Disease relevance of merbarone

• Phase II study of taxol, merbarone, and piroxantrone in stage IV non-small-cell lung cancer: The Eastern Cooperative Oncology Group Results [1].
• The most common toxic effects were leukopenia with taxol or piroxantrone treatment and thromboembolic complications with merbarone [1].
• Merbarone inhibited purified mammalian topoisomerase II with a 50% inhibitory concentration of 20 microM, as assessed by ATP-dependent unknotting of P4 phage DNA or relaxation of supercoiled pBR322 plasmid [2].
• Phase II trial of merbarone in soft tissue sarcoma. A Southwest Oncology Group study [3].
• Evaluation of merbarone (NSC 336628) in disseminated malignant melanoma. A Southwest Oncology Group study [4].

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

• METHODS: Twenty-seven patients with recurrent epithelial ovarian carcinoma who had previously received one prior cisplatin-based regimen were scheduled to receive 1000 mg/m2 of merbarone by continuous intravenous infusion through a central line each day for five days every four weeks [8].

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

• Inactivation of topoisomerase II by the catalytic inhibitor merbarone did not inhibit MLL cleavage, suggesting that the initial cleavage step for MLL rearrangement is not mediated by topoisomerase II [20].
• Merbarone, a catalytic inhibitor of DNA topoisomerase II, induces apoptosis in CEM cells through activation of ICE/CED-3-like protease [16].
• 6-dichlorobenzoyloxymethyl-ketone, inhibited merbarone-induced caspase-3/CPP32-like activity and apoptosis in a dose-dependent manner [16].
• Merbarone induces activation of caspase-activated DNase and excision of chromosomal DNA loops from the nuclear matrix [11].
• Furthermore, at concentrations showing similar levels of S-phase suppression, VM-26 caused significant DNA breaks, while merbarone had no such effect [10].

Analytical, diagnostic and therapeutic context of merbarone

• METHODS: Eligible patients (119) were randomly assigned to receive one of the three treatments given every 3 weeks: 250 mg/m2 taxol by a 24-hour intravenous infusion, 1000 mg/m2 merbarone by continuous intravenous infusion through a central catheter daily for 5 days, or 150 mg/m2 piroxantrone by intravenous infusion over 1 hour [1].
• Rapid absorption of merbarone occurred after oral administration with radiolabel first observed in the liver and kidney at 3-6 min after dosing [21].
• Continuous exposure of CEM cells to merbarone, SN22995, or VM-26 caused G2 arrest, as determined by flow cytometry [9].
• Merbarone has previously been shown to have antitumor activity of unknown mechanism in P388 and L1210 tumor models (A. D. Brewer et al., Biochem. Pharmacol., 34:2047-2050, 1985) and is currently undergoing Phase I clinical trials [2].
• Merbarone is a catalytic inhibitor of topoisomerase II that is in clinical trials as an anticancer agent [22].

References