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Chemical Compound Review

AC1MHDAW     4-hydroxy-6-oxo-N-phenyl-2- sulfanylidene...

Synonyms: CCRIS 8215, NCIMech_000589, CCG-35687, CCG-36359, UPDDI-00294859, ...
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Disease relevance of merbarone


High impact information on merbarone

  • Here, we investigate the role of p53 in the G(2) arrest that occurs in response to the topoisomerase inhibitors etoposide and merbarone [5].
  • In this study, using CEM cells selected for resistance to merbarone, we found that topo IIalpha RNA levels were reduced, compared to the parental cells, and this corresponded to reduced protein levels, whereas there was no significant difference in the RNA stability among these cell lines [6].
  • Down-regulation of topoisomerase IIalpha in CEM cells selected for merbarone resistance is associated with reduced expression of Sp3 [6].
  • Characterization of novel human leukemic cell lines selected for resistance to merbarone, a catalytic inhibitor of DNA topoisomerase II [7].
  • Karyotype analysis of three of the cell lines revealed that while CEM and drug-resistant cell lines had chromosome abnormalities in common, indicating a common origin, two of the merbarone-resistant lines (B1 and B8) each had unique structural markers [7].

Chemical compound and disease context of merbarone


Biological context of merbarone

  • By contrast, treatment of at-MDR cells with either merbarone or SN22995 produced a qualitatively different pattern; the at-MDR cells first accumulated in G2 but then escaped the G2 block and proceeded into mitosis with elongated and intertwined chromosomes but failed to divide [9].
  • Thus, while the cellular effects of VM-26 are the consequences of inhibition of topo II catalytic activities and generation of topo II-mediated DNA damage, those of merbarone may be due to inactivation of topo II catalytic function [10].
  • In contrast to the type II enzyme, inhibition of catalytic activity of topoisomerase I required about 10-fold higher concentrations of merbarone, with a 50% inhibitory concentration of approximately 200 microM [2].
  • Our data suggest that the effects of merbarone and VM-26 during mitosis are most likely due to inhibition of topo II function [10].
  • In all 12 cell lines, there was a high correlation among drug resistance ratios between etoposide and teniposide and between merbarone and SN-38 [7].

Anatomical context of merbarone

  • To investigate this issue, we established 12 merbarone-resistant cell lines from human leukemia CEM cells, designated CEM/M70-B1 through -B12 [7].
  • However, merbarone did not directly induce the excision of high molecular weight DNA fragments from the nuclear matrix by promoting topoisomerase II-catalyzed DNA cleavage, because the drug inhibited topoisomerase II-mediated cleavage in isolated nuclear matrix preparations [11].
  • Conversely, preincubation with merbarone resulted in less inhibition of VP-16-induced topoisomerase II-DNA covalent complexes in K/VP.5 cells than in parental K562 cells [12].
  • Bone marrow smears from merbarone-treated B6C3F1 mice showed a dose-related increase in micronucleated polychromatic erythrocytes with a mean of 26 MN per 1000 cells being seen at the 60 mg/kg dose [13].
  • The ability of two topoisomerase II (topo II) inhibitors, etoposide (VP-16) and merbarone (MER), to induce meiotic delay and aneuploidy in mouse spermatocytes was investigated [14].

Associations of merbarone with other chemical compounds

  • Two other inhibitors of topoisomerase II, Hoechst 33258 and Merbarone, failed to delay cells in metaphase and did not induce tetraploidy [15].
  • Treatment of CEM cells with apoptosis-inducing concentrations of merbarone caused activation of c-Jun NH2-terminal kinase/stress-activated protein kinase, c-jun gene induction, activation of caspase-3/CPP32-like protease but not caspase-1, and the proteolytic cleavage of poly(ADP-ribose) polymerase [16].
  • In vitro differential metabolism of merbarone by xanthine oxidase and microsomal flavoenzymes. The role of reactive oxygen species [17].
  • We review herein current work on the cytotoxic and cellular actions of two classes of inhibitors of DNA topoisomerase II: one represented by etoposide and teniposide, which stabilize DNA-protein complexes, and another represented by merbarone and aclarubicin, which do not stabilize such complexes [18].
  • Ultrafiltration studies showed that merbarone did not significantly displace binding of urate from albumin [19].

