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PubMed1996

Suppression of actinomycin D-induced apoptosis by the NS3 protein of hepatitis C virus.

The NS3 protein of hepatitis C virus is a multifunctional protein that is indispensable for virus replication. Little is known, however, about the possible effects of the NS3 on host cell function(s). In the present study, we demonstrated that NIH3T3 cells constitutively expressing a carboxy-terminally truncated NS3 (NS3DeltaC) were more resistant to actinomycin D-induced apoptosis than the control cells. We also observed that induction of p53 expression by actinomycin D treatment was weaker in the NS3DeltaC-expressing cells than in the control cells. However, induction of WAF1 expression by the same treatment was not different between the two groups. Taken together, our results suggest the possibility that expression of NS3DeltaC suppressed actinomycin D-induced apoptosis of NIH3T3 cells through at least partly, if not solely, a p53-dependent, WAF1-independent pathway.

3T3 Cells↗
PubMed1999

Nitric oxide ameliorates actinomycin D/endotoxin-induced apoptotic liver failure in mice.

Liver damage induced by lipopolysaccharide (LPS) in actinomycin D-sensitized mice was initiated by a Fas/CD95-independent apoptotic process that produced DNA fragmentation in hepatocytes followed by an increase of plasma ALT. The metabolic inhibitor actinomycin D blocked most of the LPS-induced increase of plasma nitrite/nitrate levels, as did administration of a nitric oxide synthase inhibitor, N(G)-monomethyl-l-arginine, which also promoted LPS-induced apoptotic liver damage. Administration of nitric oxide donors (hydroxylamine, S-nitroso-N-acetylpenicillamine or 2, 2'-(hydroxynitrosohydrazino)bis-ethanamine) resulted in elevation of the plasma nitrite/nitrate level and amelioration of actinomycin D/LPS-induced apoptotic liver damage. The protective effect of nitric oxide against apoptotic liver damage was partially reproduced by a membrane-permeable analog of cyclic GMP. On the other hand, treatment with the soluble guanylate cyclase inhibitor LY83583 overcame the protective effect of nitric oxide against apoptotic liver damage. These results suggest that nitric oxide may regulate programmed cell death in the mouse liver and that induction of genes, including inducible nitric oxide synthase, plays an important role in protecting the liver against LPS-induced apoptotic damage. This effect appears to be mediated, at least in part, via the soluble guanylate pathway.

Aminoquinolines↗
PubMed1977

Effect of actinomycin D on the structure of the chromatoid body in the rat spermatids.

The effect of actinomycin D on the chromadoid body of rat spermatids has been studied by light and electron microscopy, high resolution autoradiography and biochemical methods. Actinomycin D caused structural changes in the chromatoid body of young round nucleated spermatids. The normal irregularily lobulated chromatoid body acquired a ring-like configuration 12 h after an intratesticular injection of 2 microgram of the drug. The labelling of the chromatoid body with 3H-uridine which can normally be seen after 12 h was also abolished by actinomycin D. These observations lead to the suggestion that the chromatoid body contains a store of long-lived mRNA molecules that are activated later during spermiogenesis when transcription in the spermatid nucleus has ceased but a high level of protein synthesis still persists.

Animals↗
PubMed1980

Actinomycin D in the treatment of advanced breast cancer.

Actinomycin D is generally administered by serial low-dose injection over 5-10 days. Recent recognition of prolonged serum and tissue half-lives suggests that high-dose intermittent injecton should be equally effective and less toxic. An intermitten single dose schedule was selected for this phase II trial of actinomycin D in 23 patients with advanced breast cancer refractory to standard combination chemotherapy. The drug was given in doses of 0.75-1.5 mg/m2 at 2-week intervals or on days 1 and 8 of 28-day treatment cycles. One patient obtained a partial response with a duration of 5.7 months. Four patients experienced stabilization of advanced disease, with a mean duration of response of 6.4 months. Gastrointestinal toxicity occurred in 47% of patients and mild to moderate myelosuppression in 39%. We conclude that actinomycin D in this dosage and schedule has limited activity in advanced breast cancer. Higher doses might result in increased response rates but would be associated with greater toxicity.

