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At least 217 records · Page 12Linked to original sources
PubMed1986

Effects of actinomycin D on localization of acridine orange chromatin interaction complex in rat astrocytoma C6 cells.

The purpose of this study was to examine the effects of actinomycin D on localization of acridine orange (AO) binding to DNA in rat astrocytoma C6 cells and to discuss briefly the significance of AO chromatin interaction products. Actinomycin D markedly inhibited 3H-uridine incorporation into RNA and the percentage of AO positive cells was reduced to approximately 40% of that of the untreated control cells, whereas no distinct decrease of 3H-thymidine incorporation was induced by actinomycin D. Electron microscopic radioautography combined with the AO ultracytochemistry revealed that silver grains indicating binding of 3H-actinomycin D are located mostly over the euchromatin portion near the segregated nucleolus and heterochromatin and that no or only a few AO chromatin complex was found in nuclei labeled heavily with 3H-actinomycin D. These results of the present study together with the results of the previous studies seem to indicate that AO might selectively bind to active or derepressed DNA template sites for DNA dependent RNA polymerase in the euchromatin portion of the cell nucleus.

Acridine Orange↗
PubMed1977

Novel actinomycins formed by biosynthetic incorporation of cis- and trans-4-methylproline.

Streptomyces parvulus (Streptomyces parvullus) normally produces actinomycin D; in the presence of cis-4-methylproline, this species synthesizes two additional actinomycins, designated K(1c) and K(2c), in which one and two proline sites, respectively, are occupied by cis-4-methylproline. Analogously, actinomycins K(1t) and K(2t) are formed in the presence of trans-4-methylproline. Both mixtures were separated chromatographically, and the four novel actinomycins were obtained in crystalline form. Their biological activities were compared with that of actinomycin D in respect to inhibition of ribonucleic acid, deoxyribonucleic acid, and protein synthesis and antimicrobial potency. In all cases examined, the order of activity D > K(1t) > K(1c) > K(2t) > K(2c) was observed, and the same sequence prevailed in a spectroscopic measure of their binding to deoxyribonucleic acid. In addition, proton nuclear magnetic resonance studies revealed that the replacement of proline by cis-4-methylproline alters the conformation of the antibiotic molecule.

Bacillus subtilis↗
PubMed1977

Relationship between changes in the translational apparatus and actinomycin production in Streptomyces antibioticus.

As previously reported (G. H. Jones, 1975), transfer ribonucleic acids (tRNA's) and ribosomes from actinomycin-producing cultures of Streptomyces antibioticus show a decreased ability to function in aminoacylation and translation as compared with the corresponding components from younger cells. Further, specific changes in the isoacceptor patterns are revealed when tRNA's from actinomycin-producing cells are compared with those of younger cells by reverse- phase column chromatography. A specific glycyl-tRNA species is eliminated from the reverse-phase profile of tRNA's from actinomycin-producing S. antibioticus cells as compared with younger cells. Changes in isoacceptor patterns were also observed for the amino acids methionine, valine, phenylalanine, and leucine. Actinomycin synthesis was inhibited by growing S. antibioticus cells in the presence of alpha-methyl-DL-tryptophan. Inhibition of actinomycin synthesis reversed the changes in tRNA observed in normally grown control cultures, although it had no demonstrable effect on the growth of the cells. Thus, tRNA from 48-h-old, alpha-methyl-tryptophan-grown cells had amino acid acceptor activity that was equal to or greater than that of tRNA from 12-h-old, normally grown cells. Similarly, the reverse-phase chromatographic pattern for glycyl-tRNA's from 48-h-old, alpha-methyl-tryptophan-grown cells was identical to that of the glycyl-tRNA's from 12-h-old, normally grown cells. In contrast, the ability of ribosomes from 48-h-old, alpha-methyl-tryptophan-grown cells to function in polypeptide synthesis in vitro was essentially identical to that of 48-h-old, normally grown cells. Ribosomes from 12-h-old, normally grown cells were severalfold more active in in vitro polypeptide synthesis.

Bacterial Proteins↗
PubMed1967

Effect of actinomycin D on virus-induced ribonucleic acid polymerase formation in foot-and-mouth disease virus-infected baby hamster kidney cells.

