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PubMed1977

Proton magnetic resonance studies of actinomycin D complexes with mixtures of nucleotides as models for the binding of the drug to DNA.

The proton magnetic resonance spectra of actinomycin solutions with mixtures of deoxynucleotides have been investigated to determine the relative preference for the binding of guanine and adenine nucleotides to the two nucleotide binding sites of actinomycin D. An analysis of the chemical shifts of the actinomycin D resonances shows that adenine and guanine nucleotides competitively bind to the benzenoid portion of the phenoxazone ring of actinomycin D while guanine nucleotides bind stronger than adenine nucleotides to the quinoid portion of the phenoxazone ring. The chemical shift data for the titrations of actinomycin D with pdG-dG, pdC-dC, and an equimolar mixture of these complementary deoxydinucleotides show that: (1) pdG-dG forms a stacked complex much like dGMP; (2) pdC-dC does not bind to actinomycin D under the conditions used in these experiments; (3) in the titration of actinomycin D with the equimolar mixture of pdG-dG + pdC-dC, a miniature intercalated complex is formed.

Binding Sites↗
PubMed1975

Stopped-flow kinetic studies of actinomycin binding to DNAs.

Stopped-flow kinetic studies of the association of actinomycins with narural and synthetic DNA duplexes are presented. The actinomycins examined were D (C1), D lactam (in which the pentapeptide rings are closed by lactam instead of lactone linkages), X2, XObeta, and actinomine. The DNAs used included claf-thymus DNA, PM2, DNA, and two synthetic d(A-T)-lide copolymers containing 2,6-diaminopurine (DAP) in place of adenine residues, poly[d(DAP-T)]-poly[d(DAP-T)] and poly[d(DAP-A-T]-poly[d(DAP-A-T)]. Apparent equilibrium constants indicate that the DAP-containing polynucleotides bind actinomycin strongly. Comples formation of actinomycins D, D lactam, X2 and XObeta with these DNAs can be deconvoluted into five rate processes. These steps do not necessarily proceed to completion. The rates of two of these steps display a firstorder dependence on DNA concentration. The large negative entropies of activation of these steps suggest a high degree of restriction to freedom of motion on the respective transition states. The rates of the remaining three steps are independent of DNA concentration. Kinetic parameters of actinimycin binding to DNAs are presented and suggestions are made about some of the molecular evente believed to be responsible for the appearance of the five rate processes. For example, for DNA, poly[d(DAP-A-T)], and poly[d(DAP-T)], the observed order of apparent second-order rate constants, normalized to the concentration of actinomycin binding sites, suggests that binding of the antibiotic occurs most rapidly at binding sites (G-C of d DAT-T) near d(A-T) base pairs, where weakening of the double-helical conformation requires the least energy. Results obtained from studies of actinomycin D binding to heat-denatured poly[d(DAP-A-T)] and of actinomine and actinomycin D lactam binding to DNA suggest that the slow rate processes are related to an actinomycyl-pentapeptide-induced unwinding of the sugar-phosphate backbone of DNA accompanying insertion of the cyclic peptides into DNA.

Animals↗
PubMed1998

Actinomycin D inhibition of DNA strand transfer reactions catalyzed by HIV-1 reverse transcriptase and nucleocapsid protein.

Actinomycin D was found to be a potent inhibitor of HIV-1 reverse transcriptase catalyzed DNA strand transfer reactions. Using an oligonucleotide model system, actinomycin D inhibition of DNA strand transfer was examined to elucidate the mechanism of inhibition and further define the mechanism of DNA strand transfer. Our results show that actinomycin D inhibits HIV-1 reverse transcriptase catalyzed DNA strand transfer without inhibiting RNA-dependent or DNA-dependent DNA polymerase activity. Actinomycin D was found to strongly inhibit annealing of a primary DNA product to the DNA acceptor template, preventing the formation of a key reaction intermediate. The HIV-1 nucleocapsid protein has been shown to participate in catalytic events during reverse transcription including DNA strand transfer. Recombinant nucleocapsid protein was used in conjunction with actinomycin D in this model system to investigate how NC may participate in the mechanism of inhibition by actinomycin D and in DNA strand transfer. The inclusion of nucleocapsid protein was found to partially relieve both DNA annealing and strand transfer inhibition caused by actinomycin D. This study suggests a potential new mechanism for inhibiting retroviral replication by preventing the formation of replication intermediates.

