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PubMed1996

Sinefungin and taxol effects on cell cycle and cytoskeleton of Leishmania donovani promastigotes.

Sinefungin is an antibiotic possessing a strong anti-leishmanial activity. Among the most important effects of this molecule on Leishmania donovani promastigotes are morphological modifications and a very rapid and effective inhibition of DNA synthesis. These cells contain a single DNA-rich mitochondrion whose division cycle is coordinated with the nuclear division cycle. We have developed a flow-cytometric procedure based upon mithramycin as fluorochrome that can perform quantitative cell cycle analysis on the nuclear DNA. Cell cycle progression was analyzed to establish that sinefungin irreversibly blocks the promastigotes in early S phase. Sinefungin did not react with stationary cells as they were arrested in G1. Surprisingly, taxol, a microtubule-stabilizing drug, induced the same morphological modifications as sinefungin although it interfered with the G2/M progression. According to immunofluorescence studies, the stable microtubular network is apparently affected neither by taxol nor by sinefungin.

Actins↗
PubMed1993

Nuclear magnetic resonance comparison of the binding sites of mithramycin and chromomycin on the self-complementary oligonucleotide d(ACCCGGGT)2. Evidence that the saccharide chains have a role in sequence specificity.

A comprehensive two-dimensional 1H nuclear magnetic resonance spectral analysis of the ternary 4:2:1 mithramycin-Mg2+-d(A1C2C3C4G5G6G7T8)2 complex and the ternary 2:1:1 chromomycin-Mg(2+)-d(A21C2C3C4C4G5G6G7T8)2 complex is presented. The self-complementary oligonucleotide is found to bind two dimers of mithramycin in two identical off-center binding sites such that the twofold symmetry of the oligonucleotide is retained. In contrast, the same oligonucleotide binds only one dimer of chromomycin in a single but distinct off-center binding site. Two-dimensional nuclear Overhauser spectroscopy experiments show that the aglycone binding site of the drug dimer in each complex extends over almost four base-pairs and is similar in length to other complexes between chromomycin or mithramycin and oligonucleotides. The data demonstrate that the chromomycin dimer binding site is offset by one base-pair step from the dimer binding site in the mithramycin complex. This preferred binding site prevents two dimers of chromomycin binding to d(ACCCGGGT)2 for steric reasons and lends further support to previous work that showed the 5'-CG base-pair site is less favored by these drugs compared to the 5'GC and 5'-GG,5'-CC sites. Evidence is presented that suggests mithramycin may occupy either of two distinct binding sites on d(ACCCGGGT)2 when the drug concentration is not saturating. The nuclear magnetic resonance data demonstrate that the saccharide chains of this family of drugs do have a role in determining the binding site on nucleotides and as a consequence the CDE trisaccharide chain may alter its conformation to fulfil this role. 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.

Binding Sites↗
PubMed1995

Solution structure of mithramycin dimers bound to partially overlapping sites on DNA.

Mithramycin (MTH) is a DNA-binding antitumor agent containing A-B disaccharide and C-D-E trisaccharide segments projecting from opposite ends of an aglycone chromophore. We have previously reported on the solution structure of the MTH-DNA 6-mer complex based on a combined NMR and molecular dynamics study. This study established that the Mg(2+)-coordinated mithramycin dimer bound to a widened minor groove centered about the sequence-specific (G-C).(G-C) site and that the C-D-E trisaccharide segments from individual monomers were directed towards opposite ends of the helix spanning a six base-pair segment. This research is now extended to the binding of mithramycin dimers to partially overlapping sites on the self-complementary d(T-A-G-C-T-A-G-C-T-A) 10-mer duplex. The six base-pair mithramycin dimer footprint centered about (G-C).(G-C) steps should result in a potential steric clash in the center of the helix involving the inwardly pointing E-sugars of the pair of mithramycin dimers bound to the DNA 10-mer duplex. The MTH-d(T-A-G-C-T-A-G-C-T-A) complex (two MTH dimers per duplex) yields narrow and well-resolved NMR spectra, which have been assigned to identify intramolecular and intermolecular nuclear Overhauser enhancement (NOE) connectivities in the complex. The solution structure of the MTH-DNA 10-mer complex based on distance-restrained molecular dynamics calculations has defined the conformation of the drug and the DNA necessary for accommodation of the pair of mithramycin dimers on the DNA 10-mer helix. Specifically, the inwardly pointing E-sugars retain their face-down alignment towards the floor of the minor groove and occupy adjacent binding sites in the center of the duplex. This is achieved, in part, through torsion angle differences in the glycosidic linkage bonds along the length of the inwardly pointing aglycone-C-D-E trisaccharide segment relative to its outwardly pointing aglycone-C-D-E trisaccharide counterpart in the complex. In addition, a pronounced kink at the central (T-A).(T-A) step opens the minor groove and generates additional space to accommodate the inwardly pointing E-sugars at adjacent sites in the MTH-DNA 10-mer complex. These studies establish conformational plasticity in the C-D-E trisaccharide segment of the mithramycin dimer and deformability of the DNA helix allowing mithramycin dimers to bind to partially overlapping minor groove sites on the DNA helix.

