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PubMed1979

Actinomycin D restores in vivo sensitivity to differentiation induction of non-differentiating mouse myeloid leukemia cells.

Resistant mouse myeloid leukemia cells could not be induced to differentiate in vitro into mature macrophages and granulocytes by incubation with ascitic fluid or dexamethasone as inducer. Neither could endogenous inducers acting on resistant cells maintained in a diffusion chamber in syngeneic SL mice induce differentiation. However, when resistant cells were pretreated in vitro with low doses of actinomycin D they became sensitive to inducer in vitro or in vivo. The concentration of actinomycin D effective for this effect did not induce differentiation. The effect of actinomycin D was not due to inhibition of cell growth, since sensitivity was not observed when resistant cells were pretreated with the growth inhibitor 5-fluorodeoxyuridine. When resistant cells were kept in a diffusion chamber in mice injected with low doses of actinomycin D they showed significant differentiation, suggesting that the in vivo effect of actinomycin D is partly attributable to sensitization of the resistant cells to endogenous inducers.

Animals↗

PubMed1980

Effect of actinomycin D-containing lipid vesicles on murine renal adenocarcinoma.

Forty Balb C/CR mice inoculated with renal cell adenocarcinoma were divided into five groups. Group A (seven animals) received phosphate buffered saline intraperitoneally; group B (seven animals) received free actinomycin D 300 microgram/kg IP; group C (nine animals) received lipid vesicles containing actinomycin D 300 microgram/kg IP; group D (eight animals) received a mixture of free actinomycin D 300 microgram/kg and empty lipid vesicles IP. The median survival of group A was 32 days, of group B 30 days, of group C 45.2 days, of group D 54 days, and of group E 42 days. It is suggested that giving the mixture of the drug and the lipid vesicles produces a balance similar to that found in a vesicle solution containing the actinomycin D. It is also suggested that liposomes slow the absorption of actinomycin D from the peritoneum.

Adenocarcinoma↗

PubMed1996

Constitutively enhanced nbl expression is associated with the induction of internucleosomal DNA cleavage by actinomycin D.

Previous studies have found nbl expression to transiently rise and fall during glucocorticoid-induced thymic apoptosis. This induction of apoptosis is blocked by the transcriptional inhibitor actinomycin D. However, actinomycin D can trigger apoptosis in other cell types, e.g., HL-60 cells. This study found that internucleosomal DNA cleavage typical of apoptosis is induced by actinomycin D in cell lines such as HL-60 which constitutively express high levels of nbl above a certain "threshold." In contrast, "DNA ladder" formation was not induced by actinomycin D in cell lines with low constitutive nbl expression. Enhanced nbl expression therefore appears to be associated with apoptosis which is either blocked or induced by actinomycin D.

Amnion↗

PubMed1978

Effects of 3'deoxyadenosine and actinomycin D on RNA synthesis in toad bladder: analysis of response to aldosterone.

Previous studies have shown that aldosterone increases transepithelial active Na+ transport after a latent period of about 60 min and incorporation of 3H-uridine into polyadenylated RNA (poly(A)(+)RNA) (putatively poly(A)(+)mRNA) as early as 30 min after aldosterone addition. To assess the physiological importance of this pathway, the effects of 3'deoxyadenosine and actinomycin D were compared in studies on the urinary bladder of the toad Bufo marinus. 3'deoxyadenosine (30 microgram/ml) only partially, though significantly, inhibited the aldosterone-dependent increase in Na+ transport measured as short-circuit current (scc). The incorporation of 3H-uridine into poly(A) (+)RNA was inhibited by 70 to 80%. In contrast, Actinomycin D (2 microgram/ml) totally inhibited the aldosterone-dependent increase in scc, and the incorporation of 3H-uridine into poly(A)(+)RNA by 68 to 75%. 3'deoxyadenosine or actinomycin D alone had no significant effects on baseline scc, while inhibiting poly(A)(+)RNA to the same extent. The differential effects of deoxyadenosine and actinomycin on aldosterone-dpendent Na+ transport may be related to their different sites of action on RNA synthesis: both drugs inhibited, to a similar extent, cytoplasmic poly(A)(+)mRNA: however, 3'deoxyadenosine, in contrast to Actinomycin D, failed to inhibit poly(A)(-)RNA, sedimenting between 4S and 18S (putatively poly(A)(-)mRNA). We conclude that the mineralocorticoid action of aldosterone during the first three hours depends on the synthesis of both poly(A)(+)mRNA and poly(A)(-)mRNA.

