer, P.J. J. Clin. Oncol. (1997) [Pubmed]
  17. Use of the comet assay to identify cells sensitive to tirapazamine in multicell spheroids and tumors in mice. Olive, P.L., Vikse, C.M., Banath, J.P. Cancer Res. (1996) [Pubmed]
  18. Repair of DNA and chromosome breaks in cells exposed to SR 4233 under hypoxia or to ionizing radiation. Wang, J., Biedermann, K.A., Brown, J.M. Cancer Res. (1992) [Pubmed]
  19. In vitro hepatotoxicity of SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide), a hypoxic cytotoxin and potential antitumor agent. Costa, A.K., Baker, M.A., Brown, J.M., Trudell, J.R. Cancer Res. (1989) [Pubmed]
  20. Initial characterization of the major mouse cytochrome P450 enzymes involved in the reductive metabolism of the hypoxic cytotoxin 3-amino-1,2,4-benzotriazine-1,4-di-N-oxide (tirapazamine, SR 4233, WIN 59075). Riley, R.J., Hemingway, S.A., Graham, M.A., Workman, P. Biochem. Pharmacol. (1993) [Pubmed]
  21. Electron paramagnetic resonance spectrometry evidence for bioreduction of tirapazamine to oxidising free radicals under anaerobic conditions. Patterson, L.H., Taiwo, F.A. Biochem. Pharmacol. (2000) [Pubmed]
  22. Enzymology of the reductive bioactivation of SR 4233. A novel benzotriazine di-N-oxide hypoxic cell cytotoxin. Walton, M.I., Workman, P. Biochem. Pharmacol. (1990) [Pubmed]
  23. Multicell spheroid response to drugs predicted with the comet assay. Olive, P.L., Banáth, J.P. Cancer Res. (1997) [Pubmed]
  24. Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors: a california cancer consortium phase I and molecular correlative study. Lara, P.N., Frankel, P., Mack, P.C., Gumerlock, P.H., Galvin, I., Martel, C.L., Longmate, J., Doroshow, J.H., Lenz, H.J., Lau, D.H., Gandara, D.R. Clin. Cancer Res. (2003) [Pubmed]
  25. Establishment of an isogenic human colon tumor model for NQO1 gene expression: application to investigate the role of DT-diaphorase in bioreductive drug activation in vitro and in vivo. Sharp, S.Y., Kelland, L.R., Valenti, M.R., Brunton, L.A., Hobbs, S., Workman, P. Mol. Pharmacol. (2000) [Pubmed]
  26. On-line coupling of in vivo microdialysis sampling with capillary electrophoresis. Hogan, B.L., Lunte, S.M., Stobaugh, J.F., Lunte, C.E. Anal. Chem. (1994) [Pubmed]
  27. Resistance to endocrine therapy in breast cancer. Kurebayashi, J. Cancer Chemother. Pharmacol. (2005) [Pubmed]
  28. Tirapazamine cytotoxicity for neuroblastoma is p53 dependent. Yang, B., Reynolds, C.P. Clin. Cancer Res. (2005) [Pubmed]
  29. Repair of damage induced by SR 4233. Edwards, D.I., Virk, N.S. Int. J. Radiat. Oncol. Biol. Phys. (1992) [Pubmed]
  30. The concurrent chemoradiation paradigm--general principles. Seiwert, T.Y., Salama, J.K., Vokes, E.E. Nature clinical practice. Oncology (2007) [Pubmed]
  31. Potentiation by the hypoxic cytotoxin SR 4233 of cell killing produced by fractionated irradiation of mouse tumors. Brown, J.M., Lemmon, M.J. Cancer Res. (1990) [Pubmed]
  32. Tumor-specific, schedule-dependent interaction between tirapazamine (SR 4233) and cisplatin. Dorie, M.J., Brown, J.M. Cancer Res. (1993) [Pubmed]
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