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Chemical Compound Review

Azolastone     3-(2-chloroethyl)-2-oxo- 1,3,4,5,8...

Synonyms: Mitozolamide, Mitozolomida, Mitozolomide, Mitozolomidum, SureCN97695, ...
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Disease relevance of NSC 353451


High impact information on NSC 353451

  • The in vitro cytotoxicity, stability, and metabolism of the 8-(N,N-dimethylcarboxamide) and 8-(N-methylcarboxamide) analogues of the experimental antitumor drug mitozolomide have been investigated in conjunction with their in vivo murine pharmacokinetics and metabolism [2].
  • Cell survival analysis following exposure to the chloroethylating agent mitozolomide revealed that expression of hAT at levels two- to fourfold higher than background conferred significant resistance (p < 0.001) to the toxic effects of this drug [3].
  • These clones were assayed for cell survival following exposure to mitozolomide [3].
  • However, whilst hAT-mediated protection was ablated by 20 microM O6-beG, the hATPA/GA protein provided protection against mitozolomide under the same conditions [5].
  • MGMT antisense oligonucleotide enhanced the sensitivity of cells to the tumor therapeutic drug mitozolomide, as measured by sister chromatid exchange formation [6].

Chemical compound and disease context of NSC 353451

  • A colony-forming assay was used to demonstrate significant protection (P < 0.001) against mitozolomide or temozolomide toxicity in K562 clones expressing either hAT mutant, as determined from an in vitro assay of activity [7].

Biological context of NSC 353451


Anatomical context of NSC 353451

  • In the testis cell lines ATase activity (molecules/cell) was related to IC50s for mitozolomide (R = 0.97) but not MNU (R = 0.78) [13].
  • In addition mitozolomide and MCTIC induced DNA interstrand crosslinks in the BE but not the HT-29 cell line [12].
  • In conjunction with autologous bone marrow rescue, high-dose mitozolomide was given i.v. to 16 patients with refractory malignancies at doses ranging from 100 to 400 mg/m2 over 1 h [14].
  • Furthermore, as a result of transgene expression, the number of micronucleated polychromatic erythrocytes induced by mitozolomide was significantly reduced (P < .05) by 40% relative to mock-transduced controls, indicating the potential of this approach to reduce the frequency of mutation associated with chemotherapy exposure [15].

Associations of NSC 353451 with other chemical compounds

  • PURPOSE: To investigate the effect of temozolomide, a 3-methyl derivative of mitozolomide in combination with X-rays in human glioma-derived cell lines [16].
  • Flow cytometry showed an interesting difference: at the high concentration mitozolomide induced an accumulation of cells in S middle and S late-G2-M phase of the cell cycle whereas BCNU caused only a block in S late-G2-M [10].
  • Pretreatment of HT-29 cells (Mer+) with the DNA methylating agent MNNG allows mitozolomide or MCTIC to produce DNA interstrand crosslinks [12].
  • Acute administration of TNF produced hypoglycaemia that was more severe than observed with either mitozolomide or in pair-fed controls, a reduction in the circulatory level of free fatty acids (FFA) and an increase in plasma triglycerides, while mitozolomide and pair-feeding had no effect on the level of blood glucose or plasma triglycerides [17].
  • The results suggest that, unlike temozolomide, mitozolomide, and BCNU, the cytotoxicity of the tetrazepinones does not correlate with the alkylation of the O6 position of guanine and that the mechanism of MGMT inactivation by tetrazepinones may differ from that of hitherto known inhibitors [18].

