Olivomycin. IV. The structure of olivomycin.
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Antibiotics, Antineoplastic↗
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[Olivomycin and related antibiotics. 23. Effect of olivomycins, chromomycins and mithramycin on leukemia La of mice of strain C57B1].
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Animals↗
[Quantitative determination of olivomycin l in the total preparations of olivomycin].
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Bacteriophages↗
[Effect of neutral red on the cytotoxic activity of olivomycin].
Olivomycin accumulation in living cells first of all occurs in the cytoplasm or probably the cell lysosomes. The nuclear fluorescence of the cells incubated in olivomycin solution was observed in 60-90 minutes. Simultaneously with the nuclear fluorescence there was observed disappearance of the cytoplasm fluorescence. Intensive nuclear fluorescence was recorded in 15-30 minutes in 60-70% of the cells incubated in a solution of neutral red and subsequently treated with olivomycin. The amount of olivomycin bound to the nuclear DNA in dead cells in the presence of Mg++ and at pH 7.2 was so high that the cell nuclei produced yellow-green fluorescence. No binding of olivomycin to the nuclear DNA was observed in acid media. The cytotoxic activity of olivomycin after incubation with the human fibroblasts in a solution of neutral red increased 100 times. Olivomycin may be used for determination of vital activity of the cells when their lysosome function is not impaired.
Cell Survival↗
[Use of the antibiotic, olivomycin, for the cytochemical study of chromatin].
The possibility to use the antibiotic olivomycin for fluorescence cytochemistry of chromatin properties has been shown. It is found that the binding of olivomycin to nuclei reveals the functional state of chromatin and changes in the course of its activation. The essential condition for the application of the method described is the use of ethanol-aceton fixative. When other fixatives are used, in particular 70% ethanol, olivomycin binding reflects differences in nuclear DNA amount, rather than those in chromatin properties. The advantages of the method described, in comparison with the commonly used technique, are associated with the high affinity of olivomycin to DNA, absence of olivomycin binding with RNA, simplicity of the staining procedures , and with rather a high stability of complexes formed between olivomycin and DNA.
Animals↗
Chromomycin, mithramycin, and olivomycin binding sites on heterogeneous deoxyribonucleic acid. Footprinting with (methidiumpropyl-EDTA)iron(II).
The DNA binding sites for the antitumor, antiviral, antibiotics chromomycin, mithramycin, and olivomycin on 70 base pairs of heterogeneous DNA have been determined by using the (methidiumpropyl-EDTA)iron(II) [MPE x Fe(II)] DNA cleavage inhibition pattern technique. Two DNA restriction fragments 117 and 168 base pairs in length containing the lactose operon promoter-operator region were prepared with complementary strands labeled with 32P at the 3' end. MPE x Fe(II) was allowed to partially cleave the restriction fragment preequilibrated with either chromomycin, mithramycin, or olivomycin in the presence of Mg2+. The preferred binding sites for chromomycin, mithramycin, and olivomycin in the presence of Mg2+ appear to be a minimum of 3 base pairs in size containing at least 2 contiguous dG x dC base pairs. Many binding sites are similar for the three antibiotics; chromomycin and olivomycin binding sites are nearly identical. The number of sites protected from MPE x Fe(II) cleavage increases as the concentration of drug is raised. For chromomycin/Mg2+, the preferred sites on the 70 base pairs of DNA examined are (in decreasing affinity) 3'-GGG, CGA greater than CCG, GCC greater than CGA, CCT greater than CTG-5'. The sequence 3'-CGA-5' has different affinities, indicating the importance of either flanking sequences or a nearly bound drug.
Animals↗
Reverse banding on chromosomes produced by a guanosine-cytosine specific DNA binding antibiotic: olivomycin.
Characteristic reverse fluorescent banding patterns (R bands) on human, bovine, and mouse metaphase chromosomes are produced by treating chromosome preparations directly with olivomycin. With the DNA in solution, the repeating polymer poly[d(G-C)] - poly[d((G-C)] (where G is guanine and C is cytosine) enhanced the fluorescence of olivomycin, while the antibotic fluorescence was not affected by the alternating polynucleotide poly]d(A-T)] - poly[d(A-T)] (where A is adenine and T is thymine). Calf thymus DNA, with an intermediate G-C content of about 40 percent, showed a smaller fluorescence enhancement in the presence of olivomycin as was observed for the synthetic polynucleotide poly[d(G-C)] - poly [d(G-C)]. The closely related antibiotic chromomycin A3 showed the same results as were obtained with olivomycin either in the solution interaction with specific DNA's or with the netaphase chromosome preparations. The production of R bands by these G-C-specific DNA binding antibiotics lends credence to the suggestion that the arrangement of the nucleotide sequences along the chromosome is a primary determinant for the appearance of fluorescent bands.
