Disease relevance of MX2

• MX2, in contrast to ADM, was effective against sublines of P388 leukemia resistant to ADM or aclacinomycin A in vivo as well as in vitro [1].
• In contrast, MX2 virus was replication competent and incorporated a full complement of Env into its virions, indicating a differential role for the LLP-1 domain in Env incorporation [2].
• To elucidate the mechanism by which MX2 overcomes multidrug resistance, the intracellular pharmacology of MX2 in human myelogenous leukemia K562 and its ADM-resistant subline (K562/ADM) was examined [3].
• We suggest that MX2 may be useful for the treatment of megakaryocytic leukemia [4].
• Activity was seen against all types of cancer tested including renal (91%), melanoma (88%), ovarian (73%), breast (71%) and non-small-cell lung (67%) cancer at a MX2 concentration of 0.5 micrograms/ml after continuous exposure [5].

High impact information on MX2

• In a mitoxantrone-selected human leukemia cell line, HL-60/MX2, cellular topoisomerase II (topo II) catalytic activity is decreased, in association with the finding of reduced nuclear topo II alpha and beta protein levels [6].
• A human HL-60 leukemia cell line selected for resistance to mitoxantrone, HL-60/MX2, displays cross-resistance only to agents whose cytotoxicities result from interaction with the nuclear enzyme DNA topoisomerase II (topo II) [7].
• Using a reverse transcription-PCR assay we were able to demonstrate the presence of very low levels of topo II beta mRNA in HL-60/MX2 cells, representing < 1% of that found in the HL-60 cells [7].
• Interestingly, MX2 effectively inhibited ATP/Mg2(+)-dependent [3H]vincristine binding to K562/ADM membrane preparations, indicating that MX2 could be transported outside the cell by an active efflux pump [3].
• MX2 was effective against multidrug-resistant sublines of four human tumor cell lines; these cells, having a 4.8- to 200-fold cross-resistance to Adriamycin (ADM) showed only a 0.7- to 2.3-fold resistance to MX2 compared with the sensitive cells [3].

Chemical compound and disease context of MX2

• In the rats bearing the intracerebral C6 tumors, the life span was increased by about 40 to 100% after intravenous administration of MX2 at doses ranging from 1 to 3 mg/kg of body weight [8].
• Phase II study of KRN8602, 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride, MX2 x HCl in patients with metastatic breast cancer [9].
• Under deproteinated elution conditions (pH 12.1), DOX, morpholinyl DOX (MRA), methoxy-morpholinyl DOX (MMDX) and morpholinyl oxaunomycin (MX2) were equipotent at causing SSB in the human ovarian carcinoma cell line, ES-2 [10].
• The cellular uptake, subcellular distribution and retention of MX2, a new morpholino anthracycline, were compared with those of adriamycin (ADM) using confocal laser scanning microscopy (CLSM) in rat C6 and human T98G glioma cell lines [11].

Biological context of MX2

• The high intracellular accumulation and retention of MX2 in K562/ADM through the rapid influx of the drug into the cells may be one of the reasons why MX2 circumvents pleiotropic drug resistance [3].
• The resistant cells (HL-60/MX2) retain sensitivity to the Vinca alkaloids vincristine and vinblastine, drugs that are typically associated with the classical multidrug resistance phenotype [12].
• To quantify the extent of apoptosis induced by MX2, we used the in situ terminal deoxynucleotide transferase assay and the histone-associated DNA fragmentation assay [4].
• The effects of 4-demethoxydaunorubicin (idarubicin, IDA) and MX2, a new morpholino-anthracycline, on up-regulation of the MDR1 gene in the low-level multidrug resistant (MDR) cell line CEM/A7R were compared at similar concentrations (IC10, IC50 and IC90) over a short time exposure (4 and 24 h) [13].
• Altered expression of topoisomerase IIalpha contributes to cross-resistant to etoposide K562/MX2 cell line by aberrant methylation [14].

Anatomical context of MX2

• This p78-related protein was translated in reticulocyte lysates where it shared an antigenic determinant(s) with p78 [15].
• The lack of syncytium formation, however, correlated with a decrease of about 90% in MX2 Env fusogenicity compared to that of wild-type Env in quantitative luciferase-based cell-cell fusion assays [2].
• In addition, greater than 70% of MX2 was retained in both cell lines after 150 min of incubation in the absence of this drug [3].
• Antisera to calf thymus topoisomerase II defined a distinctive immunoreactive pattern of topoisomerase II proteins in crude nuclear extracts from the HL-60/MX2 cells [12].
• Activity of the morpholino anthracycline 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2) against human tumor colony-forming units in vitro [5].

Associations of MX2 with chemical compounds

• MX2, a new morpholino anthracycline, showed similar or superior chemotherapeutic effects to Adriamycin (ADM) against several experimental murine tumors. i.v. administration of MX2 against L1210-bearing mice induced a prolongation of life-span by twice or more compared to ADM [1].
• Substitutions were made for highly conserved arginine residues in either the LLP-1 or LLP-2 domain (MX1 or MX2, respectively) or in both domains (MX4) [2].
• These results indicate that the reduced levels of topo II alpha and beta isoenzymes observed in mitoxantrone-resistant HL-60/MX2 cells are related to changes in the levels of their respective mRNA transcripts [7].
• The mechanism of action of 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2) was examined in a human leukemia cell line (K562) and its Adriamycin (ADM)-resistant subline (K562/ADM) [16].
• Verapamil, a calcium antagonist, hardly augmented the cytotoxicity of MX2 against K562/ADM, and no distinct effect of this drug on both the time course and the maximal level of accumulation of MX2 was observed [3].

Regulatory relationships of MX2

• Both IDA and MX2 induced MDR1 expression within 4 h [13].

Other interactions of MX2

• In addition, the MMP15 and MX2 genes were identified, for the first time, as being commonly overexpressed in lung AdC cells [17].
• Mitoxantrone activated NFkappaB and stimulated IkappaBalpha degradation in the promyelocytic leukemia cell line HL60 but not in the variant cells, HL60/MX2 cells, which lack the beta isoform of topoisomerase II and express a truncated alpha isoform that results in an altered subcellular distribution [18].
• CONCLUSIONS: This study shows that filgrastim decreased the plasma clearance of MX2 by approximately 25%, possibly by inhibition of metabolism [19].

Analytical, diagnostic and therapeutic context of MX2

• The absence of topo II beta protein in nuclear and whole cell extracts from the HL-60/MX2 cells was associated with the virtual absence of detectable topo II beta mRNA in those cells by Northern blot analysis [7].
• PCR evaluation of the organization of the 3' region of the topo II alpha gene revealed that the 4.8-kb mRNA found in HL-60/MX2 cells diverges from that of the 6.3-kb mRNA at a consensus exon-intron splice donor site [6].
• Southern blot analysis of DNA extracted from the drug-sensitive and drug-resistant cells revealed a structural alteration in one topo II alpha allele in the HL-60/MX2 cells, but there was no evidence of rearrangement or hypermethylation of the topo II beta locus [7].
• Aberrant methylated CpG of Topo IIalpha gene was observed in K562/MX2 cells when compared with the parent line on methylation-specific restriction enzyme analysis [14].
• Confocal laser scanning microscopy demonstrated visually the good accumulation of MX2 in the implanted intracerebral C6 tumors, as well as its predominant distribution in the cytoplasm over the nucleus in both cell lines in vitro [8].

References