Aldosterone↗

PubMed1988

The enzymatic reduction of actinomycin D to a free radical species.

Actinomycin D is an antitumor antibiotic in current clinical use. The ability of this and other antitumor antibiotics to undergo a reductive metabolism to produce free radical species has raised considerable interest in the literature in the past few years. The ability of actinomycin D to undergo a reductive metabolism was investigated using a ferredoxin reductase/NADPH system. This enzyme system has been used by a number of authors as a model for an enzymatic drug reducing system. In this study radical production was measured using direct ESR spectroscopy, the spin trapping technique, and oxygen consumption. It was shown that under anaerobic conditions the ferredoxin reductase/NADPH system could reduce actinomycin D to produce a semiquinone-imine free radical (aN = 2.8 (2N); aH = 2.8 (3H)). This radical production was found to be both drug and NADPH dependent. The effect of DNA on the drug's metabolism was also investigated. This was thought to be important because the proposed therapeutic action of the drug is centered on the DNA. Addition of calf thymus DNA to the reaction system abolished the signal produced by the actinomycin D, suggesting that intercalated actinomycin D is not a suitable substrate for ferredoxin reductase. Under aerobic conditions the ferredoxin reductase/NADPH/actinomycin D system generated the superoxide anion radical by reducing molecular oxygen. Evidence for this was obtained by spin trapping with 5,5-dimethyl-1-pyrroline N-oxide (DMPO). The DMPO-superoxide radical adduct was produced (aN = 14.4 G; aH beta = 11.4 G; aH gamma = 1.3 G). Production of this adduct was drug and NADPH dependent, and was inhibited by superoxide dismutase. Superoxide production was also monitored by oxygen consumption studies.

Anaerobiosis↗

PubMed1992

Scattering of the silver-stained proteins of nucleolar organizer regions in Ishikawa cells by actinomycin D.

Scattering of the silver-stained proteins of nucleolar organizer regions (Ag-NOR proteins) was produced by actinomycin D in Ishikawa cells. Scattering of Ag-NOR proteins was found only in cells treated with actinomycin D and various other agents had no effect. Scattering was dose-dependent up to 10(-2) micrograms/ml of actinomycin D, but it was not found at higher concentrations that caused marked inhibition of total DNA and RNA synthesis. Actinomycin D (10(-2) micrograms/ml) caused the following changes: (i) nucleolar segregation and (ii) emergence of dense fibrillar bodies in the nucleoplasm. Ag-NOR proteins were observed on the fibrillar centers and surrounding fibrillar components in control nucleoli, on the fibrillar and amorphous zones in segregated nucleoli, and on the dense fibrillar bodies emerging in the nucleoplasm. The scattering of Ag-NOR proteins was due to the argyrophilic nature of the dense fibrillar bodies. Actinomycin D (10(-1) micrograms/ml) also caused similar morphological alterations in the nucleolus and nucleoplasm, but Ag-NOR proteins were observed only on nucleolar remnants.

Antibiotics, Antineoplastic↗

PubMed1975

Mutagenicity of actinomycin D in Neurospora crassa.

Actinomycin D is known to bind to native DNA and is widely used as an antineoplastic agent and inhibitor of DNA-dependent RNA and protein synthesis. We report here the induction by actinomycin D of purple adenine-requiring mutants (ad-3) in wild-type Neurospora crassa. A significant increase in the frequency of ad-3 mutants was evident when the organism was grown vegetatively in the presence of actinomycin D; the mutation frequency was at least 3.6 per 106 survivors. The actinomycin D-induced ad-3 mutants were 29% ad-3A and 71% ad-3B. The ad-3B mutants were classed by complementation pattern as 25% nonpolarized complementing; 14% polarized complementing; and 61% noncomplementing. The spectrum of complementation types of the actinomycin D-induced mutants most closely parallels that of mutants induced by ICR-170, known to induce base-pair insertions or deletions, or that of X ray-induced or spontaneous mutants. It is significantly different from spectra seen following treatment with nitrous acid or N-methyl-N'-nitro-N-nitrosoguanidine, agents known to induce mainly base-pair substitutions.

Adenine↗

PubMed1986

Selective binding of actinomycin D induces a reversible conformational transition of nucleosomes.