Catalysis↗
PubMed2000

Structures of five components of the actinomycin Z complex from Streptomyces fradiae, two of which contain 4-chlorothreonine.

Structure elucidation of five components of the actinomycin Z complex (Z(1)-Z(5)) isolated from Streptomyces fradiae is described. The components were separated by Si gel column chromatography and TLC/PLC and analyzed by ESIMS, FABMS, LC-MS of derivatized hydrolysates, and 2D NMR techniques. This permitted determination of the complete structures of actinomycins Z(1)-Z(5). In Z(3) and Z(5,) site 1 of the beta-depsipeptide is occupied by the rare 4-chloro-L-threonine, an amino acid not previously found in an actinomycin. The structural variants of the actinomycin Z complex have the molecular architecture typical of other actinomycins but possess greater structural diversity resulting from the presence of several highly unusual amino acids. Actinomycins Z(3) and Z(5,) but not Z(1), were more potent than actinomycin D in cytotoxicity assays against three tumor cell lines.

Antibiotics, Antineoplastic↗
PubMed1975

Comparison of the effects of zinc deprivation and actinomycin D on ribonucleic acid synthesis by stimulated lymphocytes.

1. EDTA inhibited incorporation of [3H]uridine into RNA of lymphocytes, but did not decrease uptake into the cold-acid-soluble fraction of the cells. The inhibition by EDTA was largely reversible by simultaneous addition of Zn2+. 2. Low concentrations pf actinomycin D (3 ng/ml) added at the time of stimulation of the cells inhibited [3H]uridine incorporation into RNA, but concentrations of 50-100 ng/ml were required to produce the same degree of inhibition if addition of actinomycin D was delayed until just before the incorporation was measured. This difference in sensitivity did not reg within the cells. 3. When added immediately before phytohaemagglutinin, actinomycin D (3 ng/ml) and EDTA produced similar time-courses of inhibition of uridine incorporation. 4. Uridine incorporation at 32h was inhibited when actinomycin D (3 ng/ml) or EDTA was added just before stimulation of the cells, but was only slightly affected when they were added at 32h. At intermediate times the incorporation of uridine remained sensitive to addition of EDTA for longer than it was sensitive to actinomycin D. 5. Polyacrylamide-gel separation of RNA synthesized in EDTA-treated cultures in the presence or absence of added Zn2+ showed that lower availability of Zn2+ resulted in a decreased rate of transfer of radioactivity from 32S to 28S rRNA and decreased survival of 28S rRNA relative to 18S rRNA. 6. Close similarities have been shown to exist between the effects of EDTA and low concentrations of actinomycin D. Not all the effects of EDTA could be explained by postulating that Zn2+ was a constituent of RNA polymerase I, nor were the effects of actinomycin D readily explained by previously suggested mechanisms of action of this antibiotic.

Animals↗
PubMed1972

Studies on Phytoalexins: The Relationship between Actinomycin D and Ribonucleic Acid Synthesis during the Induction of Phaseollin in the French Bean (Phaseolus vulgaris L.).

