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At least 901 records · Page 50Linked to original sources
PubMed1988

Inhibition of type II topoisomerase by fostriecin.

Fostriecin is a new antitumor antibiotic which is being developed further as an anticancer agent based on its marked activity in murine leukemias. Its mechanism of action, however, has thus far remained unknown. The present study demonstrates that fostriecin inhibits the catalytic activity of partially purified type II topoisomerase from Ehrlich ascites carcinoma. Under the experimental conditions employed, fostriecin completely inhibited the enzyme at 100 microM. A general kinetic analysis showed that fostriecin inhibited topoisomerase in an uncompetitive manner with a Ki,app of 110 microM and produced kinetics that were distinctly different from those of VM-26 which exhibited noncompetitive inhibition. Fostriecin did not cause DNA strand breaks in L1210 cells, suggesting that it did not stabilize a cleavable complex as do other known inhibitors of this enzyme. Fostriecin, however, did partially inhibit DNA strand breaks produced by amsacrine. An analysis by flow cytometry showed that L1210 cells exposed to 5 microM fostriecin for 12 hr caused a block in the G2 phase of the cell cycle. These studies thus suggest that the mechanism by which fostriecin produces its antitumor effects may be through inhibition of topoisomerase II and that the type of inhibition is markedly different from existing antitumor agents which inhibit this enzyme.

Adenosine Triphosphate↗
PubMed1996

Collateral sensitivity to the bisdioxopiperazine dexrazoxane (ICRF-187) in etoposide (VP-16)-resistant human leukemia K562 cells.

Etoposide (VP-16)-resistant K562 cells (K/VP.5) were 26-fold resistant to VP-16, due in part to a reduction in DNA topoisomerase II (topoisomerase II) protein levels. Compared with parental K562 cells, VP-16-resistant K/VP.5 cells were found to be 3.4-fold more sensitive to the effects of dexrazoxane (ICRF-187), a topoisomerase II inhibitor that does not stabilize topoisomerase II-DNA covalent complexes. In contrast, K/VP.5 cells were 4.0-fold cross-resistant to merbarone and showed no cross-resistance to fostriecin, two other topoisomerase II inhibitors that do not stabilize topoisomerase II-DNA covalent complexes. Preincubation with ICRF-187 resulted in greater inhibition of subsequent VP-16-induced topoisomerase II-DNA covalent complexes in K/VP.5 cells than in K562 cells. Conversely, preincubation with merbarone resulted in less inhibition of VP-16-induced topoisomerase II-DNA covalent complexes in K/VP.5 cells than in parental K562 cells. Preincubation with forstriecin had little effect on VP-16-induced topoisomerase II-DNA covalent complex formation in either cell line. The onset rates for ICRF-187 inhibition of VP-16-induced topoisomerase II-DNA complex formation were similar in sensitive and resistant cells. In addition, ICRF-187 had a comparable concentration-dependent inhibitory effect on the topoisomerase II catalytic activities of K562 and K/VP.5 cells. Together, our results indicate that collateral sensitivity to ICRF-187 in K/VP.5 cells is due to decreased topoisomerase II protein levels rather than to an alteration in topoisomerase II activity. Furthermore, results suggest that ICRF-187, merbarone, and fostriecin have different mechanisms of action that can be studied effectively in K/VP.5 and K562 cells.

Alkenes↗
PubMed1984

GABAB receptors and norepinephrine-stimulated cAMP production in rat brain cortex.

The ability of GABAergic compounds to influence cAMP accumulation in rat brain cortex was examined. It was found that GABAB receptor agonists such as GABA, baclofen, and kojic amine potentiate the cAMP response in cerebral cortex during exposure to norepinephrine. Isoguvacine and THIP, selective GABAA receptor agonists, did not demonstrate this effect. The response to baclofen was stereoselective, with virtually all activity residing in the (-)isomer. Bicuculline methiodide had no effect on the agonist-induced potentiation and the rank order of potency for GABAB agonists to potentiate the cAMP response is identical to their rank order of potency in the GABAB binding assay. These data suggest that GABAB receptors are capable of influencing the brain cyclic nucleotide system.