Base Composition↗
PubMed1982

Nonintercalative DNA-binding antitumour compounds.

A family of compounds which appear to bind reversibly to double stranded DNA without intercalation between DNA base pairs has been defined. Methods are described by which this non-intercalative binding can be characterised using ultraviolet spectrometry, fluorimetry with ethidium as a probe, viscometry and other hydrodynamic techniques, circular dichroism and nuclear magnetic resonance spectrometry. Antibiotics which fall into this family include the antibiotics distamycin A, netropsin, mithramycin, chromomycin and olivomycin. Synthetic antitumour agents include diarylamidines such as berenil, phthalanilides, aromatic bisguanylhydrazones and bisquaternary ammonium heterocycles. A survey has been made of the general requirements of this family of compounds for DNA binding and biological activity. Binding of drugs to the minor groove of the DNA double helix appears to be the most likely mechanism for the antitumour action of these compounds.

Amidines↗
PubMed1980

On the structure and polymorphism of the human chromosome no. 15.

Chromosome preparations from 67 randomly selected healthy individuals were consecutively stained with silver, mithramycin, pentamidine-DAPI, and quinacrine mustard. In the short arm of the chromosome 15 up to six regions, which were highly polymorphic, apparently independently of each other, could be detected by the given methods. The frequency of occurrence of each individual polymorphic feature in the population investigated ranges from 70% to 87%. They appear randomly and independently of each other.

Chromosome Banding↗
PubMed1976

Reverse fluorescent chromosome banding with chromomycin and DAPI.

Two DNA binding guanine-specific antibiotics, chromomycin A3 (CMA) and the closely related mithramycin (MM), were used as chromosome fluorescent dyes. Root-tip metaphase chromosomes of three plant species and human metaphase chromosomes were sequentially stained with CMA or MM and the DNA binding AT-specific fluorochrome 4'-6-diamidino-2-phenylindole (DAPI). In some cases a non-fluorescent counterstain was used as contrasting agent: methyl green in conjunction with CMA, and actinomycin D (AMD) in combination with DAPI.--In all three plant species, Vicia faba, Scilla siberica, and Ornithogalum caudatum, the nucleolus organiser regions and/or associated heterochromatin displayed very bright fluorescence with CMA and MM and, in general, heterochromatic segments (C-bands) which were bright with CMA and MM were pale with DAPI whereas segments which were dim with CMA and MM displayed very bright fluorescence with DAPI.--Human metaphase chromosomes showed a small longitudinal differentiation in CMA fluorescence, which was essentially the reverse of the banding pattern obtained with AMD/DAPI double-staining, but of lower contrast. The cma-banding pattern appears to be similar to the pattern found by R-banding procedures.

Amidines↗
PubMed1988

Evolutionary diversity of reverse (R) fluorescent chromosome bands in vertebrates.

Mitotic chromosomes, interphase cell nuclei, and male meiosis of 41 species representing all vertebrate classes were analyzed with distamycin A/mithramycin counterstaining. The purpose of the study was to recognize differences and common characteristics in the reverse (R) fluorescent banding patterns in the chromosomes of vertebrate species at various stages of evolution. In contrast to the warm-blooded mammals and birds, the euchromatic segments in the chromosomes of most reptiles, amphibians, and fishes contain no multiple fluorescent R-bands. This is thought to be due to the absence of the long homogeneous regions (isochores) in the DNA of the cold-blooded vertebrates. Distamycin A/mithramycin banding specifically reveals the GC-rich constitutive heterochromatin in all vertebrates. In most of the vertebrate chromosomes examined, the heterochromatic regions have opposite staining properties with mithramycin and quinacrine. Mithramycin labels the nucleolus organizer regions very brightly in the karyotypes of fishes, amphibians, reptiles and birds, but not of mammals. The lack of mithramycin fluorescence at the nucleolus organizer regions of mammals is attributed to the relatively low level of redundancy of the GC-rich ribosomal DNA in their genomes. Studies on the various meiotic stages of the cold-blooded vertebrates show that the mithramycin labeling of the nucleolus organizers is independent of their state of activity. This can be confirmed by mithramycin fluorescence at the nucleoli of actinomycin-treated cells.

Animals↗
PubMed1977

Mithramycin and DIPI: a pair of fluorochromes specific for GC-and AT-rich DNA respectively.