Actinomycin D stimulated phaseollin production in endocarp tissues of the French bean (Phaseolus vulgaris L.), maximum production being obtained with 25 to 30 micrograms per milliliter of antibiotic. Under these conditions, net incorporation of (3)H-uridine into total cell ribonucleic acid was inhibited by more than 80% over a 6-hour induction period. If allowance was made for a 2-hour lag in the action of actinomycin D, inhibition of incorporation was greater than 95%. Contrary to other reports, no evidence was obtained of an increased formation of any specific ribonucleic acid fraction. Actinomycin D applied in the cold (4 C) was not found to be effective in stimulating phaseollin production. When applied in this way, actinomycin D did not affect induction of phaseollin by a fungal peptide, Monilicolin A, although ribonucleic acid synthesis was inhibited by more than 95%. It is suggested that the induced formation of phytoalexins may not be dependent on increased ribonucleic acid synthesis as has previously been claimed.Other experiments indicated that the apparent effects of actinomycin D on ribonucleic acid synthesis could be influenced by the choice of precursor used to label ribonucleic acid and by the order of addition of precursor and antibiotic to the plant tissue. These effects were only observed in the period immediately following application of actinomycin D. It is suggested that such effects could critically influence the results obtained in short term experiments and may explain some differences in reported action of actinomycin D from different laboratories.

Journal Article↗
PubMed1997

Effects of actinomycin D on developing hamster molar tooth germs in vitro.

The aim of this study was to evaluate the toxic effects of actinomycin D on the developing hamster tooth germ in organ culture. Hamster tooth germs during early secretory amelogenesis were exposed in vitro for 24 h to 10(-9) M-5 x 10(-5) M actinomycin D. Actinomycin D dose-dependently (> or = 10(-7) M) decreased the tooth germ dry weight but mineralization was affected only by doses > or = 10(-5) M. However, the uptakes of TCA-insoluble 32P and [3H]thymidine were significantly reduced dose-dependently from > or = 10(-8) M actinomycin D, indicating that the drug inhibits the synthesis of phosphate-containing macromolecules as well as DNA synthesis. Histologically, 10(-8) M actinomycin D was the lowest dose which was not toxic to any cell type in the developing tooth germ. At 10(-7) M actinomycin D, the most sensitive cells were the proliferating pre-odontoblasts followed by pre-ameloblasts; the mature secretory ameloblasts and odontoblasts appeared unaffected. Higher doses resulted in increased cytotoxicity to the secretory cells and, eventually, total degeneration of most cells. The data suggest that children treated for cancer during tooth development using anti-chemotherapy cocktails containing actinomycin D (serum levels > 10(-7) M) may develop defects later on in the mature dentition as a direct consequence of the toxicity of the drug to the tooth organ.

Ameloblasts↗
PubMed1969

Abortive infection of Bacillus subtilis bacteriophage PBS1 in the presence of actinomycin D.

Actinomycin D caused the irreversible loss of PBS1 phage infectious centers and PBS1-mediated transductants. The loss of infectious centers occurred only within the first 4 min after the addition of phage to cells. Actinomycin did not inactivate free phage or inhibit phage adsorption. Electron micrographs indicated that phage adsorbed to cells in the presence of actinomycin ejected their deoxyribonucleic acid (DNA) normally. However, when cells were infected in the presence of actinomycin, 15 to 22% of their (32)P-labeled DNA appeared in the medium, whereas only 1.5 to 7.2% of the (32)P-labeled DNA appeared in the medium during normal infection. Neither 8-azaguanine nor chloramphenicol caused a similar loss of PBS1 infectious centers or transductants. Actinomycin also caused the loss of SP10 infectious centers but it had no effect on SP01 or phi29 infections. We conclude that actinomycin causes abortion of PBS1 infection by inhibiting the uptake or retention of phage DNA into host cells. The immunity of SP01 and phi29 infections to actinomycin probably reflects differences in the penetration mechanisms of these phages.

Adsorption↗
PubMed1998

Actinomycin D inhibits human immunodeficiency virus type 1 minus-strand transfer in in vitro and endogenous reverse transcriptase assays.