Animals↗
PubMed1985

Subchronic administration of GABAergic agonists elevates [3H]GABA binding and produces tolerance in striatal dopamine catabolism.

Directly and indirectly acting GABAergic agonists were assessed for their ability to alter striatal dopamine catabolism after subchronic administration (7-14 days) via subcutaneously implanted osmotic minipumps. THIP, kojic amine and baclofen failed to alter striatal DOPAC and HVA concentrations, but THIP and kojic amine were effective after a single acute dose. Striatal GABA levels proved difficult to elevate when inhibitors of GABA transaminase were released from minipumps, but a high dose of gamma-vinyl GABA increased GABA by 44% of control, although striatal dopamine and DOPAC levels were unaltered. [3H]GABA binding studies revealed that THIP and kojic amine, but not baclofen or gamma-acetylenic GABA, produced large increases in [3H]GABA 'A' binding (150 and 228% of control respectively) which were attributable to altered densities of binding sites without changes in affinity. Despite alterations in GABAergic function, nigrostriatal dopaminergic neurones seem to develop tolerance to the effects of GABAergic drugs.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Aluminum(III) influences the permeability of the blood-brain barrier to [14C]sucrose in rats.

To determine the influence of the metal coordination sphere on the permeability of the blood-brain barrier (BBB), rats were injected intraperitoneally with aluminum lactate (Al(lact)3), aluminum acetylacetonate (Al(acac)3), aluminum maltolate (Al(malt)3) at pH 7.5, or with physiological saline. Two h after each treatment, [14C]sucrose physiological saline solution was injected in animals, and the radioactivity was measured in 5 brain regions (cerebral cortex, mesencephalon, diencephalon, medulla-pons, cerebellum). Radioactivity was significantly elevated in brains from animals treated with Al(malt)3 (hydrolytically stable and hydrophilic), and with Al(acac)3 (hydrolytically stable and lipophilic) but not with Al(lact)3. Time-course study carried out at 2, 4 and 24 h with different aluminum compounds showed a persistent radioactivity 24 h after treatment only in the brain from animals treated with Al(acac)3. Morin stain localized AlIII only in neurons from animals treated with Al(acac)3. These findings indicate that AlIII alters the BBB function in the rat either permanently or transiently depending on the physiochemical properties of the metal coordination sphere. Implications of these results, in terms of AlIII as a potential toxic factor in humans, are considered and discussed.

Aluminum↗
PubMed1996

Quantitative image analysis of temporal changes in tau and neurofilament proteins during the course of acute experimental neurofibrillary degeneration; non-phosphorylated epitopes precede phosphorylation.

Perturbation of the neuronal cytoskeleton represents an integral feature of neurofibrillary tangles which are characteristic neuropathological findings seen in Alzheimer's disease. Microtubule associated protein tau (tau) is considered to be the major component of these lesions although neurofilament proteins also are present. The present study explores the formation of intraneuronal tau and neurofilament protein aggregates using intracisternal administration of aluminum maltolate to rabbits. The time course of the formation of these aggregates and subsequent phosphorylation have been investigated by immunohistochemical methods using a panel of monoclonal antibodies, with quantitation of the staining by image analysis. Neurofilament proteins begin to aggregate by day 1 following aluminum maltolate injection on day 0. Increases in non-phosphorylated neurofilament proteins are observed first, with phosphorylated epitopes being recognized by day 3. Tau follows a similar pattern in that non-phosphorylated epitopes appear to precede phosphorylation. The monoclonal antibody Alz-50 which recognizes a phosphorylation-independent epitope of tau in Alzheimer's disease paired helical filaments, demonstrates positivity in the aluminum maltolate-treated rabbits by day 3. Other tau monoclonal antibodies which recognize phosphorylated tau in paired helical filaments (AT8 and PHF-1) show positive immunostaining on days 6-8. These results indicate that intraneuronal aggregation of cytoskeletal proteins can be initiated by factors other than phosphorylation. However, phosphorylation occurring as a secondary event probably contributes to stabilization of the aggregates.