Gene context of merbarone


Analytical, diagnostic and therapeutic context of merbarone


  1. Phase II study of taxol, merbarone, and piroxantrone in stage IV non-small-cell lung cancer: The Eastern Cooperative Oncology Group Results. Chang, A.Y., Kim, K., Glick, J., Anderson, T., Karp, D., Johnson, D. J. Natl. Cancer Inst. (1993) [Pubmed]
  2. In vitro and intracellular inhibition of topoisomerase II by the antitumor agent merbarone. Drake, F.H., Hofmann, G.A., Mong, S.M., Bartus, J.O., Hertzberg, R.P., Johnson, R.K., Mattern, M.R., Mirabelli, C.K. Cancer Res. (1989) [Pubmed]
  3. Phase II trial of merbarone in soft tissue sarcoma. A Southwest Oncology Group study. Kraut, E.H., Bendetti, J., Balcerzak, S.P., Doroshow, J.H. Investigational new drugs. (1992) [Pubmed]
  4. Evaluation of merbarone (NSC 336628) in disseminated malignant melanoma. A Southwest Oncology Group study. Slavik, M., Liu, P.Y., Kraut, E.H., Natale, R.B., Flaherty, L.E., Sondak, V.K. Investigational new drugs. (1995) [Pubmed]
  5. G2 arrest in response to topoisomerase II inhibitors: the role of p53. Clifford, B., Beljin, M., Stark, G.R., Taylor, W.R. Cancer Res. (2003) [Pubmed]
  6. Down-regulation of topoisomerase IIalpha in CEM cells selected for merbarone resistance is associated with reduced expression of Sp3. Mo, Y.Y., Wang, Q., Beck, W.T. Cancer Res. (1997) [Pubmed]
  7. Characterization of novel human leukemic cell lines selected for resistance to merbarone, a catalytic inhibitor of DNA topoisomerase II. Kusumoto, H., Rodgers, Q.E., Boege, F., Raimondi, S.C., Beck, W.T. Cancer Res. (1996) [Pubmed]
  8. A phase II trial of merbarone (NSC 336628) in the treatment of recurrent epithelial ovarian carcinoma. A Gynecologic Oncology Group Study. Look, K.Y., Blessing, J.A., Adelson, M.D., Morris, M., Bookman, M.A. Am. J. Clin. Oncol. (1996) [Pubmed]
  9. Teniposide-resistant CEM cells, which express mutant DNA topoisomerase II alpha, when treated with non-complex-stabilizing inhibitors of the enzyme, display no cross-resistance and reveal aberrant functions of the mutant enzyme. Chen, M., Beck, W.T. Cancer Res. (1993) [Pubmed]
  10. Differences in inhibition of chromosome separation and G2 arrest by DNA topoisomerase II inhibitors merbarone and VM-26. Chen, M., Beck, W.T. Cancer Res. (1995) [Pubmed]
  11. Merbarone induces activation of caspase-activated DNase and excision of chromosomal DNA loops from the nuclear matrix. Otake, Y., Mims, A., Fernandes, D.J. Mol. Pharmacol. (2006) [Pubmed]
  12. Collateral sensitivity to the bisdioxopiperazine dexrazoxane (ICRF-187) in etoposide (VP-16)-resistant human leukemia K562 cells. Fattman, C.L., Allan, W.P., Hasinoff, B.B., Yalowich, J.C. Biochem. Pharmacol. (1996) [Pubmed]
  13. Catalytic inhibitors of topoisomerase II are DNA-damaging agents: induction of chromosomal damage by merbarone and ICRF-187. Wang, L., Eastmond, D.A. Environ. Mol. Mutagen. (2002) [Pubmed]
  14. Molecular cytogenetic analysis in mouse sperm of chemically induced aneuploidy: studies with topoisomerase II inhibitors. Attia, S.M., Schmid, T.E., Badary, O.A., Hamada, F.M., Adler, I.D. Mutat. Res. (2002) [Pubmed]
  15. Inhibitors of topoisomerase II delay progress through mitosis and induce a doubling of the DNA content in CHO cells. Sumner, A.T. Exp. Cell Res. (1995) [Pubmed]
  16. Merbarone, a catalytic inhibitor of DNA topoisomerase II, induces apoptosis in CEM cells through activation of ICE/CED-3-like protease. Khélifa, T., Beck, W.T. Mol. Pharmacol. (1999) [Pubmed]
  17. In vitro differential metabolism of merbarone by xanthine oxidase and microsomal flavoenzymes. The role of reactive oxygen species. Muindi, J.F., Stevens, Y.W., Warrell, R.P., Young, C.W. Drug Metab. Dispos. (1993) [Pubmed]
  18. Novel actions of inhibitors of DNA topoisomerase II in drug-resistant tumor cells. Beck, W.T., Kim, R., Chen, M. Cancer Chemother. Pharmacol. (1994) [Pubmed]
  19. Induction of profound hypouricemia by a non-sedating thiobarbiturate. Warrell, R.P., Muindi, J., Stevens, Y.W., Isaacs, M., Young, C.W. Metab. Clin. Exp. (1989) [Pubmed]
  20. Cleavage of the MLL gene by activators of apoptosis is independent of topoisomerase II activity. Betti, C.J., Villalobos, M.J., Jiang, Q., Cline, E., Diaz, M.O., Loredo, G., Vaughan, A.T. Leukemia (2005) [Pubmed]
  21. Distribution of [2-14C]merbarone in mice by autoradiography of whole-body cryosections. Kemmenoe, B.H., Malspeis, L. Cancer Res. (1987) [Pubmed]
  22. Merbarone inhibits the catalytic activity of human topoisomerase IIalpha by blocking DNA cleavage. Fortune, J.M., Osheroff, N. J. Biol. Chem. (1998) [Pubmed]
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