Animals↗
[Pharmacokinetics of C14-olivomycin in the body of mice with lymphosarcoma (L10-1 strain)].
The pharmacokinetics of C14-olivomycin after its single intravenous administration to mice with lymphosarcome (LIO-I) was studied. It was shown that according to the specific radioactivity the organs may be placed in the following order: I hour after the antibiotic administration-the blood, liver, spleen, thymus, tumor, muscle; 3 hour after the administration-the liver, spleen, thymus, blood, tumor, muscle. Accumulation of olivomycin in the mouse organs was mainly in direct dependence on the dose of the antibiotic administered. Chromatography of the substances extraceted with ethylacetate from the urine collected at various periods after C14-olivomycin administration showed the presence of a new radioactive product (Rf 0.35-0.37) in addition to the unchanged antibiotic (Rf 0.53). Bioautographic analysis of the chromatograms showed that the product of C14-olivomycin conversion preserved its biological activity. The analysis of the substances extracted with ethylacetate from the liver, spleen and tumors 3 hours after the antibiotic administration reveiled (except of the liver) the presence of a spot with Rf corresponding to that of the initial drug.
Animals↗
[Effect of olivomycin on the microsomal oxidation enzymes, the mitochondria and the protein-synthesizing apparatus of the rat liver in acute tetrachloromethane poisoning].
Influence of olivomycin an inhibitor of protein biosynthesis on the enzymes of microsomal oxidation, bioenergetic processes in mitochondria and the polyribosomal profile in liver of rats intoxicated with tetrachloromethane was studied. It was established that the pretreatment of rats with olivomycin protected the hepatocytes from the effect of tetrachloromethane, reducing the hyperenzymaemia, hyperbilirubinemia, the degree of mitochondrial enzymes inhibition and the destruction of polyribosomes. Administration of olivomycin to healthy animals diminished the cytochrome P-450 content and led to slight changes of polyribosomal profile. Possible mechanisms of the protective effects of olivomycin under conditions of acute hepatic injury are discussed.
Alanine Transaminase↗
[Experimental study of the action of olivomycin on a melanoblastoma of the vascular tract of the eye].
A total of 66 experiments were performed with a purpose of studying the effect of olivomycin on the melanoblastoma cells of the human eye vascular tract. Heterotransplants of the human eye vascular tract melanoblastoma in the anterior chamber of the rabbit eye served the objects of the studies. Olivomycin was used in 34 out of 66 experiments and 32 experiments were control. Separate tumor cells together with pronounced signs of necrosis were detected on histological examination only in 1 out of 34 transplants treated with olivomycin. The transplants in the other 33 experiments resolved. The transplant in the control experiments consisted of viable cells at the same period. On the basis of the experiments it was concluded that olivomycin had a pronounced destroying effect on melanoblastoma cells under conditions of heterotransplantation and may be recommended for clinical use for prophylaxis of metastasis in post-operative periods.
Animals↗
[Mechanism of various degrees of tumor sensitivity to olivomycin].
Efficiency and duration of suppression of the synthesis of low-polymer (4S) and ribosomal (18S and 28S) fractions of total RNA due to exposure of the cells of Ehrlich's carcinoma and Zajdela's hepatoma to olivomycin were studied. The tumors differed in their sensitivity to the antibiotic. The efficiency of the rRNA synthesis inhibition by olivomycin on its addition to the cells of Ehrlich's carcinoma and Zajdela's hepatoma in vitro was of the same order. Study on the kinetics of rRNA synthesis after addition of olivomycin showed that the maximum inhibition of rRNA synthesis in the cells of Ehrlich's carcinoma was achieved 1 hour after the drug addition. After 2 hours the inhibition level returned to normal. The most efficient inhibition of rRNA synthesis in the cells of Zajdela's hepatoma was observed 2 hours after addition of the drug. The inhibition level in this case did not return to normal after 24 hours. It is concluded that tumor sensitivity to olivomycin is determined by the duration of the affection of the DNA template activity during the synthesis of RNA.
Animals↗
Preparation and antitumor activity of olivomycin A analogues.
Novel analogues of olivomycin A were prepared by selective reactions involving the carbonyl and hydroxyl groups of the aglycon moiety. Electrophilic substitution of the aglycon also was successful. Of 11 analogues, all but two were active in the P-388 murine leukemia assay. One compound, the 2'-methoxime, showed superior activity to olivomycin A based on its wider dose range and greater potency. The methyl imine and the 8-O-methyl ether were equal to olivomycin A in potency and efficacy. Most of the other analogues were slightly less potent or effective.
Animals↗
[Effect of olivomycin on denervation changes in the membrane of frog tonic muscle fibers].