Actinomycin D, at a concentration that inhibits cellular ribonucleic acid (RNA) synthesis, inhibited the production of foot-and-mouth disease virus-induced RNA polymerase in baby hamster kidney cells. Inhibition was proportional to exposure time and reached 85% when actinomycin D was added 90 min before infection. Polymerase production was inhibited to the same extent in growth and minimal media, and the kinetics of its appearance were slightly different than in untreated cells. Enzyme preparations from actinomycin-treated cells having one-third to one-tenth the activity of untreated samples gave products with RNA profiles similar to those of controls. The 37S viral peak, 20S ribonuclease-resistant peak, and 26 to 28S peaks were present in all cases. Actinomycin D did not consistently inhibit virus production in either medium. Insulin did not prevent the actinomycin induced inhibition of polymerase and virus production from occurring.

Animals↗
PubMed1988

Effect of actinomycin D and cycloheximide on replication of Sindbis virus in Aedes albopictus (mosquito) cells.

Production of Sindbis virus in the presence of transcription and translation inhibitors was examined in three Aedes albopictus cell lines. Addition of cycloheximide to heat-resistant Sindbis virus (SVHR)-infected mosquito cells arrested viral RNA synthesis completely, in contrast to the effects of this drug on virus-infected vertebrate cells. Production of mature virus by both SVHR (a variant commonly used as a wild-type virus) and SBamr (a mutant which is resistant to the effects of 18 h of pretreatment of vertebrate cells with actinomycin D) in mosquito u4.4, C6-36, and C7-10 cells was inhibited by 2 h of pretreatment with actinomycin D. Pretreatment with this drug for 2 h slightly enhances virus production in vertebrate cells. Treatment of mosquito cells with actinomycin D resulted in shutoff of SVHR RNA synthesis. The mutant SBamr was able to overcome the effects of actinomycin D on viral RNA synthesis and produced both 26S and 49S RNAs, even though no viral structural proteins or mature particles were produced in the presence of the drug. This result suggests that, in the presence of actinomycin, the nonstructural genes of SBamr are translated sufficiently to allow for RNA synthesis but that 26S RNA may not be translated to an extent that allows significant virus production. These data demonstrate that host components are involved in at least two distinct steps in the production of Sindbis virus in mosquito cells: (i) production of viral RNA and (ii) synthesis of viral structural polypeptides.

Aedes↗
PubMed1975

Correlation between resistance to actinomycin D, karyology, agglutination by concanavalin A and tumorigenicity in Chinese hamster hybrid cells.

Subclones isolated from a Chinese hamster hybrid line, derived from fusion of an actinomycin D-resistant and an actinomycin D-sensitive strain, were studied with respect to their resistance to actinomycin D, karyology, transplantability and agglutination by concanavalin A. Statistical analysis of the results allowed the establishment of a classification of the strains based on increasing resistance to actinomycin D. There appeared to be an inverse correlation between actinomycin D-resistance and tumorigenicity and a positive correlation between this resistance and the presence of a marker chromosome.

Agglutination Tests↗
PubMed1979

Effect of actinomycin D on uterine prostaglandin production and oestrous cycle length in guinea-pigs.

Intrauterine, but not systemic, administration of actinomycin D on Day 10 increased oestrous cycle length in guinea-pigs. Peripheral plasma progesterone levels remained elevated during these lengthened cycles presumably because luteal life-span had been extended. Prostaglandin (PG) F-2 alpha production in vitro, on Day 15, by the uterus of guinea-pigs which had received intrauterine actinomycin D was much lower than control values. This decrease in PG production was not due to lack of precursor, increased metabolism, re-direction of synthesis towards PGE-2, or a direct inhibition by actinomycin D of the conversion of arachidonic acid to PGs. The effects of actinomycin D treatment were not reversed by oestradiol. It is proposed that actinomycin D prevents the increase in uterine PG synthetase levels that normally takes place after Day 11, thereby reducing uterine PGF-2 alpha synthesis and output in vivo, and resulting in luteal maintenance and longer oestrous cycles.

Animals↗
PubMed2000

[The effect of heat shock on the formation and composition of actinomycins].