In this report we demonstrate that human immunodeficiency virus type 1 (HIV-1) minus-strand transfer, assayed in vitro and in endogenous reactions, is greatly inhibited by actinomycin D. Previously we showed that HIV-1 nucleocapsid (NC) protein (a nucleic acid chaperone catalyzing nucleic acid rearrangements which lead to more thermodynamically stable conformations) dramatically stimulates HIV-1 minus-strand transfer by preventing TAR-dependent self-priming from minus-strand strong-stop DNA [(-) SSDNA]. Despite this potent activity, the addition of NC to in vitro reactions with actinomycin D results in only a modest increase in the 50% inhibitory concentration (IC50) for the drug. PCR analysis of HIV-1 endogenous reactions indicates that minus-strand transfer is inhibited by the drug with an IC50 similar to that observed when NC is present in the in vitro system. Taken together, these results demonstrate that NC cannot overcome the inhibitory effect of actinomycin D on minus-strand transfer. Other experiments reveal that at actinomycin D concentrations which severely curtail minus-strand transfer, neither the synthesis of (-) SSDNA nor RNase H degradation of donor RNA is affected; however, the annealing of (-) SSDNA to acceptor RNA is significantly reduced. Thus, inhibition of the annealing reaction is responsible for actinomycin D-mediated inhibition of strand transfer. Since NC (but not reverse transcriptase) is required for efficient annealing, we conclude that actinomycin D inhibits minus-strand transfer by blocking the nucleic acid chaperone activity of NC. Our findings also suggest that actinomycin D, already approved for treatment of certain tumors, might be useful in combination therapy for AIDS.

Anti-HIV Agents↗
PubMed1980

Actinomycin D cytotoxicity for mouse peritoneal macrophages and effect on lactate dehydrogenase-elevating virus replication.

Treatment of lactate dehydrogenase-elevating virus(LDV)-infected mouse peritoneal macrophage cultures with actinomycin D (1 microgram/ml) resulted in a progressive reduction in the formation of LDV-specific RNA and mature virus as the time of incubation with actinomycin D increased beyond 2-3 h. This effect, however, seemed to reflect an unusual sensitivity of macrophages to toxic effects of actinomycin D. Macrophage cytotoxicity and lysis became apparent 3-4 h after addition of actinomycin D; the initiation of synthesis of Sindbis virus RNA, which is insensitive to inhibition by actinomycin D in other cell culture systems, was also reduced in actinomycin-D-treated macrophages. Macrophages propagated in L-cell-conditioned medium were found to be less sensitive to actinomycin D cytotoxicity and, correspondingly, the initiation and synthesis of LDV RNA were less affected.

Animals↗
PubMed1981

Failure of actinomycin D entrapped in liposomes to prolong survival in renal cell adenocarcinoma-bearing mice.

The potential prolongation of survival of actinomycin D entrapped in liposomes was examined in Balb C/Cr mice inoculated intrarenally with renal cell adenocarcinoma. There were five groups of animals: group A, a control group, received phosphate-buffered saline 0.3 cm3 i.p.; group B received free actinomycin D 300 micrograms/kg i.p.; group C received liposomes containing actinomycin D 300 micrograms/kg i.p.; group D received a mixture of free actinomycin D 300 micrograms/kg and empty liposomes i.p.; group E received empty liposomes i.p. The best median survival was of group D (free drug) - 54 days followed by group C (liposome entrapped actinomycin D) 45.2 days and group E (a mixture of free and entrapped actinomycin D) - 42 days. In vitro studies utilizing cell lines obtained from the tumor showed no statistical difference in ID50 or in cytotoxicity between the cells treated with free actinomycin D and those treated with liposomes containing drug.

Adenocarcinoma↗
PubMed2003

Facilitation of fas mediated apoptosis of human chondrocytes by the proteasome inhibitor and actinomycin D.

