Mithramycins

Ahn SY, Cho CH, Park KG, Lee HI, Lee S, Park SK, Lee IK, Koh GY (2004) Tumor necrosis factor-alpha induces fractaUdne expression preferentially in arterial endothelial cells and mithramycin A suppresses TNF-alpha-induced fractaUdne expression. Am J Pathol 164 1663-1672 Alfano M, Schmidtmayerova H, Amelia CA, Pushkarsky T, Bukrinsky M (1999) The B-oligomer of pertussis toxin deactivates CC chemokine receptor 5 and blocks entry of M-tropic HIV-1 strains, [see comments]. J Exp Med 190 597-605 Ambrosini E, Alois F (2004) Chemokines and glial cells a complex network in the central nervous system. [Review] [239 refs]. Neurochem Res 29 1017-1038 Azuma Y, Ohura K (2002) Endomorphins 1 and 2 inhibit IL-10 and IL-12 production and innate immune functions, and potentiate NE-kappaB DNA binding in THP-1 differentiated to macrophagelike cells. Scand J Immunol 56 260-269... 

Ahn S Y, Cho CH, Park KG, et al. Tumor necrosis factor-alpha induces fractalkine expression preferentially in arterial endothelial cells and mithramycin A suppresses TNF-alpha-induced fractalkine expression. Am J Pathol 2004 164(5) 1663-1672. 

The answer is c. (Hardman, p 15230 Administration of intravenous CaG would immediately correct the tetany that might occur in a patient in whom a thyroidectomy was recently performed. Parathyroid hormone would act more slowly but could be given for its future stabilizing effect. Long-term control of a patient after a thyroidectomy can be obtained with vitamin D and dietary therapy Calcitonin is a hypocalcemic antagonist of parathyroid hormone. Plicamycin (mithramycin) is used to treat Paget s disease and hypercalcemia. The dose employed is about one-tenth the amount used for plicamycin s cytotoxic action. 

The answer is g. (Hardman, p 1268.) Plicamycin (mithramycin) can be used to treat hypercalcemia associated with malignancies Its mechanism of action involves inhibition of Ca reabsorption from bone, leading to a reduction in serum Ca levels. 

M. Sastry, and D. J. Patel, Solution structure of the mithramycin dimer-DNA complex, Biochem. 32 6588 (1993). 

Since the second complex contains two molecules of drug, therefore, we refer to it as dimer complex. Keeping in view the milli molar concentration of the metal ion present in the cell, possibility of the formation of dimer complex is more under in vivo conditions. However, in certain cases of cancer the metal ion concentration goes down to micro molar range. Under these unusual conditions, complex I is formed. Recently we have shown that mithramycin forms only dimer complex with Zn +, another metal ion playing an important role as cofactor in many enzymes and DNA binding proteins like transcription factors. 

Two approaches are usually taken to study the effect of the association of DNA binding anticancer drugs upon the structure of chromatin and nucleosome. The first one is reconstitution of the model nucleosome in the presence of the drugs. This has been reported earlier in the case of mithramycin (Fox and Cons, 1993 Carpenter et al., 1993). In our laboratory, so far we have taken the second approach of comparing the association of the anticancer drugs with isolated chromatin at various levels. 

Aich P, Dasgupta D (1990) Role of Mg(ll) in the Mithramycin-DNA interaction evidence for two types of Mithramycin-Mg(II) complex. Biochem Biophys Res Commun 173 689-696 Aich P, Dasgupta D (1995) Role of magnesium ion in mithramycin-DNA interaction binding of mithramycin-Mg + complexes with DNA. Biochemistr 34 1376-1385 Aich P, Sen R, Dasgupta D (1992a) Interaction between antitumor antibiotic Chromomycin A3 and Mg(ll) 1. Evidence for the formation of two types of Chromomycin A3-Mg(ll) complexes. Chem Biol Interact 83 23-33... 

Chakrabarti S, Bhattacharyya D, Dasgupta D (2000-2001) Structural basis of DNA recognition by anticancer antibiotics, chromomycin A3 and mithramycin roles of minor groove width and ligand flexibility. Biopolymers 56(2) 85-95... 

Fitzgerald DJ, Anderson JN (1999) Selective nucleosome disruption by drugs that bind in the minor groove of DNA. J Biol Chem 274(38) 27128-27138 Fox KR, Cons BM (1993) Interaction of mithramycin with DNA fragments complexed with nucleosome core particles comparison with distamycin and echinomycin. Biochemistry. 32(28) 7162—7171 Friedman HS, Kerby T, Calvert, H (2000) Temozolomide and treatment of malignant gliomas. CUn Cancer Res 6 2585-2597... 

Keniry MA, Banville DL, Simmonds PM, Shafer RH (1993) Nuclear magnetic resonance comparison of the binding sites of mithramycin and chromomycin on the self-complementary oUgonucleotide d(ACCCGGGT)2. Evidence that the saccharide chains have a role in sequence specificity. J Mol Biol 31 753-767... 

Mir MA, Dasgupta D (2001a) Interaction of antitumor drug, mithramycin, with chromatin, Biochem. Biophys Res Commun 280 68-74... 

Saenger W (1984) Principles of nucleic acid structure. Springer-Verlag, New York Sastry M, Fiala R, Patel DJ (1995) Solution structure of mithramycin dimers bound to partially overlapping sites on DNA. J Mol Biol 251 674-689 Schafer S, Jung M (2005) Chromatin modifications as targets for new anticancer drugs. Arch Pharm (Weinheim) 338(8) 347-357... 

Synder RC, Ray R, Blume S, Miller DM (1991) Mithramycin blocks transcriptional initiation of the c-myc PI and P2 promoters. Biochemistry 30 4290-4297 Szyf M (2003) DNA methylation and cancer therapy. Drug Resist Updat 6(6) 341—353 Szyf M, Pakneshan P, Rabbani SA (2004) DNA demethylation and cancer therapeutic implications. 

Wohlert SE, Kunzel E, Machinek R, Mendez C, Salas JA, Rohr J (1999) The structure of mithramycin reinvestigated. J Nat Prod 62 119-121... 

After intracellular and surface staining are complete, it is often possible to utilize a stain for nucleic acids, such as propidium iodide (PI), DAPI, mithramycin, or... 

There are other fluorochromes that can be used for DNA analysis. The following three are the most straightforward and reproducible with regard to application mithramycin, 4, 6-diamidino-2-phenylindole hydrochloride (DAPI), and Hoechst 33258. Concentrations must be determined empirically (see Chapter 30). 

Actinomycin D, Antibiotic 205-2B, Blasticidin, Cycloheximide(actidione), Daunomycin DPB, Mithramycin, Mitomycin C, Pentaene G8, and Tubercidin. 

Mithramycin (24) bears the terminal sugar unit -mycarose. By a similar preparation as for the methyl-branched glycals and the -enantiomer of namely the labile g-mycaral 40 w s obtained ( ). Its NIS condensation with the 3, 4 -Saol disaccharide proceeds smoothly, but the reaction turned out to be rather slow with respect to the stability of the g-mycaral. This results in only a modest yield (12%) of the trisaccharide which was hydrogenolyzed to compound 4. This in turn constitutes an isomer of the trisaccharide sequence in... 

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