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At least 163 records · Page 9Linked to original sources
PubMed1983

Comparative study of available medical therapy for hypercalcemia of malignancy.

The relative efficacy of five drugs in the treatment of hypercalcemia of malignancy was assessed in a randomized study. The drugs were oral phosphate, mithramycin, glucocorticoids, indomethacin, and ethane-1-hydroxy-1, 1-diphosphonate (EHDP). No single agent was universally effective. Oral phosphate and mithramycin were the most efficacious, each producing a decrease in serum calcium concentrations in four of five patients, although there were serious disadvantages with the use of each. Glucocorticoids were effective in only two of five patients who received randomized treatment. A further five patients received nonrandomized treatment with glucocorticoids, and only three of these showed response. Indomethacin was effective in only one of five patients to whom it was given, and EHDP was effective also in only one of five patients. The new diphosphonate, 3-amino-1-hydroxypropane-1, 1-diphosphonate (APD) was evaluated in the treatment of hypercalcemia in 13 patients with malignant disease and two with primary hyperparathyroidism. APD caused a significant decrease in serum calcium concentration in nine of 12 patients within 72 hours. These results indicate that there is no currently available pharmacologic agent that is entirely satisfactory in the treatment of hypercalcemia. The most effective agents were mithramycin, oral phosphate, and APD. Glucocorticoids and orally administered EHDP showed limited effectiveness, and indomethacin was ineffective in the majority of patients.

Administration, Oral↗
PubMed1983

Therapy of malignancy-associated hypercalcemia: 1983.

Hypercalcemia is common among patients with cancer and may be due to secretion by tumors of a humoral, calcemic, bone-resorbing factor or, alternatively, to skeletal metastases. In each case, hypercalcemia ultimately results from osteoclastic bone resorption. Therapy should be aimed at (1) reducing or eliminating tumor burden, (2) increasing renal calcium clearance, and (3) inhibiting osteoclastic bone resorption. Hydration with saline infusion and augmentation of calciuresis with furosemide should be the initial modes of therapy in most patients. Oral phosphorus should be used in hypophosphatemic patients. Glucocorticoids, calcitonin, and prostaglandin synthetase inhibitors may be effective in reducing bone resorption in selected patients. Mithramycin reliably induces a fall in serum calcium but long-term use is usually complicated by toxicity. A new class of drugs that inhibit osteoclastic bone resorption, the diphosphonates, is being employed in clinical trials in patients with malignancy-associated hypercalcemia. Results have been particularly promising with dichloromethylene diphosphonate.

Administration, Oral↗
PubMed1988

Selective inhibition of c-myc expression by the ribonucleic acid synthesis inhibitor mithramycin.

Expression of the c-myc proto-oncogene has been shown to correlate with the rate of cellular proliferation and malignant transformation in a number of cell types. JEG-3 choriocarcinoma cells demonstrate c-myc transcript levels that are greater than those of nonmalignant trophoblastic tissue at any stage of gestation. Southern blot analysis documents c-myc gene amplification in JEG-3 cells, with a gene copy number of approximately 20. The methylation pattern and genomic structure of the amplified c-myc oncogene in JEG-3 choriocarcinoma cells are identical to those of normal placenta. Treatment of JEG-3 cells with mithramycin, a ribonucleic acid synthesis inhibitor, results in a dramatic decrease in c-myc expression relative to that of the c-Ha-Ras gene. The apparent selectivity of mithramycin for c-myc expression represents the only example, to date, of the selective pharmacologic modulation of oncogene expression.

Cell Line↗
PubMed1989

Interaction of mithramycin with metal ions and DNA.

The interaction of mithramycin with metal ions has been studied by absorbance and fluorescence spectroscopy. Magnesium shifts the drug absorbance spectrum to longer wavelengths and displays a weak binding constant (Kd = 1mM); no interaction with calcium was detected. The drug requires magnesium for binding to DNA and this is characterised by small additional hypochromic and bathochromic changes. Mithramycin does not bind to DNA in the presence of calcium. With 10mM magnesium the drug binds to DNA with an association constant of 9.2 x 10(4) M-1. The inability of calcium to substitute for magnesium has been confirmed by 'footprinting' experiments using both DNase I and hydroxyl radicals.