OBJECTIVE: We investigated the susceptibility of chondrocytes to apoptosis induced by anti-Fas and various potentiators, and the relevant signaling pathway. METHODS: Chondrocytes were cultured from cartilages obtained at the time of joint replacement surgery for knee osteoarthritis (OA) or femur neck fracture. Fas receptor ligation was performed with agonistic anti-Fas antibody (clone CH-11) at concentrations ranging from 0.5 to 1.0 micro g/ml. Mitogen activated protein kinase inhibitors SB203580 and PD98059, cycloheximide, bisindolylmaleimide, actinomycin D, or MG132 were added with anti-Fas to facilitate cell death. Chondrocyte surface expression of Fas was analyzed by FACS, and the expression of apoptosis related proteins analyzed by Western blot. RESULTS: Cell death increased upon coculture with 0.5 micro g/ml of anti-Fas and 0.2 micro g/ml of actinomycin D or 20 micro M MG132. Apoptosis potentiated by actinomycin D or MG132 was effectively inhibited by caspase inhibitors, implicating the involvement of the caspase cascade in chondrocyte apoptosis. Compared with untreated cells or actinomycin D treated cells, cells treated with MG132 showed distinct shifts in the distribution of surface Fas fluorescence. Although concentrations of Bcl-2, Bax, FLICE inhibitory protein (FLIP), and Fas ligand were unaffected by MG132 or actinomycin D, both treatments led to a significant increase of p53. The expression of the p53 response proteins, MDM2 and p21, was elevated in MG132 treated chondrocytes. CONCLUSION: Our results suggest that chondrocytes can be rendered sensitive to anti-Fas mediated apoptosis by the proteasome inhibitor MG132 and the transcription inhibitor actinomycin D. MG132 and actinomycin D show different characteristics in terms of apoptosis signaling.

Antibodies, Monoclonal↗
PubMed1989

7-Azidoactinomycin D: a novel probe for examining actinomycin D-DNA interactions.

The technique of photoaffinity labeling is applied to the actinomycin D system to provide a novel probe for the examination of the interactions of actinomycin D with nucleic acids. The capacity for covalent attachment of actinomycin D will aid greatly in the study of target-site specificities and the correlations of biological effects with biophysical DNA interactions. Through chemical modification of the parent actinomycin D molecule with a photoreactive azido substituent, a functional analog of the parent actinomycin D is generated having equilibrium binding properties identical to those of the parent molecule yet with the capacity to form a covalent attachment to DNA upon photolysis. The results presented here describe the noncovalent interactions of this photoreactive probe to DNA (absence of light) and compares the binding properties observed to those of the parent actinomycin D and 7-aminoactinomycin D analog. These studies demonstrate that the DNA binding properties (i.e. binding affinity, binding site size, and sequence specificity) retained by the 7-azidoactinomycin D, thus providing a suitable probe for examining actinomycin D-DNA interactions.

Affinity Labels↗
PubMed1989

Potentiation of vincristine and actinomycin D by a new synthetic imidazole anti-tumor agent YM534 active against human cancer cells and multidrug-resistant cells.

Ethyl 6-p-5-(l-imidazolyl) pentyloxyphenoxy-2, 2-dimethylhexanoate hydrochloride (YM534) is a new synthetic anti-tumor compound. Combinations of YM534 with other anti-cancer agents were examined to ascertain whether YM534 potentiated other anti-cancer agents against the KB cell line and its multidrug-resistant counterpart, VJ-300. YM534 potentiated the cytotoxic action of vincristine and actinomycin D about 2-fold against KB cells, but not those of daunomycin and adriamycin. By contrast, YM534 only slightly reversed drug-resistance to adriamycin and daunomycin in VJ-300 while it reversed 5-fold vincristine resistance and 60-fold actinomycin D resistance in VJ-300. The reversal effect of YM534 on actinomycin D and vincristine-resistance in VJ-300 cells appeared to be due to enhanced accumulation of [3H] actinomycin D and [3H] vincristine in VJ-300 cells by YM534. YM534 inhibited efflux of actinomycin D and vincristine from VJ-300 cells, and it also enhanced cellular uptake of these anti-cancer agents. YM534 enhanced cellular accumulation of both actinomycin D and vincristine in the sensitive KB cells. YM534 is thus a unique anti-cancer agent since combinations of other anti-cancer agents with YM534 are expected to augment anti-tumor activity of them. By contrast, YM212, a carboxy analog of YM534, had much less activity to potentiate vincristine and actinomycin D). YM534 at 100-1000 microM almost completely inhibited the photoaffinity labeling of [3H] azidopine to the 170-kD P-glycoprotein of VJ-300 cell membranes, but YM212 showed much less inhibitory action on the photoaffinity labeling. YM534 could also inhibit the photoaffinity labeling of deglycosylated P-glycoprotein.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1980

Actinomycin D binds with highest affinity to nonribosomal DNA.

