Actinomycins inhibition

G. Weber, R.L. Singhal and lA. B. Stamm, Actinomycin Inhibition of Cortisonein-duced Synthesis of Hepatic Gluconeogenic Enzymes, Science, N. Y. 142, 390-392 (1963). 

The analysis of actinomycin inhibition on the differentiation of a number of organs (Table 2) demonstrated the appearance of stable mRNA during certain periods of embryogenesis, differing for the various embryonic parts. This stable mRNA determined the resistance of developed organs to antibiotic action (Collier, 1966). 

Actinomycin inhibits the growth of gram-positive bacteria and its mechanism of action appears to be related to its abihty to inhibit the DNA-dependent RNA synthesis. Since S. antibioticus synthesizes 70 to 120 (xg of actinomycin/ml of culture medium, the apparent insensitivity of the organism to the high concentrations of the elaborated antibiotic is paradoxical in light of the mode of action proposed for actinomycin. Furthermore, 70 to 75 % of the mycehum synthesized occurs before antibiotic synthesis is detected in the medium and very little growth takes place after the actinomycin titer reaches 15 to 20 (xg/ml of medium. 

Those herbicides that block mitotic entry decrease or prevent the formation of mitotic figures in meristems. Amino acid, protein, RNA, DNA, and ATP synthesis and/or utilization can all attest cell growth (163,166). Although not registered as herbicides, cycloheximide [66-81-9] inhibits mitotic entry by inhibiting protein synthesis (167) hydroxyurea/727-(97-/7 inhibits DNA synthesis (168) and actinomycin D [50-76-0] nh2oix.s RNA synthesis (167). 

Phenoxazines — The microbial phenoxazines like actinomycins are well-known antibiotics. Actinomycin D produced by Streptomyces anibioticus is an effective antineoplastic agent that inhibits nucleic acid synthesis. The main function of ommochromes is to act as screening pigments in the eyes of insects and other arthropods, as pattern pigments in the integument, and as excretion products of excess tryptophan. ... 

There is a single prokaryotic RNA polymerase that synthesizes all types of RNA in the cell. The core polymerase responsible for making the RNA molecule has the subunit structure Ojpp. A protein factor called sigma (a) is required for the initiation of transcription at a promoter. Sigma factor is released immediately after initiation of transcription. Termination of transcription sometimes requires a protein called rho (p) faaor. This enzyme is inhibited by rifampin. Actinomycin D binds to the DNA preventing transcription. 

Transcription factors (such as TFIID for RNA polymerase II) help to initiate transcription. The requirements for termination of transcription in eukaryotes are not well understood. All transcription can be inhibited by actinomycin D. In addition, RNA polymerase II is inhibited by a-amanitin (a toxin from certain mushrooms). These points are summarized in Table 1-3-1,... 

Inhibited by rifampin Actinomycin D RNAP 2 inhibited by a-amanitin (mushrooms) Actinomycin D... 

Perhaps a bit more subtle than those agents that react chemically with DNA are those that insert themselves between the stacked bases of the DNA double helix— intercalation. This alters the regular structure of the DNA molecule and may lead, for instance, to inhibition of mRNA synthesis. The structures of the intercalcating agents are generally quite complex and I will spare you the complexity. However, three names may be familiar—dactinomycin (Actinomycin D), daunorubicin (daunomycin), and doxorubicin (Adriamycin)— and intercalation is how they work. All three are natural products and were isolated from the fermentation broths of Streptomyces species. 

In this situation, cell lines are shown to be resistant to colchicine, doxorubicin, vinblastine, and actinomycin D. This syndrome is accompanied by an increase in measurable membrane glycoprotein (the P-170 or permeability glycoprotein). It is believed that this protein transports hydrophobic chemicals out of cells and thereby prevents drug action. Current efforts to inhibit this efferent transport protein are currently underway but, sadly, have to date been largely unsuccessful (i5). 

The use of antibiotics for the control of plant virus diseases( ) is of interest. Several antibiotics have been tested for inhibition of replication of viral nucleic acid and/or protein synthesis within the host cell. Chloramphenicol, cycloheximide, actinomycin D and others are the most used antibiotics and the disease caused by tobacco mosaic... 