Animals↗
PubMed1994

An evaluation of a new lactic acid polymer drug delivery system: a preliminary report.

A new drug delivery system, made of a mixture of DL-lactic acid polymer and a copoly (L-lactic acid/delta-valerolactone) polymer (LAP) containing varying concentrations of Ofloxacin, has been evaluated. Results revealed that a LAP drug delivery system containing 0.03% Ofloxacin inhibited the in vitro growth of clinically derived Staphylococcus aureus and Pseudomonas aeruginosa. Further, in an in vivo situation in rats, at 1 week after the wound was inflicted, no infection was macroscopically seen in split-thickness wounds that had been covered by LAP drug delivery system containing 0.5 or 0.03% Ofloxacin, and more than 80% of the wound area had epithelialised.

Animals↗
PubMed1992

Changes in nuclear chromatin related to apoptosis or necrosis induced by the DNA topoisomerase II inhibitor fostriecin in MOLT-4 and HL-60 cells are revealed by altered DNA sensitivity to denaturation.

The antitumor drug fostriecin (phosphotrienin, FST) has been reported to exert its cytostatic and cytotoxic effects via inhibition of DNA topoisomerase II. The sensitivity of human lymphocytic leukemic MOLT-4 and promyelocytic HL-60 leukemic cells to a wide range of FST concentrations was studied by analyzing the cell cycle-specific effects and changes in nuclear chromatin induced by this inhibitor. The latter was evaluated by assaying the sensitivity of DNA in situ to acid-induced denaturation cytofluorimetrically, with the use of the metachromatic fluorochrome acridine orange (AO), which differentially stains double-stranded and denatured DNA. The cytostatic effects were observed soon after addition of FST (at concentrations of 1-30 microM for MOLT-4 cultures and 1-5 microM for HL-60 cultures) as a perturbation of cell progression through S and G2 phases of the cell cycle. Cell progression through the cycle was halted at greater than 30 microM FST in MOLT-4 cultures and at greater than 5 microM in HL-60 cultures; the effect was instantaneous and affected all phases of the cycle, so that no changes in the cell cycle distribution were apparent with increasing length of exposure to the drug. Instead, at these high FST concentrations, immediate cytotoxic effects became evident, manifesting either as cell apoptosis or necrosis. Apoptosis was observed only in the case of HL-60 cells, at FST concentrations of 5-100 microM, and was characterized by markedly increased sensitivity of DNA to denaturation combined with a decrease in overall DNA stainability, either with the DNA-specific dye DAPI or with AO, indicative of the activation of endogenous nucleases. Necrotic cell death was observed at FST concentrations of 1 mM and at greater than 30 microM for HL-60 and MOLT-4 cells, respectively: in both cases the overall DNA stainability, with either DAPI or AO, was unchanged compared to the control, but their DNA was very sensitive to denaturation. Interestingly, DNA in G2 and late S phase MOLT-4 cells, which were undergoing necrotic death, was much more sensitive to denaturation than was DNA in G1 cells of this lineage. The data indicate that chromatin changes induced by DNA topoisomerase II inhibitors in cells that undergo apoptotic or necrotic death can be conveniently monitored by the assay of DNA in situ sensitivity to denaturation.

Acridine Orange↗
PubMed1990

On the etiology of subcapsular lenticular opacities produced in dogs receiving HMG-CoA reductase inhibitors.