Based on previous evidence (T.J. Lindell (1976) Nature 263, 347-350 and T.J. Lindell, A.F. O'Malley, and B. Puglisi (1978) Biochemistry 17, 1154-1160) it was anticipated that actinomycin D in a low concentration would bind to DNA which is involved in the regulation of rRNA transcription in eukaryotes. This was examined by digestion of rat (liver) DNA with EcoRI, adding [3H]actinomycin D (0.004 microgram/ml) and resolution of the restriction fragments by RPC-5 chromatography. Labeled actinomycin D was found to bind with highest affinity to a single fraction consistently eluting at 0.63 M KCl. A similar digestion and fractionation of nucleolar DNA, which is enriched in rDNA sequences, did not reveal a similar high affinity binding of actinomycin D. This fraction of DNA which binds actinomycin D with highest affinity did not contain any rDNA as evidenced by hybridization with [32P]rRNA. Therefore, at the concentration of 0.004 microgram/ml, actinomycin D does not selectively bind to rDNA as evidenced by two independent criteria. Whether this high affinity actinomycin D-binding DNA has any function in the regulation of rRNA transcription remains to be determined.

Animals↗
PubMed1975

Inhibitory effect of actinomycin D on the inductio of rat mammary tumors by in vitro exposure to 7,12-dimethylbenz(a)anthracene.

The inhibitory effect of actinomycin D on the induction of tumors by in vitro exposure of mammary glands to 7,12-dimethylbenz(a)anthracene was studied. When actinomycin D was given i.p. 24 hr before excision of the mammary glands, the induction of tumors by in vitro exposure of the glands to 7,12-dimethylbenz(a)anthracene was significantly decreased. On the other hand, when actinomycin D was administered 24 hr after excision, it had no effect on the induction of tumors. In vitro exposure of excised glands to 7,12-dimethylbenz(a)anthracene and actinomycin D significant decreased tumor induction. However, the order of exposure to 7,12-dimethylbenz(a)anthracene and actinomycin D influenced the inhibitory effect of actinomycin D on tumor induction. Results indicated that this might be due to a difference in the amounts of 7,12-dimethylbenz(a)anthracene and actinomycin D bound to the mammary glands.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1979

[Aspects of the biosynthesis of actinomycin C].

The protoplasts of Actinomyces sp. 26--115 producing actinomycin C were obtained by the action of lysozyme on the mycelial paste of a 48-hour microbial culture. The protoplast capacity for synthesizing actinomycin was decreased as compared to that of the intact mycelium. The transport of L-isoleucine, a precursor of actinomycin C biosynthesis in the protoplasts also decreased but this could not be the only cause of the decrease in the actinomycin biosynthesis capacity. The biosynthesis of actinomycin C by the protoplasts of Actinomycin sp. 26--115 did not require galactose and was not inhibited by glucose and exogenic actinomycin.

Actinomyces↗
PubMed1996

[Absorption of various actinomycins by Staphylococcus aureus cells].

The absorption of actinomycin D by the cell suspension of Staphylococcus aureus via diffusion linearly depended on the antibiotic concentration in the suspension within the ranges of 2 to 15 micrograms/ml. The absorption of active actinomycins C2, C3 and Au6 was the same as that of actinomycin D. The Staphylococcus intact membranes limited the inlet of the actinomycins to the cells since the membranotropic substances such as gramicidin S and its derivatives and thyrocidin increased their absorption by 30-70 per cent. The absorption of a low active actinomycin D0 and inactive actinomycinic acid even after the exposure to the membranotropic substances was not detectable. These compounds did not form any complexes with DNA. The level of the absorption of the actinomycins by the cells was likely defined by their ability to complex with DNA.

Absorption↗