Breast Neoplasms↗
PubMed1976

Status spongiosus of rat central nervous system induced by actinomycin D.

The effect on central myelin of Actinomycin D, an RNA--and, secondarily, a protein-synthesis inhibitor, has been studied by light and electron microscopy. The intracranial injection of this drug produced an extensive status spongiosus of the white matter in the cerebrum, cerebellum, brain stem and optic nerve within 48 h. The status spongiosus was due to vacuole formation within the myelin sheath and to enlargement of the extracellular space. Three types of vacuoles were observed: (a) the most common varieties formed between the inner tongue and the remainder of the myelin sheath; (b) a second variety formed by enlargement of the periaxonal space with separation of the axon from its myelin sheath, and (c) a less common type of vacuolization was due to splitting of the myelin lamellae at the interperiod line to form large intramyelinic vacuoles. Myelinic vacuoles were preceded by nuclear and cytoplasmic changes in oligodendrocytes, which included nucleolar segregation, disaggregation, and diminution in number of ribosomes. These changes were similar to those previously reported in a variety of cells exposed to Actinomycin D. It is suggested that myelin vacuoles result secondarily from the Actinomycin D inhibitory effect on oligodendroglial RNA--and protein-synthesis, rather than from a direct effect of this drug on the myelin sheath.

Animals↗
PubMed1997

Delocalization of some small nucleolar RNPs after actinomycin D treatment to deplete early pre-rRNAs.

Retention of some components within the nucleolus correlates with the presence of rRNA precursors found early in the rRNA processing pathway. Specifically, after most 40S, 38S and 36S pre-rRNAs have been depleted by incubation of Xenopus kidney cells in 0.05 microg/ml actinomycin D for 4 h, only 69% U3 small nucleolar RNA (snoRNA), 68% U14 snoRNA and 72% fibrillarin are retained in the nucleolus as compared with control cells. These nucleolar components are important for processing steps in the pathway that gives rise to 18S rRNA. In contrast, U8 snoRNA, which is used for 5.8S and 28S rRNA production, is fully retained in the nucleolus after actinomycin D treatment. Therefore, U8 snoRNA is in a different category than U3 and U14 snoRNA and fibrillarin. It is proposed that U3 and U14 snoRNA and fibrillarin, but not U8 snoRNA, bind to the external transcribed spacer or internal transcribed spacer 1, and when these binding sites are lost after actinomycin D treatment some of these components cannot be retained in the nucleolus. Other binding sites may also exist, which would explain why only some and not all of these components are lost from the nucleolus.

Animals↗
PubMed1979

Effects of actinomycin D on ribosomal RNA and protein synthesis as revealed by high resolution autoradiography.

Incorporation of tritiated amino acids and uridine was studied in untreated and actinomycin D treated HeLa cells by high resolution autoradiography. Results showed a non-selective inhibition of protein synthesis by actinomycin, as measured by the decrease in radioactive amino acid uptake. When cells pretreated with actinomycin D were incubated with radioactive amino acids and uridine, amino acid uptake in the nucleolus still occurred, while uridine uptake was almost completely eliminated. These findings suggest that in the absence of ribosomal RNA precursor synthesis, nucleolar protein synthesis continues to some extent, and that this protein is transported to the nucleolus.

Cell Nucleolus↗
PubMed1999

Tumor necrosis factor-alpha plus actinomycin D-induced apoptosis of L929 cells is prevented by nitric oxide.