Membrane properties of frog denervated tonic muscle fibers were investigated after the action of olivomycin, which is an inhibitor of protein synthesis. Olivomycin injected as a single dose (7.5 mg) during 1--2 days after the denervation of m. pyriformis decreases the regenerative action potentials. This action is decreased three weeks after denervation. After denervation, olivomycin failed to prevent the appearance of extrajunctional cholinoergic receptors, but blocked the increase of junctional ones. The data support the view that some neuronal factor may influence the synthesis of functional membrane proteins.
Animals↗
[Immunosuppressive properties of olivomycin].
The effect of olivomycin on the cell and humoral immune response was studied on mice. It was shown that antibody genesis stimulated by sheep red blood cells or E. coli lipopolysaccharide was almost equally inhibited by olivomycin when administered 24 hours before administration of the antigen. The magnitude of the delayed type hypersensitivity induced by the antigen low doses (10(5) cells) did not change when the antibiotic was administered in a dose of 1.5 mg/kg. When the antibiotic dose was 3 mg/kg, it decreased 2 times as compared to the control. On immunization of the mice with sheep red blood cells in a dose of 10(9) cells olivomycin administered in the doses inhibiting the antibody genesis induced an increase in the delayed type hypersensitivity. Such an effect of the antibiotic has much in common with the effect of other cytostatics.
Animals↗
[Effect of diuretics (diacarb and lasix) on the experimental antitumor activity, toxicity and pharmacokinetics of the antibiotic, olivomycin].
Diacarb or lasix in combination with olivomycin increased the antibiotic antiblastomic activity and toxicity when used for the course treatment of mice with transplanted lymphosarcoma LIO-I. The chemotherapeutic indices of such combinations did not differ from those of olivomycin used alone. Diacarb decreased excretion of olivomycin with the urine in healthy mice, while lasix increased it.
Acetazolamide↗
[Transplantability, development and methotrexate sensitivity of mouse leukemia L1210 resistant to olivomycin].
A total of 52-fold passages of leukemia L-1210 were carried out for a year on mice treated intraperitoneally with olivomycin. Prolonged exposure to olivomycin resulted in decreased transplantability of the tumor cells. The tumor cells obtained under the effect of olivomycin were more sensitive (collateral sensitivity) to methotrexate as compared to the cells of the initial strain L-1210. An intramuscular route for transplantation of the tumor cells of leukemia L-1210 is recommended. The dosage intramuscular transplantation of the tumor cells provided simultaneously data on transplantability, tumor size and lifer-time of mice.
Animals↗
[Interaction of the antitumor antibiotic olivomycin with Mg2+ ions].
The study on the mechanisms of olivomycin and olivin interaction with the magnesium ions showed that formation of the olivomycin complexes with Mg2+ involved 2 stages. At the first (rapid) stage Mg2+ is attached to keto-oxygen of the aglycone polycyclic part. At the second (slow) stage the complex is relaxed into the stable state with a more compact configuration. the equilibrium constants (Ce) of the main processes of olivomycin and olivin interaction with Mg2+ were determined. In the first case Ce = 3 . 10(3) M+1 and in the second case Ce = 1.6 . 10(2) M-1. It was shown that the geometric and optic characteristics of the complexes were consistently related: formation of the stable complex was accompanied by a 10-time decrease in the fluorescence quantum efficiency.
Anthracenes↗
Species specific differences in the toxicity of mithramycin, chromomycin A3, and olivomycin towards cultured mammalian cells.
Three structurally related anticancer drugs, mithramycin, chromomycin A3, and olivomycin, showed large unexpected differences (up to more than 1000 fold) in their toxicity towards cultured cells from various species (human, Chinese hamster, Syrian hamster, and mouse). Among the cell types examined, human cells (both a diploid fibroblast cell strain and HeLa cells) were maximally sensitive to all these drugs, followed by the Syrian hamster kidney cells (BHK 21). The mouse (LMTK- cells) and Chinese hamster (CHO) cells, which were more resistant, showed interesting differences in their sensitivity towards these drugs. For example, whereas the mouse cells were more resistant to mithramycin than CHO cells, the sensitivity pattern was reversed for both chromomycin A3 and olivomycin. In cell extracts derived from human, mouse, and Chinese hamster cells RNA synthesis, which is the cellular target of these drugs, showed identical sensitivity to both mithramycin and chromomycin A3, indicating that the species specific differences in the toxicity to these drugs are at the level of cellular entry of these compounds. Based on the structures of these glycosidic antibiotics and their patterns of toxicity, it is suggested that the intracellular transport of these drugs involves specific interactions between the sugar residues on these compounds and some type of cell surface receptor(s), which differ among different cell types. Some implications of these results for toxicity studies are discussed.
Animals↗