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Chemical Compound Review

CHEMBL63753     1-(aziridin-1-yl)-3-(2- nitroimidazol-1...

Synonyms: RSU-1069, KST-1B9409, NSC-347503, LS-78581, Rsu 1069, ...
 
 
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Disease relevance of RSU-1069

  • Unfortunately, preliminary clinical studies have revealed a dose-limiting gastrointestinal toxicity for RSU 1069 [1].
  • The ability of cellular systems to repair damage induced by RSU-1069 may play a significant role in determining its efficiency to act as a hypoxic cell radiosensitizer and a hypoxia selective cytotoxin [2].
  • RSU-1069 is a highly effective hypoxic cell cytotoxin in KHT sarcomas treated in vivo [3].
  • At the cellular level, the cytoxicity of RSU-1069 was determined for a series of repair deficient mutants of E. coli under both aerobic and hypoxic conditions [2].
  • Administration of equitoxic doses of SR-2508 (3.0 g/kg) and RSU-1069 (0.1 g/kg) also promoted metastases formation [4].
 

High impact information on RSU-1069

  • Hoechst-labelled cells sorted from these tumours were more sensitive to killing by hypoxic cell cytotoxins (tirapazamine, RSU-1069) and less sensitive to damage by ionizing radiation [5].
  • Chinese hamster V79 spheroids, exposed for 1 h to RSU 1069, were disaggregated and individual cells were analysed for DNA damage [6].
  • Detection of hypoxia by measurement of DNA damage in individual cells from spheroids and murine tumours exposed to bioreductive drugs. II. RSU 1069 [6].
  • The ability of the dual-function bioreductive drug, RSU 1069, to identify hypoxic cells in multicell spheroids and murine SCCVII squamous cell carcinomas was examined using the alkaline comet method [6].
  • Pharmacologic/pharmacokinetic evaluation of emesis induced by analogs of RSU 1069 and its control by antiemetic agents [7].
 

Chemical compound and disease context of RSU-1069

 

Biological context of RSU-1069

  • For equivalent levels of DNA strand breakage following such treatment it is evident from the relative transformation frequencies that interactions with reduced RSU-1069 lead to DNA damage consistent with bifunctional action of a metabolite(s) [2].
  • Experimental pharmacokinetics of RSU-1069 and its analogues: high tumor/plasma ratios [13].
  • Cell survival in both tumours following combined RSU-1069 and radiation (1500 or 2000 cGy) treatment was similar when the drug was given 60 min before or immediately after irradiation suggesting that the effect observed was due to hypoxic cell cytotoxicity rather than radiosensitization [14].
  • Strand breakage of plasmid DNA by parent and radiation-reduced RSU-1069 (2.0-8.0 mmol dm-3) has been measured in air over 4 hr at 310K [15].
  • Whereas the relative order of DNA damage was RSU 1069 greater than CB 1954 greater than misonidazole the order in inducing SOS repair was RSU 1069 greater than misonidazole greater than CB 1954 [16].
 

Anatomical context of RSU-1069

  • The effects of three bioreductive drugs (mitomycin C, RSU-1069 and SR4233) on cell lines selected for their sensitivity to mitomycin C or ionising radiation [17].
  • Toxicity of RSU 1069 toward bone marrow stem cells was also less after po administration than after ip administration; 0.1 mmol/kg ip RSU 1069 and 0.38 mmol/kg po RSU 1069 both reduced the surviving fraction of clonogenic CFU-A cells by 50% [18].
  • In contrast, differential toxicities of between 3 and 30 have been observed for all CHO cells treated with RSU-1069 and SR4233 [17].
  • Results using the hypoxic cell cytotoxin RSU 1069 confirmed that the extent of hypoxia was not as severe in the testis as in the SCCVII murine tumour [19].
  • In one set of experiments, the bioreductive drug RSU-1069 was injected once via the portal vein with or without degradable starch microspheres (DSM) 10 mins after tumour cell inoculation [20].
 

Associations of RSU-1069 with other chemical compounds

 

Gene context of RSU-1069

  • Both parent and reduced RSU-1069 cause single strand breaks (ssbs) in pSV2 gpt plasmid DNA with the reduced compound causing a greater number of breaks [25].
  • We conclude that the repair of cellular DNA damage induced by RSU-1069 involves activation of the gene products under the control of the recA gene and not those under the control of the ada gene [2].
  • Drug-induced damage by RSU 1069 involves enhanced damage by endonuclease III suggesting drug-induced pyrimidine damage [16].
 