Equilibrium and hydrodynamic studies on the complex of actinomycin D with H1-H5 depleted, 175 basepair nucleosomes are reported. By spectral titration the intrinsic affinities of actinomycin D for nucleosomes and for DNA are found strictly comparable. Sedimentation analysis shows that actinomycin can apparently unfold the nucleosome, like ethidium bromide and daunomycin, but it does so at a much lower bound drug to DNA molar ratio (about 1 drug molecule to 45 basepairs). Since about four bound actinomycin molecules are able to induce the reversible conformational transition of a nucleosome, it is suggested that the sites of interaction may correspond to the kinked DNA sites evidenced by Klug and collaborators (Richmond, T.J., Finch, J.T., Rushton, B., Rhodes, D. and Klug, A. (1984) Nature 311, 532-537) in the structure of the nucleosome. A relevance of these findings to the interaction of actinomycin with "active chromatin" is also suggested.

Animals↗

PubMed1988

Rubella virus replication: effect of interferons and actinomycin D.

The effect of alpha and gamma interferon (IFN alpha, IFN gamma) and actinomycin D on the expression of wild type rubella virus in African green monkey kidney cells (Vero 76) was studied. Viral protein synthesis in the infected cells was significantly reduced upon treatment of the cells with IFN alpha or IFN gamma, which is accompanied by the reduction in the level of both the (+) stranded and the (-) stranded viral RNAs. The residual rubella viral RNA from interferon-treated cells, however, was structurally intact as judged by Northern blot analysis and in vitro translation. These results suggest that the effect of IFN alpha and IFN gamma on rubella viral protein synthesis is both at the transcriptional and the translational level. The effect of actinomycin D on rubella virus replication was found to be time-dependent. It is much more pronounced during the eclipse phase of the viral growth (first 4 h) than after 8 h at which time actinomycin D had lesser effect. A similar effect on rubella virus replication was observed when alpha-amanitin was used instead of actinomycin D. These results were taken to indicate that during the viral infection, host cell DNA directs the synthesis of a cellular factor(s) which is essential for the viral replication. When the synthesis of this cellular factor(s) is terminated at an early stage of viral infection by actinomycin D or by alpha-amanitin, viral replication is impaired.

Amanitins↗

PubMed1989

Substitution in the poliovirus replicase gene determines actinomycin D sensitivity of viral replication at elevated temperature.

A series of ts+ revertants and recombinants derived from a temperature-sensitive plurimutant of poliovirus type 1 showed identical plaquing efficiencies at 37 degrees C and at 39 degrees C and exhibited similar yields and plaque morphology to wild-type virus. However, these viruses were characterized by clear inhibition of viral RNA synthesis at 39 degrees C, as measured by uridine incorporation in the presence of actinomycin D. Similarly, virus yields were decreased by one log in the presence of actinomycin D during infection at 39 degrees C. All the ts+ recombinants formed between temperature-sensitive mutants of poliovirus that were inhibited by actinomycin D carried a glutamine----histidine modification at residue 170 of their viral replicase (polypeptide 3D), due to a G----U substitution at nucleotide 6496. Inhibition of viral growth was increased by pretreatment of cells with actinomycin D for 3 h prior to infection, suggesting that actinomycin D sensitivity could reflect an increased dependence of viral RNA replication on host factor(s).

Dactinomycin↗

PubMed1995

Intracellular ATP is required for actinomycin D-induced apoptotic cell death in HeLa cells.

In the present report, we demonstrate that reduction of cellular ATP content with antimycin A blocks actinomycin D-induced apoptotic cell death in HeLa cells. Compared to cells (approximately 80%) treated with actinomycin D (1 microgram/ml; 48 h) alone in glucose-containing medium, a much smaller percentage of cells (approximately 20%) treated with actinomycin D in the presence of antimycin A in glucose-free medium shows morphological characteristic of apoptosis. ATP-depleted cells with or without actinomycin D treatment, on the other hand, die necrotically. In cells under actinomycin D short exposure treatment (1 microgram/ml; 1 h), apoptosis occurs when cellular ATP content is rapidly recovered after the removal of antimycin A and resupplementation of glucose-containing medium. In the incubation of isolated Triton-permeabilized cells with ATP ( > 0.5 mM), apoptotic nuclei become abundant 4 h after ATP treatment. These results implicate the requirement of ATP for the induction of apoptosis.