The induction of PAL activity at the onset of vascular differentiation can be shown by the use of plant tissue cultures (37-39). Xylem cells with secondary and lignified walls are differentiated over a time course of 3-14 days by the application of the plant growth factors naphthylene acetic acid (NAA) and kinetin in the ratio 5 1 (1.0 mg/liter NAA, 0.2 mg/liter kinetin) to tissue cultures of bean cells (Phaseolus vulgaris) (37,40). The time for differentiation varies with the type of culture, solid or suspension, and with the frequency and duration of subculture, but for any one culture it is relatively constant (37,41,42). At the time of differentiation when the xylem vessels form, the activity of PAL rises to a maximum. The rising phase of the enzyme activity was inhibited by actinomycin D and by D-2,4-(4-methyl-2,6-dinitroanilino)-N-methylpropionamide (MDMP) applied under carefully controlled conditions (42). This indicated that both transcription and translation were necessary for the response to the hormones. Experiments using an antibody for PAL and a cDNA probe for the PAL-mRNA have also shown that there is an increase in the amount of transcript for PAL during the formation of lignin when Zinnia mesophyll cells are induced to form xylem elements in culture (Lin and Northcote, unpublished work). 

Dactinomycin (actinomycin D, Cosmegen) is one of a family of chromopeptides produced by Streptomyces. It is known to bind noncovalently to double-strand DNA by partial intercalation, inhibiting DNA-directed RNA synthesis. The drug is most toxic to proliferating cells, but it is not specific for any one phase of the cell cycle. Resistance to dactinomycin is caused by decreased ability of tumor cells to take up and retain the drug, and it is associated with cross-resistance to vinca alkaloids, the anthracyclines, and certain other agents (multidrug resistance). 

The early work of Fineberg and Greenberg 128) as well as that of Drysdale and Monroe 129) indicate that oral or intramuscular administration of iron enhances the rate of ferritin synthesis in the intestinal mucosa as well as other tissue. Drysdale and Monroe foimd little effect of actinomycin, an inhibitor of RNA synthesis, on iron-induced ferritin synthesis and suggested that the apoferritin was stabilized by being bound to the iron core. Recently Yoshino et al. 130) using higher concentrations of actinomycin were able to inhibit markedly the induced synthesis of ferritin. The mechanism for iron induction of ferritin is certainly not clear at this time. 

Induction involves increased synthesis of enzyme protein, which may be detected as an increase in total enzyme level as with phenobarbital induction or increase in a particular isoenzyme. Protein synthesis is increased, and this usually seems to be necessary as inhibition of protein synthesis results in inhibition of induction. The increased protein synthesis may involve increased mRNA synthesis and inhibitors of this, such as actinomycin D, block induction. For a simple diagram explaining the relationship of protein synthesis to DNA see Figure 6.38. 

It is well established that actinomycin D inhibits DNA-directed RNA synthesis by binding to guanosyl residues in the DNA molecule. This disrupts the transcription of genetic information and thereby interferes with the production of essential proteins. DNA synthesis may also be inhibited, being reduced by 30% to 40% in utero. It is clear that in the initial stages of embryogenesis, synthesis of RNA for protein production is vital, and it is not surprising that inhibition of this process may be lethal. 

The elongation of RNA strands by RNA polymerase in both bacteria and eukaryotes is inhibited by the antibiotic actinomycin D (Fig. 26-10). The planar portion of this molecule inserts (intercalates) into the doublehelical DNA between successive G=C base pairs, deforming the DNA. This prevents movement of the polymerase along the template. Because actinomycin D... 

Streptolydigin inhibits both initiation and elongation. Actinomycin D, by binding to DNA, inhibits DNA polymerases as well as RNA polymerases, the... 

Acid DNase is strongly inhibited by actinomycin D. In contrast with the claim (44) that actinomycin causes the same extent of inhibition of... 

Actinomycin D. An antibiotic that binds to DNA and inhibits RNA chain elongation. 

The antibiotics that bind to DNA are nonspecific to the cell-cycle phase. Dactinomycin (actinomycin D and Cosmegen) binds to double-stranded DNA and prevents RNA synthesis by inhibiting DNA-dependent RNA polymerase. It is administered intravenously in the treatment of pediatric solid tumors such as Wilms tumor and rhabdomyosarcoma and for gestational choriocarcinoma. Dactinomycin causes skin reactions, gastrointestinal injury, and delayed bone marrow depression. 

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