The effect of various conditions of heat shock on production of actinomycins by Streptomyces chrysomallus 2 and their composition was studied. The actinomycin biosynthesis was shown to be the function of the growing mycelium and changed in accordance with changes in the volume of the mycelium and its morphological features after heat shock at various suboptimal temperatures. The temperature shock had a specific action on the antibiotic synthesis: the index of the actinomycin maximum quantity increased after the heat shock at 35 and 38 degrees C and lowered more sharply than that of the biomass volume after the heat shock at the temperatures of 40, 42, 45 and 50 degrees C for 1 hour. After the shock at 38 degrees C the component composition of the actinomycin complex did not significantly change while with addition of exogenic amino acids such as L-valine, L-leucine and L-isoleucine the shock effect on the component composition of the actinomycin complex was marked.

Anti-Bacterial Agents↗
PubMed1992

Purification and characterization of actinomycin synthetase I, a 4-methyl-3-hydroxyanthranilic acid-AMP ligase from Streptomyces chrysomallus.

Actinomycin synthetase I was purified to homogeneiety from actinomycin-producing Streptomyces chrysomallus. The purified enzyme is a single polypeptide chain of M(r) 45,000. It catalyzes the formation of the adenylate of 4-methyl-3-hydroxyanthranilic acid (4-MHA) from the free acid and ATP in an equilibrium reaction. 4-MHA is the precursor of the chromophoric part of actinomycin. By using the 4-MHA analogue, 4-methyl-3-hydroxybenzoic acid, as a model substrate it could be established that the equilibrium constant Keq is independent on enzyme concentration, which suggests that no stoichiometric acyladenylate-enzyme complex is formed in contrast to observations made with aminoacyl adenylates formed by aminoacyl-tRNA synthetases or multifunctional peptide synthetases. Actinomycin synthetase I does not charge itself with substrate carboxylic acid via a covalent thioester bond as is usual for amino acid activation in non-ribosomal peptide synthesis. In addition, the enzyme does not act as an acyl-coenzyme A ligase as revealed by its inability to release AMP in the presence of 4-MHA or other structurally related aromatic carboxylic acids, coenzyme A and ATP. Additional analysis of the activation reaction showed that it is exothermic, whereas the free enthalpy change delta G0 is positive due to a negative entropy change indicating a strong influence of restriction of random motion on the course of the reaction. Determinations of Km and kcat of various substrate carboxylic acids revealed the highest kcat/Km ratio for the natural substrate 4-MHA. From these properties, actinomycin synthetase I represents the prototype of novel chromophore activating enzymes involved in non-ribosomal synthesis of chromopeptide lactones in streptomycetes.

Adenosine Triphosphate↗
PubMed2004

Veno-occlusive disease in pediatric patients receiving actinomycin D and vincristine only for the treatment of rhabdomyosarcoma.

OBJECTIVES: Veno-occlusive disease (VOD) following standard chemotherapy has been reported in patients receiving vincristine actinomycin D, and cyclophosphamide for the treatment of Wilms tumor and more rarely rhabdomyosarcoma. The dose and schedule of administration of actinomycin D in patients with Wilms tumor and the increased dose of cyclophosphamide administered to patients with rhabdomyosarcoma have been considered the likely etiology for VOD. METHODS: The authors report four cases of VOD in patients with rhabdomyosarcoma treated with vincristine and actinomycin D only. No risk factors for the development of VOD were identified. VOD was diagnosed clinically by the presence of at least two of three findings as defined by McDonald et al. VOD occurred after two to four doses of actinomycin D and approximately 7 to 14 days after the dose. All patients recovered with no evidence of permanent hepatic damage. CONCLUSIONS: VOD can occur in patients with "low-stage" rhabdomyosarcoma treated with vincristine and actinomycin D alone. Although chemotherapy-related VOD is a potentially severe disease, the outcome is good and resumption of chemotherapy is well tolerated.

Adolescent↗
PubMedDate not supplied

[1H NMR analysis of the complex formation of aromatic molecules of antibiotic and vitamin in aqueous solution: heteroassociation of actinomycin D and flavin mononucleotide].