Adenosine Triphosphate↗

PubMed2005

Investigation of cell cycle arrest effects of actinomycin D at G1 phase using proteomic methods in B104-1-1 cells.

Actinomycin D was previously reported as an inhibitor of Shc/Grb2 interaction in B104-1-1 cells. Actinomycin D arrested the cell cycle at the G1 phase at 1nM, which is about 10 times lower than the inhibition of Shc/Grb2 interactions in B104-1-1 cells. To evaluate other mechanisms of actinomycin D affected suppression of tumors and cell growth, except inhibition of Shc/Grb2 interactions, we examined the proteomic expression profile by proteomic technology. We found up-regulation of MEKK3 and down-regulation of Hsp70 expression from proteomic analysis, which is a very interesting observation because MEKK3 is strongly related with G1 arrest of cell cycle and Hsp70 is also involved in cell cycle regulation. These results indicate that the anti-tumor effects of actinomycin D is due to synergic effects of various proteins regulated by the compound including inhibition of the Shc/Grb2 interaction and other signaling pathways in the cytoplasm. Here we provide a mechanism-based explanation for growth inhibition by actinomycin D using proteomic technology. Thus, this approach may be a potentially useful method to reveal new mechanisms of active compounds or drugs with unknown cellular function.

Animals↗

PubMed2006

Binding of actinomycin C1 (D) and actinomin to base-modified oligonucleotide duplexes with parallel chain orientation.

The binding of actinomycin D (C1, 1) and its analog actinomin (2) was studied on base-modified oligonucleotide duplexes with parallel chain orientation (ps) and with anti-parallel chains (aps) for comparison. Actinomycin D binds not only to aps duplexes containing guanine-cytosine base pairs but also to those incorporating modified bases such as 7-deazaguanine or its 6-deoxo derivative. For this, novel phosphoramidites were prepared. The new building block of 7-deaza-2'-deoxyguanosine is significantly more stable than the one currently used and allows normal oxidation conditions during solid-phase oligonucleotide synthesis. Actinomycin binds weakly to ps duplexes containing guanine-isocytosine base pairs but not to ps-DNA incorporating pairs of isoguanine-cytosine residues. On the contrary, the actinomycin D analog actinomin, which contains positively charged side chains instead of the chiral peptide rings, is strongly bound to both ps- and aps-DNA. Guanines, isoguanine, as well as other 7-deaza derivatives are accepted as nucleobases. Apparently, the pentapeptide lacton rings of actinomycin do not fit nicely into the groove of ps-DNA thereby reducing the binding strength of the antibiotic while the groove size of ps-DNA does not affect actinomin binding notably.

Binding Sites↗

PubMed1982

Vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum combination chemotherapy in metastatic testis cancer--a 1-year program.

Vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum were given in 31 men with stage III or bulky stage II malignant germ cell tumors of the testis and no previous chemotherapy, 25 of whom were evaluable. This regimen was given for 1 year and began with 3 successive inductions at 3 to 4-week intervals: 600 mg./m.2 intravenous cyclophosphamide, 4 mg./m.2 intravenous vinblastine, 30 mg. intravenous bleomycin and 1 mg./m.2 intravenous actinomycin D on day 1, followed by continuous 24-hour infusion of 20 mg./m.2 bleomycin per day on days 1 to 3 and 120 mg./m.2 intravenous cis-platinum with mannitol-enhanced diuresis on day 4. Any residual disease was resected 1 month after the third induction. If the resected specimen contained malignant tissue an additional 2 inductions (total 5) were given before brief maintenance with 6 mg./m.2 intravenous vinblastine and 1 mg./m.2 intravenous actinomycin D every 3 weeks for the remainder of 1 year. Complete remission occurred in 23 of 25 evaluable patients (92 per cent) and 20 (80 per cent) remain free of disease with a median followup of more than 27 months. Patients with minimal metastatic deposits and those without teratoma in the testis tumor had high complete remission rates with chemotherapy alone. Patients with advanced disease and with teratoma in the primary tumor benefited more frequently from the combined approach. Myelosuppression was the major potentially serious toxic effect. Vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum were superior to prior vinblastine, actinomycin D and bleomycin programs because higher complete remission rates were achieved with shorter duration of treatment and lesser disability.

Adolescent↗

PubMed1997

Comparison of the lethal effects of different actinomycins on a repair-deficient strain of Escherichia coli.