Treatment with the nitric oxide-(NO)-generating compound S-nitroso-N-acetylpenicillamine protected cul-tured L929 cells from apoptosis induced by tumor necrosis factor-alpha (TNF-alpha) plus actinomycin D, as determined by the detection of DNA fragmentation and morphological changes. NO also prevented an enhancement of the production of reactive oxygen intermediates by TNF-alpha plus actinomycin D, as assessed by the oxidation of dihydrorhodamine 123 and hydroethidine. Because the inhibition of mitochondrial respiration by rotenone or antimycin A suppressed the increased oxidation of both dihydrorhodamine 123 and hydroethidine, it was suggested that TNF-alpha accelerated the leakage of reactive oxygen intermediates from the mitochondrial electron transport system. Polarography showed that NO reversibly inhibited mitochondrial respiration at either complexes I-III, II-III, or IV, thus suggesting the inhibition of cytochrome oxidase. Taken together, these findings indicate that the decreased mitochondrial formation of reactive oxygen intermediates in the presence of NO might have a protective effect against TNF-alpha plus actinomycin D-induced apoptosis.

Animals↗
PubMed1975

The effect of actinomycin D on estrogen-induced uterine blood flow.

The effect of actinomycin D on estrogen-induced uterine blood flow was studied in four nonpregnant, oophorectomized sheep, utilizing electromagnetic flow probes chronically implanted around the uterine arteris. Two hours after the intravenous injection of 1 mug of estradiol-17beta per kilogram of body weight, incorporation of [3H]-uridine into RNA was two- to threefold higher (2.7 plus or minus 0.4 S.E.M.) in the control horn than the uterine horn that had received an intra-arterial injection of actinomycin D. Actinomycin D had no effect on the estrogen-induced increase in uterine blood flow.

Animals↗
PubMed1977

Actinomycin D inhibits hemoglobin synthesis in rabbit reticulocyte lysates and binds to a 15 S cytoplasmic particle involved in the initiation step of translation.

Actinomycin D inhibits hemoglobin synthesis in rabbit reticulocyte lysates by affecting initiation of globin polypeptide chains. To obtain information on the distribution of actinomycin-sensitive structures among the components of the translation machinery, a reticulocyte lysate is incubated with [3H]actinomycin. The tritium label is found associated with ribosomes actively engaged in protein synthesis and with a 15 S cytoplasmic particle. During cell-free incubation or when initiation is inhibited by aurintricarboxylic acid, the labeling of the 15 S particles increases, suggesting that they are relased from ribosomes into the cytoplasm and play a role in the initiation process. The 15 S cytoplasmic particles contain a DNAase-sensitive component, probably complexed with ribonucleic acids and proteins. A possible role of these DNA-containing particles in the initiation step of translation is discussed.

Aurintricarboxylic Acid↗
PubMed1978

The interaction of 7-substituted actinomycin D analogs with DNA.

The interaction of actinomycin D and three new 7-substituted analogs with calf thymus DNA has been studied by a number of physical techniques. The methods utilized in this investigation include visible absorption spectrometry and ultrafiltration methodology for the determination of equilibrium binding constants; viscometry; and circular dichroism. The studies show that the 7-substituted actinomycin D analogs retain the G . C base pair specific DNA binding demonstrated by actinomycin D. The mode of binding to native DNA, despite substitution at position 7, is practically unaltered. The retention of this binding specificity by these analogs seems to be unaffected by changes in the electon properties of the chromophore.

Animals↗
PubMed1976

Actinomycin D-induced enhancement of ubiquinone biosynthesis in rat.

Administration of actinomycin D to fasted rats induces an enhancement of the labeling of hepatic ubiquinone by [2-14C] acetate both in vivo and in vitro. The incorporation of [2-14C] mevalonate into ubiquinone is also increased, although to a significantly lesser extent; this, however, presumably results from greater uptake of the labeled precursor by liver of drug-treated rats. The drug-administered animals show increased activity of liver microsomal mevalonate: NADP oxidoreductase, the rate-limiting enzyme in isoprenoid biogenesis. The incorporation of [u-14C] benzoic acid and CH3-[14C] methionine into ubiquinone in liver slices, however, reveals a decrease in actinomycin D administered rats. This appears to be due to a specific inhibition of the pathway leading to the benzoquinone moiety of ubiquinone and not to an increase in the pool-size of the precursors. The stimulatory effect of the drug on ubiquinone biosynthesis is also observable in cholesterol-fed rats. The actinomycin D-induced increase in ubiquinone biosynthesis is dependent on new protein synthesis since the effect is abolished by treating the animals with either cycloheximide or puromycin.

