Actinomycins characteristics

Fig. 1. Time course of cell death parameters in tumor necrosis factor (TNF)-induced apoptosis. Human hepatoma cells (HepG2) were incubated in the presence of 400 nM actinomycin D plus 1.6 ng/ml recombinant human TNF (rhTNF)-a. MTT-dye reduction (parameter of mitochondrial function), lactate dehydrogenase (LDH) release (parameter for cell membrane rupture), and DNA fragmentation (parameter associated with typically apoptotic nuclear changes) were determined over a time period of 24 h. As is characteristic of apoptotic cell death, DNA fragmentation always preceded the other death parameters. Similar findings have been obtained in primary hepatocyte cultures and murine livers...

For this review another classification is used. As the majority of peptide antibiotics are of unknown structure and cannot therefore be classified chemically, they are grouped according to the organism which produces them. At the beginning of every section, the peptide antibiotics are listed in a table which gives the known characteristics and the literature. Only the clinically useful members are described in detail. Furthermore, only those peptide antibiotics which consist mainly of amino acids in peptide linkages are fully considered. The important actinomycins , penicillins and cephalosporins, which have been reviewed several times in recent years, are not included here. Amino acids and amino acid residue sequences are denoted in accordance with the suggestions of the committee on nomenclature which reported at the Fifth European Peptide Symposium . When necessaiy the direction of the —CO NH— bond is indicated by an arrow (— )., ... 

Many other examples were then discovered. The principal androgenic steroid, dihydrotestosterone, was found to be quite specifically bound by an acidic protein in androgen-dependent tissues such as the prostate gland (Anderson and Liao, 1968). Corticosteroids, too, are bound by specific protein in the cytoplasm of liver and some other cells, and the complex enters the nucleus where it is bound by DNA. This leads to the appearance of a specific mRNA (its formation suppressable by actinomycin D) which, in turn, produces enzymes characteristic of the corticosteroid (Sekeris, 1971). A similar sequence governs the diuretic effect of aldosterone (Edelman, Bogoroch and Porter, 1963). 

Suppression by excess nutrients has been found in the biosynthesis of polyketides (D 3.3), of gibberellins (D 6.3), of certain antibiotics, e.g., streptomycin (D 1.3), neomycin C (D 1.3), actinomycins (D 8.4.1), chloramphenicol (D 8.2), bacitracin A (D 23), enniatin B (D 23), cephalosporins (D 23.3), and penicillins (D 23.3), of alkaloids, e.g., benzodiazepines (D 8.4.2), and ergolines (D 21.2) etc. Usually the suppression of secondary product formation is accompanied by the suppression of other characteristics of cell specialization (such as conidiospore formation in Peni-cillium cyclopium), indicating a general influence of nutrient supply on cell specialization. 

Protein synthesis in mitochondria is dependent on the suppty of ATR either oxidative phosphorylation, or a steady supply of ATP must be provided. From a pharmacological standpoint, it is interesting that the incorporation of amino acids is affected by th3iroid hormone in vivo. The labelled amino acids are incorporated into an insoluble protein fraction present in the membrane and none of the soluble mitochondrial enzymes studied so far become labelled to any appreciable extent. The process of protein synthesis in mitochondria, as monitored by the incorporation of amino acids, displays some peculiar characteristics it is inhibited by a variety of other amino acids, possibly due to competitive effects among different amino acids for a common transport mechanism. Also peculiar is the sensitivity to chloramphenicol, and the insensitivity to cycloheximide, which is typical of bacterial systems, and not of microsomal systems. Then, there is the observation that actinomycin-D (a known inhibitor of the nuclear DNA-dependent RNA polymerase), inhibits protein synthesis in mitochondria after treatments have been applied which affect the permeability of the membrane, thus permitting penetration of the antibiotic. This last observation indicates synthesis of messenger RNA in mitochondria via a specific DNA-dependent RNA polymerase. Protdn synthesis in mitochondria is thus apparently dependent on the continuous synthesis of RNA this is possibly due to a peculiar lability of mitochondrial messenger RNA. 

Chromomycin, mithramycin, and olivomycin are tetrahydroanthracene derivatives bearing two glycosidic side-chains. The strong binding to double-stranded DNA of these drugs at low concentrations has many characteristic features of the binding to DNA of actinomycin-D. It requires the presence of divalent cations in stoichiometric amounts. 

Ben-Porat et al. (1971) showed that the larger polysomes that are characteristic of cells infected with PRV contained more RNA that would hybridize to viral DNA and a lower proportion of lysine in nascent polypeptides than the smaller polysomes of infected or uninfected cells. Using the declining ratio of lysine to leucine as a measure of the shut-off of host protein synthesis, they found that the decline was prevented by actinomycin added at the time of infection and arrested by actinomycin added at 3 hr after infection. The effect... 

Actinomycin A, thus prepared, is in the form of bright red crystalline platelets, melting at 250° with decomposition. The pigment is easily soluble in chloroform, benzene, or ethanol, less soluble in acetone and hot ethyl acetate, and slightly soluble in water and ether. Actinomycin A is levorotatory [ ]d = —320° (c = 0.25% in ethanol). It possesses a characteristic absorption spectrum in visible and in ultraviolet light (612), with maxima at 4500 A and between 2300 and 2500 A. 

Isozyme pattern is characteristic for differentiated tissue, actinomycine stimulated specific synthesis, stabilization of RNA... 

Actlnomvcin D - Kinetic studies with actinomycin D (act-D) in transplanted leukemic mice showed that a single dose provided cytotoxic concentrations for up to 24 hours,The characteristics of act-D resistance in L5178Y cells show that alterations in membrane composition and conformation in the drug-resistant subline accounts for the observed changes in the permeability of this drug.91 Act-D enhances the toxicity of morphine by increasing brain permeability. ... 

The major effect of 21 is to affect cells in S phase and the capacity of these cells to go through Gq phase.127 inhibition of DNA synthesis in L-1210 cells by camptothecin is initially reversible, but becomes irreversible when exposure to the drug is prolonged,131 Camptothecin resistant L-1210 subline is not characterized by a drug permeability barrier nor by altered levels of cell surface glycoprotein, which differ from characteristics of actinomycin D-resistance cell lines.131... 

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