The molecular mechanism of the combined action of antibiotic and vitamin was studied by NMR spectroscopy. The heteroassociation of the antitumor antibiotic actinomycin D and flavin mononucleotide was investigated as a function of concentration and temperature by 500 MHz 1H NMR spectroscopy. The equilibrium association constant, the thermodynamic parameters (deltaH, deltaS) of heteroassociation of actinomycin D with flavin mononucleotide, and the limiting values of proton chemical shifts in the heterocomplex were determined from the concentration and temperature dependences of proton chemical shifts of molecules. The most favorable structure of the 1:1 actinomycin D-flavin mononucleotide heteroassociation complex was determined using both the molecular mechanics methods (X-PLOR software) and the limiting values of proton chemical shifts of the molecules. In the calculated structure, the planes of the chromophores of actinomycin D and flavin mononucleotide molecules in the 1:1 heterocomplex are parallel and separated from each other by a distance of about 0.34 nm. At the same time, there is a probability of formation of intermolecular hydrogen bonds in the calculated structure of 1:1 actinomycin D-flavin mononucleotide complex. The analysis of the results obtained suggests that aromatic molecules of vitamins, e.g., flavin mononucleotide, can form energetically favorable heterocomplexes with aromatic antitumor antibiotics in aqueous solution, modulating thereby the efficacy of their medical and biological action.

Anti-Bacterial Agents↗
PubMed1975

The compatibility of netropsin and actinomycin binding to natural deoxyribonucleic acid.

The simultaneous binding of netropsin and actinomycin to four natural DNAs was studied to determine the influence of one ligand on the binding of the other. Actinomycin binds specifically to GC sites, whereas netropsin binds specifically to AT sites. Spectral titrations, thermal denaturation, and analytical buoyant density centrifugation were employed to measure the binding interference of these drugs. The binding of actinomycin to DNA was decreased by the presence of netropsin. Increasing the GC content of the DNA resulted in a decreased effect of netropsin on actinomycin binding. Quantitative analysis of the binding parameters indicated that netropsin and actinomycin can bind in close proximity along the DNA chain. Supercoiled DNA gave the same result as linear DNA. These results imply that DNA can absorb alterations in conformation within a short distance.

Anti-Bacterial Agents↗
PubMed1979

Synthesis and biological properties of N2-substituted spin-labeled analogues of actinomycin D.

We have synthesized N2-[4-(2,2,6,6-tetramethyl-1-piperidinyloxy)]actinomycin D And the related 1,2-diaminoethane and 1,3-diaminopropane derivatives and evaluated their biological properties. Binding studies with the spin-labeled actinomycin D analogues and DNA were carried out by using circular dichroism, electron spin resonance, and thermal denaturation. These studies have suggested that the derivatives bind to DNA and that their DNA-binding modes are similar but not identical. Spin-labeled actinomycin D derivatives were less potent in inhibiting Escherichia coli DNA-dependent RNA polymerase reaction than actinomycin D and were less toxic to L1210 cells in vitro than the parent compound. Spin-labeled actinomycin D derivatives were more common than the parent compounds against P-388 leukemia cells in vitro with little or no toxicity.

Animals↗
PubMed1985

Treatment of high-risk gestational trophoblastic disease with methotrexate, actinomycin D, and cyclophosphamide chemotherapy.

Seventy-three patients with metastatic high-risk gestational trophoblastic disease were treated with methotrexate, actinomycin D, and cyclophosphamide chemotherapy at the Brewer Trophoblastic Disease Center between 1968 and 1982. Forty-six patients were treated primarily with methotrexate, actinomycin D, and cyclophosphamide because of the presence of one or more high-risk factors. Twenty-seven additional patients who had not responded to initial single-agent chemotherapy with methotrexate and/or actinomycin D were subsequently treated with methotrexate, actinomycin D, and cyclophosphamide. Adjuvant surgery and radiotherapy were used in selected patients. The overall cure rate was 51% (37 of 73): 63% (29 of 46) for primary treatment and 30% (eight of 27) for secondary treatment (P less than .01). Several factors that influenced response to primary treatment with methotrexate, actinomycin D, and cyclophosphamide chemotherapy were determined: 1) clinicopathologic diagnosis of choriocarcinoma versus invasive mole (59 versus 100%), 2) metastases to sites other than the lung and/or vagina (44 versus 74%), 3) antecedent term gestation compared with hydatidiform mole or abortion (50 versus 75%), and 4) presence of three or more high-risk factors (27 versus 74%). There were no significant differences in cure rates during the course of the study period.