Gene context of NSC 353451


Analytical, diagnostic and therapeutic context of NSC 353451


  1. Activity of mitozolomide (NSC 353451), a new imidazotetrazine, against xenografts from human melanomas, sarcomas, and lung and colon carcinomas. Fodstad, O., Aamdal, S., Pihl, A., Boyd, M.R. Cancer Res. (1985) [Pubmed]
  2. Metabolism and murine pharmacokinetics of the 8-(N,N-dimethylcarboxamide) analogue of the experimental antitumor drug mitozolomide (NSC353451). Horspool, K.R., Quarterman, C.P., Slack, J.A., Gescher, A., Stevens, M.F., Lunt, E. Cancer Res. (1989) [Pubmed]
  3. Recombinant adeno-associated virus-mediated expression of O6-alkylguanine-DNA-alkyltransferase protects human epithelial and hematopoietic cells against chloroethylating agent toxicity. Longhurst, S.J., Rafferty, J.A., Arrand, J.R., Cortez, N., Giraud, C., Berns, K.I., Fairbairn, L.J. Hum. Gene Ther. (1999) [Pubmed]
  4. Phase II evaluation of mitozolomide in ovarian cancer. Harding, M., Northcott, D., Smyth, J., Stuart, N.S., Green, J.A., Newlands, E. Br. J. Cancer (1988) [Pubmed]
  5. Protection of mammalian cells against chloroethylating agent toxicity by an O6-benzylguanine-resistant mutant of human O6-alkylguanine-DNA alkyltransferase. Hickson, I., Fairbairn, L.J., Chinnasamy, N., Dexter, T.M., Margison, G.P., Rafferty, J.A. Gene Ther. (1996) [Pubmed]
  6. Targeting of O6-methylguanine-DNA methyltransferase (MGMT) activity by antimessenger oligonucleotide sensitizes CHO/Mex+ transfected cells to mitozolomide. Citti, L., Boldrini, L., Preuss, I., Kaina, B., Mariani, L., Rainaldi, G. Carcinogenesis (1996) [Pubmed]
  7. Chemoprotective gene transfer I: transduction of human haemopoietic progenitors with O6-benzylguanine-resistant O6-alkylguanine-DNA alkyltransferase attenuates the toxic effects of O6-alkylating agents in vitro. Hickson, I., Fairbairn, L.J., Chinnasamy, N., Lashford, L.S., Thatcher, N., Margison, G.P., Dexter, T.M., Rafferty, J.A. Gene Ther. (1998) [Pubmed]
  8. Antitumor imidazotetrazines. 20. Preparation of the 8-acid derivative of mitozolomide and its utility in the preparation of active antitumor agents. Horspool, K.R., Stevens, M.F., Newton, C.G., Lunt, E., Walsh, R.J., Pedgrift, B.L., Baig, G.U., Lavelle, F., Fizames, C. J. Med. Chem. (1990) [Pubmed]
  9. Upregulation of O6-alkylguanine-DNA-alkyltransferase expression and the presence of double minute chromosomes in alkylating agent selected Chinese hamster cells. Morten, J.E., Bayley, L., Watson, A.J., Ward, T.H., Potter, P.M., Rafferty, J.A., Margison, G.P. Carcinogenesis (1992) [Pubmed]
  10. Mitozolomide activity on human cancer cells in vitro. Erba, E., Pepe, S., Ubezio, P., Lorico, A., Morasca, L., Mangioni, C., Landoni, F., D'Incalci, M. Br. J. Cancer (1986) [Pubmed]
  11. Antitumour imidazotetrazines--XVI. Macromolecular alkylation by 3-substituted imidazotetrazinones. Bull, V.L., Tisdale, M.J. Biochem. Pharmacol. (1987) [Pubmed]
  12. The effects of pretreatment of human tumour cells with MNNG on the DNA crosslinking and cytotoxicity of mitozolomide. Gibson, N.W., Erickson, L.C. Br. J. Cancer (1985) [Pubmed]
  13. O6-alkylguanine-DNA-alkyltransferase activity and nitrosourea sensitivity in human cancer cell lines. Walker, M.C., Masters, J.R., Margison, G.P. Br. J. Cancer (1992) [Pubmed]
  14. A clinical and pharmacological study of high-dose mitozolomide given in conjunction with autologous bone marrow rescue. McKeage, M., Dady, P., Clear, M., MacDonald, A. Cancer Chemother. Pharmacol. (1992) [Pubmed]
  15. Enhancing hemopoietic drug resistance: a rationale for reconsidering the clinical use of mitozolomide. Fairbairn, L.J., Chinnasamy, N., Lashford, L.S., Chinnasamy, D., Rafferty, J.A. Cancer Gene Ther. (2000) [Pubmed]
  16. Survival of human glioma cells treated with various combination of temozolomide and X-rays. van Rijn, J., Heimans, J.J., van den Berg, J., van der Valk, P., Slotman, B.J. Int. J. Radiat. Oncol. Biol. Phys. (2000) [Pubmed]
  17. Induction of weight loss and metabolic alterations by human recombinant tumour necrosis factor. Mahony, S.M., Tisdale, M.J. Br. J. Cancer (1988) [Pubmed]
  18. Tetrazepinones are equally cytotoxic to Mer+ and Mer- human tumor cell lines. Jean-Claude, B.J., Mustafa, A., Watson, A.J., Damian, Z., Vasilescu, D., Chan, T.H., Leyland-Jones, B. J. Pharmacol. Exp. Ther. (1999) [Pubmed]
  19. Activity and distribution studies of etoposide and mitozolomide in vivo and in vitro against human choriocarcinoma cell lines. Brindley, C.J., Pedley, R.B., Antoniw, P., Newlands, E.S. Cancer Chemother. Pharmacol. (1987) [Pubmed]
  20. Anti-tumour imidazotetrazines. Part XXI. Mitozolomide and temozolomide: probes for the major groove of DNA. Clark, A.S., Stevens, M.F., Sansom, C.E., Schwalbe, C.H. Anticancer Drug Des. (1990) [Pubmed]
  21. Inhibition of cellular esterases by the antitumour imidazotetrazines mitozolomide and temozolomide: demonstration by flow cytometry and conventional spectrofluorimetry. Dive, C., Workman, P., Watson, J.V. Cancer Chemother. Pharmacol. (1989) [Pubmed]
  22. Phase II study of mitozolomide (M & B 39,565) in colorectal and breast cancer. Herait, P., Rougier, P., Oliveira, J., Delgado, F.M., May-Levin, F., Hayat, M., Armand, J.P. Investigational new drugs. (1988) [Pubmed]
  23. Relationship between the pharmacokinetics and toxicity of mitozolomide. Kerr, D.J., Slack, J.A., Secrett, P., Stevens, M.F., Blackledge, G.R., Bradley, C., Kaye, S.B. Cancer Chemother. Pharmacol. (1990) [Pubmed]
  24. Antitumour imidazotetrazines. VII. Quantitative analysis of mitozolomide in biological fluids by high-performance liquid chromatography. Slack, J.A., Goddard, C. J. Chromatogr. (1985) [Pubmed]
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