The administration of high dosages of various hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors has resulted in the development of subcapsular lenticular opacities in dogs. While dogs receiving cataractogenic doses of HMG-CoA reductase inhibitors experienced profound decreases in circulating serum cholesterol concentrations (40-60% reductions in total serum cholesterol), a causal relationship between serum cholesterol lowering and cataractogenesis was not established. A strong relationship was demonstrated, however, between the systemic exposure to inhibitor (plasma drug levels) and the cataractogenic potential of the various compounds studied. Analysis of lenses from dogs chronically dosed with various HMG-CoA reductase inhibitors revealed the presence of low drug levels in the lens (less than 500 ng equivalents g-1), but no correlation was observed between the amount of drug associated with the lens after chronic treatment and cataract development. In addition, no abnormalities in cholesterol content or sterol composition were observed in clear and/or cataract containing lenses from dogs chronically dosed with HMG-CoA reductase inhibitors. The kinetics of drug appearance in the aqueous and lens cortex was assessed after doses of various HMG-CoA reductase inhibitors, and suggested somewhat higher but not statistically significant peak concentrations of inhibitor were achieved by compounds which produced a higher incidence of cataracts. These data have suggested that high doses of HMG-CoA reductase inhibitors may increase lenticular exposure to drug via the aqueous humor by producing a substantial systemic exposure to drug substance. This may result in an increased concentration of inhibitor in the outer cortical region of the lens where cholesterol synthesis is critical, thereby resulting in the development of opacities. The production of lenticular changes by a HMG-CoA reductase inhibitor of diverse chemical structure establishes, with reasonable assurance, that these lens changes are mechanism based (i.e. a product of the biochemical mechanism of action of this class of compounds). An extrapolation of these findings to patients receiving therapeutic dosages enables a favorable risk evaluation since the doses to be employed clinically are much lower and result in a far lower systemic exposure to drug substance.

Animals↗
PubMed1995

Oxidation reactions catalyzed by manganese peroxidase isoenzymes from Ceriporiopsis subvermispora.

A total of 11 manganese peroxidase isoenzymes (MnP1-MnP11) with isoelectric points (pIs) in the range of 4.58-3.20 were isolated from liquid- and solid-state cultures of the basidiomycete Ceriporiopsis subvermispora. In the presence of hydrogen peroxide, these isoenzymes showed different requirements for Mn(II) in the oxidation of vanillylacetone, o-dianisidine, p-anisidine and ABTS, whereas oxidation of guaiacol by any isoenzyme did not take place when this metal was omitted. Km values for o-dianisidine and p-anisidine in the absence of Mn(II) are in the range of 0.5-1.0 mM and 4.5-42.0 mM, respectively. Oxalate and citrate, but not tartrate, accelerate the oxidation of o-dianisidine, both in the presence and in the absence of Mn(II). MnPs from this fungus are able to oxidize kojic acid without externally added hydrogen peroxide, indicating that they can also act as oxidases. In this reaction, however, the requirement for Mn(II) is absolute.

Basidiomycota↗
PubMed1995

Long-term potentiation requires activation of calcium-independent phospholipase A2.

The predominant phospholipase activity present in rat hippocampus is a calcium-independent phospholipase A2 (302.9 +/- 19.8 pmol/mg.min for calcium-independent phospholipase A2 activity vs. 14.6 +/- 1.0 pmol/mg.min for calcium-dependent phospholipase A2 activity). This calcium-independent phospholipase A2 is exquisitely sensitive to inhibition by the mechanism-based inhibitor, (E)-6-(bromomethylene)-tetrahydro-3-(1-naphthalenyl)-2H-pyran -2-one (BEL). Moreover, treatment of hippocampal slices with BEL prior to tetanic stimulation prevents the induction of LTP (40.8 +/- 5.6% increase in excitatory post-synaptic potential (EPSP) slope for control slices (n = 6) vs. 5.8 +/- 8.5% increase in EPSP slope for BEL-treated slices (n = 8)). Importantly, LTP can be induced following mechanism-based inhibition of phospholipase A2 by providing the end product of the phospholipase A2 reaction, arachidonic acid, during the application of tetanic stimulation. Furthermore, the induction of LTP after treatment with BEL is dependent on the stereoelectronic configuration of the fatty acid provided since eicosa-5,8,11-trienoic acid, but not eicosa-8,11,14-trienoic acid, rescues LTP after BEL treatment (37.6 +/- 16.1% increase in EPSP slope for eicosa-5,8,11-trienoic acid vs. -3.7 +/- 5.2% increase in EPSP slope for eicosa-8,11,14-trienoic acid). Collectively, these results provide the first demonstration of the essential role of calcium-independent phospholipase A2 in synaptic plasticity.

Animals↗