Abortion, Spontaneous↗
PubMed1984

Acyl pentapeptide lactone synthesis in actinomycin-producing streptomycetes by feeding with structural analogs of 4-methyl-3-hydroxyanthranilic acid.

Several structural analogs of 4-methyl-3-hydroxyanthranilic acid (4-MHA) that had been established as substrates of the 4-MHA-activating enzyme from Streptomyces chrysomallus (Keller, U., Kleinkauf, H., and Zocher, R. (1984) Biochemistry 23, 1479-1484) were fed in short term labeling experiments to cultures of two actinomycin-producing streptomycetes. Besides inhibition of actinomycin synthesis, the addition of 4-methyl-3-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-aminobenzoic acid, or 4-methyl-3-methoxy-benzoic acid induced the formation of novel compounds. The data indicate that these compounds are structural analogs of 4-MHA pentapeptide lactones, which are the most probable precursors of actinomycins (Katz, E. (1967) in Antibiotics II (Gottlieb, D., and Shaw, P. D., eds) pp. 276-341, Springer-Verlag, New York). Since the structural analogs of 4-MHA are missing the o-aminophenol configuration, the corresponding acyl pentapeptide lactones cannot react with each other to give phenoxazines. Therefore, they accumulate and thus become detectable. Feeding cultures with 4-MHA resulted in an inhibition of actinomycin synthesis apparently at the level of acyl pentapeptide lactone synthesis. In such experiments, the formation of pentapeptide lactones, which are most likely derived from 4-MHA pentapeptide lactones, could be detected. The results provide experimental evidence that the biosynthesis of actinomycins proceeds via the 4-MHA-pentapeptide lactones.

Amino Acids↗
PubMedDate not supplied

[Effect of actinomycin D, cycloheximide and hypertonic concentrations of NaCl on the reproduction of the tick-borne encephalitis virus].

Synthesis of virus-specific polypeptides occurs in pig embryo kidney cells infected with tick-borne encephalitis virus and treated with actinomycin D, cycloheximide, and hypertonic concentrations of NaCl in various combinations. Despite the fact that virus-specific matrix RNAs function under such conditions, production of infectious virus particles is inhibited considerably. Virus yield is greatly decreased by treatment with actinomycin D alone and by combined effect of actinomycin D and cycloheximide. Sodium chloride and combined treatment of the infected cells with cycloheximide and NaCl do not affect the intact virus production. The mechanism of the inhibiting effect of actinomycin D on production of infectious tick-borne encephalitis virus is assumed to consist in the impairment of the synthesis of virus-specific ribonucleic acid and/or in marked reduction of its infectivity. Actinomycin D may possibly inhibit somehow the morphogenesis of intact virions of tick-borne encephalitis virus.

Animals↗
PubMed1998

Actinomycin D specifically inhibits the interaction between transcription factor Sp1 and its binding site.

The mode of action of many anticancer drugs involves DNA interactions. We here examine the ability of actinomycin D to alter the specific binding of transcription factors Spl and NFkappaB to their DNA sequences. Employing an electrophoretic mobility shift assay, it is shown that actinomycin D inhibits complex formation between nuclear proteins present in the extracts from stimulated human umbilical vein endothelial cells and the Sp1-binding site. Actinomycin D is also able to induce disruption of preformed DNA-protein complexes, pointing to the importance of an equilibrium of three components: actinomycin D, protein and DNA for drug action. The effect of actinomycin D is sequence-specific, since no inhibition is observed for interaction of nuclear proteins with the NFkappaB binding site. The results support the view that DNA-binding drugs displaying high sequence-selectivity can exhibit distinct effects on the interaction between DNA and different DNA-binding proteins.

Antibiotics, Antineoplastic↗
PubMed1964

ACTINOMYCIN: CORRELATION OF STRUCTURE AND FUNCTION OF ITS COMPLEXES WITH PURINES AND DNA.

Actinomycin inhibits strand separation of helical DNA at concentrations corresponding to those which inhibit DNA polymerase activity in vitro. This report proposes first that actinomycin affects DNA polymerase indirectly by way of the changed physical properties of the template and that it functions in the major groove of helical DNA; second, that RNA polymerase functioning in the minor groove is subject to direct steric inhibition by bound actinomycin; and third, that the reaction of actinomycin with free purines is unrelated to its reaction with DNA.

Chemical Phenomena↗