Analytical, diagnostic and therapeutic context of RSU-1069

References

  1. In vitro cytotoxicity and chemosensitizing activity of the dual function nitroimidazole RB 6145. Siemann, D.W. Int. J. Radiat. Oncol. Biol. Phys. (1994) [Pubmed]
  2. Assessment of the repair and damage of DNA induced by parent and reduced RSU-1069, a 2-nitroimidazole-aziridine. O'Neill, P., Cunniffe, S.M. Int. J. Radiat. Oncol. Biol. Phys. (1989) [Pubmed]
  3. Toxicity of RSU-1069 for KHT cells treated in vivo or in vitro: evidence for a diffusible toxic product. Hill, R.P., Gulyas, S., Whitmore, G.F. Int. J. Radiat. Oncol. Biol. Phys. (1989) [Pubmed]
  4. Influence of misonidazole, SR-2508, RSU-1069 and WR-2721 on spontaneous metastases in C57BL mice. Kanclerz, A., Chapman, J.D. Int. J. Radiat. Oncol. Biol. Phys. (1988) [Pubmed]
  5. Local hypoxia is produced at sites of intratumour injection. Olive, P.L., Luo, C.M., Banáth, J.P. Br. J. Cancer (2002) [Pubmed]
  6. Detection of hypoxia by measurement of DNA damage in individual cells from spheroids and murine tumours exposed to bioreductive drugs. II. RSU 1069. Olive, P.L. Br. J. Cancer (1995) [Pubmed]
  7. Pharmacologic/pharmacokinetic evaluation of emesis induced by analogs of RSU 1069 and its control by antiemetic agents. Sebolt-Leopold, J.S., Vincent, P.W., Beningo, K.A., Elliott, W.L., Leopold, W.R., Heffner, T.G., Wiley, J.N., Stier, M.A., Suto, M.J. Int. J. Radiat. Oncol. Biol. Phys. (1992) [Pubmed]
  8. A comparison of the techniques of alkaline filter elution and alkaline sucrose sedimentation used to assess DNA damage induced by 2-nitroimidazoles. Crump, P.W., Fielden, E.M., Jenner, T.J., O'Neill, P. Biochem. Pharmacol. (1990) [Pubmed]
  9. Potentiation of RSU-1069 tumour cytotoxicity by 5-hydroxytryptamine (5-HT). Chaplin, D.J. Br. J. Cancer (1986) [Pubmed]
  10. The differential cytotoxicity of RSU 1069: cell survival studies indicating interaction with DNA as a possible mode of action. Stratford, I.J., Walling, J.M., Silver, A.R. Br. J. Cancer (1986) [Pubmed]
  11. 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]
  12. Potentiation of melphalan activity in the KHT sarcoma by the radiosensitizer RSU 1069. Siemann, D.W., Maddison, K., Wolf, K. Int. J. Radiat. Oncol. Biol. Phys. (1984) [Pubmed]
  13. Experimental pharmacokinetics of RSU-1069 and its analogues: high tumor/plasma ratios. Deacon, J.M., Holliday, S.B., Ahmed, I., Jenkins, T.C. Int. J. Radiat. Oncol. Biol. Phys. (1986) [Pubmed]
  14. Studies of the in vivo and in vitro cytotoxicity of the drug RSU-1069. Hill, R.P., Gulyas, S., Whitmore, G.F. Br. J. Cancer (1986) [Pubmed]
  15. The phosphate-group of DNA as a potential target for RSU-1069, a nitroimidazole-aziridine radiosensitizer. Silver, A.R., O'Neill, P., Jenkins, T.C., McNeil, S.S. Int. J. Radiat. Oncol. Biol. Phys. (1986) [Pubmed]
  16. Comparative DNA damage and repair induced by misonidazole, CB 1954 and RSU 1069. Dale, L.D., Widdick, D.A., Edwards, D.I., Biol, G.I. Int. J. Radiat. Oncol. Biol. Phys. (1989) [Pubmed]
  17. The effects of three bioreductive drugs (mitomycin C, RSU-1069 and SR4233) on cell lines selected for their sensitivity to mitomycin C or ionising radiation. Keohane, A., Godden, J., Stratford, I.J., Adams, G.E. Br. J. Cancer (1990) [Pubmed]
  18. Oral (po) dosing with RSU 1069 or RB 6145 maintains their potency as hypoxic cell radiosensitizers and cytotoxins but reduces systemic toxicity compared with parenteral (ip) administration in mice. Cole, S., Stratford, I.J., Bowler, J., Nolan, J., Wright, E.G., Lorimore, S.A., Adams, G.E. Int. J. Radiat. Oncol. Biol. Phys. (1991) [Pubmed]
  19. Influence of oxygen on radiation-induced DNA damage in testicular cells of C3H mice. Zheng, H., Olive, P.L. Int. J. Radiat. Biol. (1997) [Pubmed]
  20. Adverse effects at adjuvant treatment of liver metastases in rat with RSU-1069 + microspheres, or liposomal MTP-PE. Wang, L., Roos, G., Stenram, U. Anticancer Res. (1995) [Pubmed]
  21. Radiation sensitization and chemopotentiation: RSU 1069, a compound more efficient than misonidazole in vitro and in vivo. Adams, G.E., Ahmed, I., Sheldon, P.W., Stratford, I.J. Br. J. Cancer (1984) [Pubmed]
  22. Interaction of RSU 1069 and 1137 with DNA in vitro. Biological implications and mechanistic aspects. Lafleur, M.V., Westmijze, E.J., Visser, O.J., Wagenaar, N., Soetekouw, R., Loman, H., Retèl, J. Biochem. Pharmacol. (1991) [Pubmed]
  23. Pharmacology of the mixed-function radio- and chemosensitizers CB 1954 and RSU 1069. Workman, P., Walton, M.I. Int. J. Radiat. Oncol. Biol. Phys. (1984) [Pubmed]
  24. Enhancement of DNA damage in mammalian cells upon bioreduction of the nitroimidazole-aziridines RSU-1069 and RSU-1131. Jenner, T.J., Sapora, O., O'Neill, P., Fielden, E.M. Biochem. Pharmacol. (1988) [Pubmed]
  25. Induction of DNA strand breaks by RSU-1069, a nitroimidazole-aziridine radiosensitizer. Role of binding of both unreduced and radiation-reduced forms to DNA, in vitro. Silver, A.R., O'Neill, P., Jenkins, T.C. Biochem. Pharmacol. (1985) [Pubmed]
  26. The influence of elevated levels of platelet-derived endothelial cell growth factor/thymidine phosphorylase on tumourigenicity, tumour growth, and oxygenation. Griffiths, L., Stratford, I.J. Int. J. Radiat. Oncol. Biol. Phys. (1998) [Pubmed]
  27. Bioreductive drugs for cancer therapy: the search for tumor specificity. Adams, G.E., Stratford, I.J. Int. J. Radiat. Oncol. Biol. Phys. (1994) [Pubmed]
 
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