Disease relevance of MITHRAMYCIN

• Toxic epidermal necrolysis after mithramycin [1].
• Mithramycin for hypoglycemia in malignant insulinoma [2].
• Antibiotic-producing polyketide synthases (PKSs) are enzymes responsible for the biosynthesis in Streptomyces and related filamentous bacteria of a remarkably broad range of bioactive metabolites, including antitumour aromatic compounds such as mithramycin and macrolide antibiotics such as erythromycin [3].
• A patient with chronic granulocytic leukemia in acute blastic transformation was treated with mithramycin, an RNA synthesis inhibitor, after in vitro exposure of her leukemic cells to mithramycin showed differentiation to normal appearing granulocytes [4].
• Maytansine and vincristine were given to CDF1 mice with P388 leukemic ascites, and the cytokinetic response of the tumor cells was analyzed with a flow microfluorometer; mithramycin was used as the DNA fluorochrome [5].

Psychiatry related information on MITHRAMYCIN

• Chemotherapy for the brain: the antitumor antibiotic mithramycin prolongs survival in a mouse model of Huntington's disease [6].

High impact information on MITHRAMYCIN

• Mithramycin selectively inhibits collagen-alpha 1(I) gene expression in human fibroblast [7].
• At a concentration of 100 nM, mithramycin efficiently reduces basal and TGF-beta-stimulated alpha 1(I) gene expression in human primary fibroblasts [7].
• Promoter-dependent in vitro transcription of a DHFR template is selectively inhibited by mithramycin when compared to the human H2b histone gene [8].
• The G-C specific DNA binding drug, mithramycin, binds to both consensus sequences and prevents subsequent Sp1 binding [8].
• Each of the six Sp1 binding sites of this promoter is protected from DNAse 1 digestion by mithramycin binding [9].

Chemical compound and disease context of MITHRAMYCIN

• Three structurally related anticancer drugs, mithramycin, chromomycin A3, and olivomycin, exhibited large differences (greater than 100-fold) in their toxicity towards cultured cells from various species [10].
• To gain initial structure-activity relationships regarding the highly functionalized pentyl side chain attached at C-3 of mithramycin (MTM), we focused on a post-polyketide synthase (post-PKS) tailoring step of the MTM biosynthesis by Streptomyces argillaceus ATCC 12956, which was proposed to be catalyzed by ketoreductase (KR) MtmW [11].
• Formation of a diolivosyl derivative in the mithramycin producer Streptomyces argillaceus was found to require the cooperative action of two mithramycin glycosyltransferases (MtmGI and MtmGII) responsible for the formation of the diolivosyl disaccharide, which is then transferred by ElmGT to 8-DMTC [12].
• Potentiation of the toxicity of mithramycin by bacterial lipopolysaccharide [13].
• Several measures are available to reduce bone resorption, of which the most efficacious are the bisphosphonates and plicamycin (mithramycin) [14].

Biological context of MITHRAMYCIN

• Mithramycin binding to the G-C rich sequences in the SV40 early promoter prevents subsequent protein binding to these sequences [9].
• Mithramycin blocks protein binding and function of the SV40 early promoter [9].
• These observations indicate that mithramycin can induce differentiation both in vitro and in vivo and suggest that such changes may be associated with altered oncogene expression [4].
• This suggests that mithramycin prevents transcriptional activation of the SV40 early promoter by blocking binding of transcriptional activating proteins to G-C rich promoter regions [9].
• Together, these results suggest that mithramycin A and its structural analogs may be effective agents for the treatment of neurological diseases associated with aberrant activation of apoptosis and highlight the potential use of sequence-selective DNA-binding drugs as neurological therapeutics [15].

Anatomical context of MITHRAMYCIN

• The gel retardation of the SV40 early promoter fragment incubated with a HeLa cell extract is completely abrogated by pretreatment of the DNA fragment with mithramycin [9].
• K562 cells were exposed to 0.25-2.0 micrograms of doxorubicin/mL for up to 60 minutes at 37 degrees C. Commencing within 15 minutes, leukoregulin increased the entry of doxorubicin approximately twofold and the uptake of mitomycin, mithramycin, and propidium iodide twofold to tenfold [16].
• Mithramycin inhibits myointimal proliferation after balloon injury of the rat carotid artery in vivo [17].
• METHODS AND RESULTS--Ten-week-old male Sprague-Dawley rats received mithramycin (150 micrograms/kg IP) or distilled H2O 1 hour before and 1 hour after balloon injury of the right common carotid artery [17].
• Mithramycin induces fetal hemoglobin production in normal and thalassemic human erythroid precursor cells [18].

Associations of MITHRAMYCIN with other chemical compounds

• Footprinting patterns reveal that the binding sites for AT- or GC-specific antibiotics (distamycin or mithramycin, respectively) are completely changed in the modified DNAs, as expected for direct sequence readout involving contact with the purine 2-amino group [19].
• The combined pharmacological treatment with mithramycin and cystamine down-regulates ESET gene expression and reduces hypertrimethylation of histone H3 (K9) [20].
• Tumor necrosis factor-alpha induces fractalkine expression preferentially in arterial endothelial cells and mithramycin A suppresses TNF-alpha-induced fractalkine expression [21].
• Evaluation by flow cytometry after staining with acridine orange or mithramycin indicated that PGE2 had no effect on initial B cell entry into the G1 phase of the cell cycle, passage through G1, and entry into S, G2, and M [22].
• The preferred binding sites for mithramycin on three different DNA fragments have been determined by hydroxyl radical footprinting [23].

Gene context of MITHRAMYCIN

• We show that these GC boxes are binding sites for Sp-family transcription factors and are functionally important since mithramycin, an inhibitor of Sp1/Sp3 binding, blocks MUC2 gene expression in HT29 cells [24].
• Western blot analysis also demonstrated an increase in cellular amounts of VEGF by TNF-alpha and a decrease by co-administration with mithramycin [25].
• Endogenous HDAC4 mRNA, protein levels and promoter activity were all readily repressed by mithramycin, suggesting regulation by GC-rich DNA sequences [26].
• Mithramycin, an inhibitor of binding of nuclear transcription factor Sp1 to the promoter consensus sequence, blocked activation of VEGFR-2, suggesting that the up-regulation of the receptor required Sp1 binding sites [27].
• Indeed, mithramycin blocked TGF-beta-stimulated Sp1 binding activity [28].

Analytical, diagnostic and therapeutic context of MITHRAMYCIN

• Here, we demonstrate that the DNA binding drug mithramycin displays a high affinity binding to the GC-rich elements in the collagen-alpha 1(I) promoter as measured by DNAse I protection and gel retardation assays [7].
• This was shown by the lack of cytotoxicity on erythroid and myeloid in vitro primary cell cultures treated with mithramycin at concentrations effective for HbF induction [18].
• Each histogram was obtained by flow microfluorimetry, using the DNA-specific fluorochrome, mithramycin [29].
• A sensitive enzyme immunoassay for mithramycin (MTM) has been developed by using antibody induced in rabbits, beta-D-galactosidase-labeled MTM, and a double-antibody separation technique, which allowed us to measure accurately as little as 100 pg of MTM per assay tube [30].
• Titration of mithramycin up to a drug-duplex ratio of 7:1 reveals further association of mithramycin with the complex but no new drug-oligonucleotide nuclear Overhauser enhancement contacts [31].

References