We report here the isolation and purification of a genotoxic antibiotic from the culture medium of a Streptomyces strain. The antibiotic was identified as actinomycin X2 by using a database search (AntiBase). In the previous studies a related compound, actinomycin D, has been shown to be non-mutagenic in the salmonella/microsome assay and several other bacterial systems. The fact that an actinomycin was detected by a bacterial repair assay seems to contradict these results. Therefore we tested several actinomycins by differential killing assay based on the same Escherichia coli strains that were used in our screening bioassays. According to our results the uvrA, recA double mutant sensitizes E. coli to the genotoxic effects of actinomycins.

Adenosine Triphosphatases↗

PubMed1994

Use of a photoactive derivative of actinomycin to investigate shuffling between binding sites on DNA.

A photoreactive analog of actinomycin (7-azidoactinomycin D) has been used in experiments to probe directly the shuffling hypothesis of Fox and Waring [Fox, K. R., & Waring, M. J. (1984) Nucleic Acids Res. 12, 9271-9285]. According to this theory, actinomycin D molecules initially interact with non-sequence-specific sites on DNA and subsequently "shuffle" along the polymer in a one-dimensional migratory fashion so as to locate their preferred sequence-dependent binding sites. In the study presented here, the drug-DNA complex was allowed to equilibrate (in the dark) for various periods of time, followed by photolysis which renders the complex irreversible and traps the ligand at its instantaneous binding sites. Visualization of the piperidine-labile sites and investigation of how the intensity of reaction at each site changes with time can provide direct confirmation of the shuffling hypothesis. The data reveal that actinomycin D does indeed engage in shuffling along the DNA. After only short equilibration times (20 s) actinomycin D is observed to bind to a variety of sites on the DNA, including many which are not regarded as canonical preferred binding sites at equilibrium. However, after longer periods of equilibration the intensity of reaction is shown to drop as a function of time at nonspecific sites, with corresponding increase at sequence-specific sites. In addition, base sequences which flank the intercalation sites can be seen to play a major role in influencing the binding and sequence specificity of actinomycin.

Base Sequence↗

PubMed1975

Synthesis and antitumor activity of 2-deamino- and N2-(gamma-hydroxypropyl)actinomycin D.

2-Deamino- and N2-(gamma-hydroxypropyl)actinomycin D were synthesized by modification of the parent actinomycin D molecule at the 2 position of the phenoxazinone moiety. The common intermediate was 2-deamino-2-chloroactinomycin D. Catalytic hydrogenation of this material afforded the 2-deamino derivative while treatment with gamma-hydroxypropylamine yielded the N2-(gamma-hydroxypropyl) derivative. These 2-substituted actinomycin D derivatives were less potent in microbiological assays than the parent compound. Evaluation of activity in vivo against three murine tumor systems indicated that optimal dose levels of 2-deaminoactinomydin D were 50 times greater than toxic dose levels of actinomycin D. N2-(gamma-hydroxyporpyl)actinomycin D exhibited antitumor activity similar to the parent compound.

1-Propanol↗

PubMed1985

"Reverse" and "symmetrical" analogues of actinomycin D: metabolic activation and in vitro and in vivo tumor growth inhibitory activities.

Two new classes of actinomycin D analogues, tetracyclic "reverse" analogues and a tricyclic "symmetrical" analogue of actinomycin D, are reported. These analogues bind to DNA and the binding does not occur by an intercalation mechanism. The analogues inhibit the synthesis of DNA and RNA in P388 tumor cells and the growth of CCRF-CEM cells in vitro at nanomolar concentrations. The tetracyclic "reverse" analogues, which are structurally related to the previously reported actinomycin D oxazolyl analogues, are metabolized in the presence of rat hepatic microsomes and tumor cell homogenates. The metabolism takes place with the loss of the oxazole ring; thus the "reverse" analogues produce a major metabolite which is the "symmetrical" analogue; the actinomycin oxazolyl analogues generate 7-hydroxyactinomycin D. Further, the microsomes activate the analogues to free-radical states which catalyze the production of superoxide as shown by stimulation of epinephrine oxidation and also indicated by electron paramagnetic resonance studies. The "symmetrical" and "reverse" analogues also demonstrate very high activities in these systems. In in vivo studies using P388/S, P388/ADR leukemia, and B16 melanoma in mice, the analogues showed increased activity and superior therapeutic index values, in comparison to actinomycin D.

Animals↗