The AT specificity of the fluorochromes DIPI and DAPI and the GC specificity of mithramycin are evidenced by observations in human, mouse, and bovine chromosomes. DIPI and DAPI produce a pattern similar to Hoechst 33258 in all three species, whereas mithramycin results in a reverse pattern. The AT-rich centromeric heterochromatin in mouse is brilliantly stained by DIPI or DAPI and remains nearly invisible after mithramycin staining. In the GC-rich centromeric heterochromatin of cattle the opposite behavior is observed.

Animals↗
PubMed1978

Selective excitation of mithramycin or DAPI fluorescence on double-stained cell nuclei and chromosomes.

Fluorescence spectra of leukocytes stained by both mithramycin and DAPI showed that the fluorescence of the two dyes can be separated efficiently by using different excitation wavelengths, for instance the 435 nm and the 365 nm mercury lines. In human chromosomes the complementary ("reverse") banding pattern produced by these dyes may thus be observed on double stained chromosome spreads. In plants, for instance in Anemone blanda, the two dyes may reveal two different banding patterns. The results of absorption and fluorescence measurements suggest the existence of at least two binding sites, or types, for each dye, with different fluorescent yields and binding strengths.

Amidines↗
PubMed1980

Effects of preparation and fixation on three quantitative fluorescent cytochemical procedures.

A series of experiments was undertaken in which cells dissociated from the abdominal lymph nodes of mice were lightly centrifuged into slides and fixed either wet or after drying in 70% ethanol, 1% glutaraldehyde, 1% formaldehyde, or neutral formalin. Three fluorescent cytochemical methods were evaluated: staining of DNA with mithramycin; fluorochroming of basic groups of proteins with brilliant sulfaflavine (BSF); and staining of sulfhydryl and disulfide groups with N-(7-dimethylamino-4-methylcoumarinyl)maleimide (DACM). In the case of mithramycin, the best results were obtained after fixation in 70% ethanol without drying. Staining of dried preparations fixed in 1% glutaraldehyde also yielded reasonably consistent results, although the fluorescence was lower, and the variability higher, than in the group fixed without drying in 70% ethanol. The use of fixatives containing formaldehyde resulted in fluorescence values of only about one-third those of the other two groups, and the variability of the data was higher. In material stained with BSF, satisfactory results were obtained in preparations fixed without drying in neutral formalin containing mersalyl acid. Other fixatives could be used, but the resulting coefficients of variation were higher than those of formalin-fixed material. Sulfhydryl to disulfide ratios approaching those expected from biochemical evidence were obtained in DACM-stained material only after fixation without drying in neutral formalin containing mersalyl acid. Inverted sulfhydryl-disulfide ratios were observed in material fixed without drying in 70% ethanol; and in dried material fixed in 1% formaldehyde, neutral formalin, or 1% glutaraldehyde.

Animals↗
PubMed1975

Furosemide, mithramycin, and salmon calcitonin in hypercalcemia.

Twenty-nine patients with acute hypercalcemia secondary to carcinoma, myeloma and parathyroid adenoma have been treated with large doses of furosemide, mithramycin, or salmon calcitonin perfusion. With furosemide administration the treatment was successful in 6 of 10 patients. Furosemide was injected intravenously at the rate of 125 mg every 3 hours. With mithramycin perfusion only 2 of 8 patients have a return of the serum calcium levels to normal. With salmon thyrocalcitonin 3 of 10 patients obtained a good result. It can be interesting to suggest the association of furosemide and salmon calcitonin infusion to treat hypercalcemia of myeloma.

Adenoma↗
PubMed1982

The use of percoll gradients, elutriator rotor elution, and mithramycin staining for the isolation and identification of intraerythrocytic stages of plasmodium berghei.

Intraerythrocytic parasites of Plasmodium vinckei and Plasmodium berghei were separated according to their developmental stages using discontinuous Percoll gradients. Contaminating nucleated blood cells such as leukocytes were removed by elutriation centrifugation. The stages were unequivocally identified in smears using a newly developed DNA-specific staining procedure with mithramycin and fluorescence microscopy. This stain can also be used to detect parasites in human blood of very low parasitemias. The combination of methods described has many possible applications in immunologic and biochemical parasite research.

Animals↗
PubMed1978

Effect of mithramycin on bone beta-glucuronidase and resorption.

Mithramycin suppresses bone resorption. Its effect on the synthesis and release of beta-glucuronidase (a referent for lysosomal enzymes) in mouse calvarial explants was studied in an in vitro culture system. A newly described medium (designated as KT medium) was introduced in this specific study. Mithramycin initially inhibited the release of beta-glucuronidase into the medium and resulted in an ultimate accumulation of this enzyme in the bone. These results suggest that inhibition of bone resorption by mithramycin may be attributed to interference in release of lysosomal enzymes from bone cells.

Animals↗