Alcohol Oxidoreductases↗
PubMed1986

Inhibition of microtubule assembly by actinomycin D, an anti-tumour drug.

Effect of actinomycin D, an antibiotic, was investigated on the biological function of tubulin from bovine brain. The microtubule assembly was inhibited nearly completely when an equal molar ratio of actinomycin D and tubulin was used. The depolymerisation of the same, however, was not altered under the same conditions. The competence of tubulin to bind colchicine and GTP was also not affected. Chromatographic and the spectrophotometric studies showed that 0.94 mol of actinomycin D binds per mole of tubulin.

Animals↗
PubMed1986

Effects of actinomycin D on contractile properties of denervated rat skeletal muscle.

We studied the mechanical and electrical properties in the extensor digitorum longus muscle of Wistar rats in vitro 4 days after denervation. In a group of animals, actinomycin D was injected intravenously at the time of denervation. The prolongation of contraction and relaxation time, and the increase in twitch tension observed in denervated muscles were prevented by the drug. Other denervatory changes such as the elimination of cooling potentiation, posttetanic potentiation, staircase phenomenon, and shortening of caffeine contracture were also inhibited or partially reverted by actinomycin D. In addition, some electrical denervatory changes such as the decrease of resting membrane potential and slowing of maximum rate of fall of the action potential were partially abolished by actinomycin D. These results support the hypothesis that a new synthesis of proteins is related to denervation changes.

Animals↗
PubMed1986

Computer modeling of actinomycin D interactions with double-helical DNA.

We have performed molecular mechanical calculations on intercalation complexes of actinomycin D with a series of base-paired hexanucleoside pentaphosphates; d(GCGCGC)2, d(GCCGGC)2, d(GCATGC)2, d(GCTAGC)2 and d(ATGCAT)2. Our results are in good agreement with previous experimental work on sequence selectivity. The results provide a rationalization for the strong preference of actinomycin D to intercalate on the 3' side of guanine residues, consistent with previously proposed models. Finally, the computed structures for d(ATGCAT)2-actinomycin D complexes have been compared with two-dimensional nuclear magnetic resonance nuclear Overhauser effect experimental results. To our knowledge, this is the first extensive comparison of molecular mechanical model structures for a drug-DNA complex with experimental solution phase data. We find generally good agreement between our computational models and the experimental solution phase structures.

Computers↗
PubMed1992

Crystal structure of the 2:1 complex between d(GAAGCTTC) and the anticancer drug actinomycin D.

The crystal structures of the 2:1 complex of the self-complementary DNA octamer d(GAAGCTTC) with actinomycin D has been determined at 3.0 A resolution. This is the first example of a crystal structure of a DNA-drug complex in which the drug intercalates into the middle of a relatively long DNA segment. The results finally confirmed the DNA-actinomycin intercalation model proposed by Sobell & co-workers in 1971. The DNA molecule adopts a severely distorted and slightly kinked B-DNA-like structure with an actinomycin D molecule intercalated in the middle sequence, GC. The two cyclic depsipeptides, which differ from each other in overall conformation, lie in the minor groove. The complex is further stabilized by forming base-peptide and chromophore-backbone hydrogen bonds. The DNA helix appears to be unwound by rotating one of the base-pairs at the intercalation site. This single base-pair unwinding motion generates a unique asymmetrically wound helix at the binding site of the drug, i.e. the helix is loosened at one end of the intercalation site and tightened at the other end. The large unwinding of the DNA by the drug intercalation is absorbed mostly in a few residues adjacent to the intercalation site. The asymmetrical twist of the DNA helix, the overall conformation of the two cyclic depsipeptides and their interaction mode with DNA are correlated to each other and rationally explained.