Base Sequence↗
PubMed1990

Effects of sequence selective drugs on the gel mobility of a bent DNA fragment.

The effects of various drugs on the structure of a bent DNA fragment have been investigated by studying DNA mobility in polyacrylamide gels. This DNA fragment has an anomalously slow rate of migration on account of its phased runs of adenines. Nogalamycin and echinomycin increase the gel mobility of kinetoplast DNA suggesting that the bending has been removed. Mithramycin, actinomycin, distamycin and ethidium have either no effect or cause a further reduction in mobility. These results are compared with other, non-bent DNA species which always show a decrease in gel mobility in the presence of DNA binding drugs.

Adenine↗
PubMed1991

Mithramycin cannot bind to left-handed poly(dG-m5dC) in the presence of Mg2+ ion.

Mithramycin (MTR) is an antitumor compound that inhibits RNA and DNA polymerase action by forming a non covalent complex with double strand DNA, in the presence of divalent cations. We have shown that in the presence of Mg2+, MTR binds to right-handed poly(dG-m5dC) as a dimer in the right-handed screwness conformation but cannot bind to left-handed poly(dG-m5dC).

Calcium↗
PubMed1992

In vitro inhibition of c-myc transcription by mithramycin.

Mithramycin is a DNA-binding antibiotic that has been reported to selectively affect c-myc expression [Snyder, R. C. et al., (1991) Biochemistry 30, 4290-4297]. We used in vitro transcription to investigate the specificity of mithramycin action. We found that mithramycin inhibited transcription from the human c-myc P1 and P2 promoters, as well as from a minimal adenovirus-2 major late promoter, with equal efficiencies. Mithramycin also inhibited transcription elongation by creating kinetic blockades to the passage of RNA polymerase II. These data suggest that mithramycin may inhibit transcription non-specifically by affecting general processes such as transcription elongation.

Genes, myc↗
PubMed1985

Free radical damage to deoxyribose by anthracycline, aureolic acid and aminoquinone antitumour antibiotics. An essential requirement for iron, semiquinones and hydrogen peroxide.

Anthracycline, aureolic acid and aminoquinone antitumour antibiotics damage deoxyribose in cell-free systems when reduced in air by the enzyme ferredoxin reductase. Damage to deoxyribose is inhibited by the iron chelator desferrioxamine, the copper-containing protein caeruloplasmin and catalase but not by superoxide dismutase. Scavengers of the hydroxyl radical such as formate, butan-1-ol, ethanol and benzoate do not offer much protection, whereas mannitol and thiourea do. These findings point to a site-specific Fenton reaction in which the drug semiquinones reduce complexed iron and dioxygen leading to the formation of hydrogen peroxide and a ferrous complex.

Antibiotics, Antineoplastic↗
PubMed1993

Synthesis of the C'D' disaccharide of aureolic acid.

Arylbis(arylthio)sulfonium salts have been used to activate glycals towards nucleophilic addition to form principally 2-deoxy-beta-glycosides. This method was applied to the synthesis of the 2-(methylphenylthio)-2'-phenylthio derivative (22) of methyl O-(4-O-benzyl-2,6-dideoxy-beta-D-arabino- hexopyranosyl)-(1-->3)-3,4-di-O-benzyl-2,6-dideoxy-2,6-beta-D-arabino- hexopyranoside, the C'D' ring analog of an aureolic acid disaccharide. The condensation of 1,5-anhydro-2,6-dideoxy-D-arabino-hex-1-enitol with methanol in the presence of the phenylbis(phenylthio)sulfonium salt resulted in formation of the first beta-glycoside linkage. The methyl 6-deoxyglucoside obtained was deprotected at HO-3 to give the 2-thiophenyl-substituted 2,6-dideoxy-beta-glucoside. This was coupled with 1,5-anhydro-3,4-di-O-benzyl-2-deoxy-D-arabino-hex-1-enitol in the presence of 4-methylphenyl[bis(4-methylphenyl)thio]sulfonium salt to give the (1-->3)-linked disaccharide 22. Finally, desulfurization of 22 using WII Raney nickel generated the required 2,2'-dideoxydisaccharide.

Carbohydrate Sequence↗