Base Composition↗
PubMed1986

Depletion-replenishment of the testicular estrogen receptor: sensitivity to cycloheximide and actinomycin D.

Male rats (30-35 days old) were utilized to examine the process of depletion and replenishment of the testicular cytosolic estrogen receptor and to investigate the effects of cycloheximide and actinomycin D on these processes. The dose dependence and temporal nature of receptor depletion and replenishment were investigated. Maximum depletion (greater than 90%) occurred by 1 h after in vivo administration of either 5 or 10 micrograms estradiol-17 beta. Depletion of the cytosolic receptor at 1 h occurred concomitant to a marked increase in nuclear receptor thus indicating translocation. Receptor replenishment to control levels was observed by 6 h post treatment. To determine the requirements for transcriptional and translational events in the replenishment process, actinomycin D and cycloheximide were administered in vivo. Simultaneous treatment with cycloheximide and estradiol resulted in a significant inhibition of replenishment at 6 and 12 h post treatment of 46 and 60% below control levels, respectively. Cycloheximide treatment alone had no effect on receptor levels. A significant inhibition of replenishment at 6 h was also shown when cycloheximide was given 3 h after estradiol treatment. Cycloheximide administration at 6 h after estradiol significantly suppressed receptor levels at 12 h suggesting that replenished receptor levels at 6-12 h are in a state of rapid turnover. Receptor replenishment exhibited a different response to actinomycin D treatment in that significant inhibition was observed only when the drug was administered at 3 h after estradiol treatment. These results demonstrate that testicular cytosolic receptor depletion is dose and time dependent. The results further demonstrate that receptor replenishment involves protein synthesis and suggests that synthesis of new RNA might also be required.

Animals↗
PubMed1982

Multi-enzyme-targeted chemotherapy by acivicin and actinomycin.

On the basis of our observation of the increased specific activities of glutamine-utilizing enzymes in purine and pyrimidine metabolism in hepatoma 3924A, and because the concentration of glutamine is ten times lower in the hepatomas than in the liver, the biochemical pharmacology of the anti-glutamine agent, acivicin, was examined. (1) Acivicin competitively inhibited the activities of amidophosphoribosyl-transferase, CTP synthetase and carbamoyl-phosphate synthetase II from extracts of liver and hepatoma 3924A. (2) In addition to the competitive inhibition exerted by acivicin, evidence was obtained that this drug also irreversibly inactivated in vitro the glutamine-utilizing enzymes. It is particularly relevant for the selectivity of acivicin that the activity of aspartate carbamoyltransferase, an enzyme present in the same complex as carbamoyl-phosphate synthetase II, was not affected by the anti-glutamine agent. (3) Acivicin in vivo brought down the activities of glutamine-utilizing enzymes in a period of 10 min to 1 hr after injection. CTP synthetase activity declined to less than 10% of that observed in the uninjected rats. The decreases were not reversible by various in vitro methods, but in vivo the activities returned to normal range in 72 hr. (4) The activity of aspartate carbamoyltransferase, which exists as a multi-enzyme complex with synthetase II, was not altered by acivicin injection. Similar results were observed in transplantable sarcoma in the rat. (5) The acivicin-induced decrease in enzymic activities could not be restored by purification of the enzymes. (6) In vitro studies indicated that addition of acivicin to liver or hepatoma extracts or purified enzymes rapidly decreased enzymic activities; the activities could not be restored. These results are consistent with an interpretation that acivicin acts either as a tight-binding inhibitor or as an inactivator through alkylation of the enzymes of glutamine utilization. (7) Acivicin in combination with actinomycin provided a synergistic kill of hepatoma cells in tissue culture and also inhibited the growth of transplantable solid hepatoma 3924A in the rat. (8) The synergistic biological results of combination chemotherapy with acivicin and actinomycin can be accounted for by the action of acivicin in inhibiting GMP and CTP synthetases, resulting in a decrease in GTP and CTP content, and by the actinomycin-caused inhibition of RNA polymerase in selectively blocking the utilization of GTP and CTP.

Animals↗