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F Cattabeni

Publications and source records attributed to F Cattabeni.

At least 145 records · Page 8Linked to original sources
PubMed1989

Cellular and molecular pharmacology of 4'-epidoxorubicin in HeLa cells. Comparison with its parent drug, doxorubicin.

The effects on cellular DNA and cytotoxicity produced by doxorubicin (Dx) and its epimer 4'-epidoxorubicin (4'E-Dx) were investigated in cultured HeLa cells. 4'E-Dx was 2.3 times more cytotoxic than Dx after 1 h of treatment, but the two anthracyclines were equally cytotoxic on longer-term (24 h) drug exposure. The different kinetics of cell lethality were related to pharmacodynamic differences between the two drugs. In fact, cellular uptake and efflux rates of 4'E-Dx were faster than those of Dx on 1 h of drug exposure but similar after 24 h of treatment. 4'E-Dx caused more protein-concealed strand breaks in DNA (single and double) than did Dx, despite a lower potency for free-radical formation. The degree of strand breakage by 4'E-Dx was not a linear function of exposure time and, in fact, the rate of strand-break induction declined continuously with time. In contrast, Dx caused an almost linear increase in DNA single-strand breaks with time during 1 h of drug exposure; this was apparently due to its slower uptake. There was little repair of the DNA single-strand breaks produced by Dx upon postincubation for 5 h in a drug-free medium, whereas DNA lesions caused by 4'E-Dx were removed with a t1/2 of about 1.7 h. These findings underline the importance of the cellular pharmacokinetics of anthracyclines in relation to their cytotoxic and DNA-damaging effects.

DNA Damage↗
PubMed1989

Lethality of hydrogen peroxide in wild type and superoxide dismutase mutants of Escherichia coli. (A hypothesis on the mechanism of H2O2-induced inactivation of Escherichia coli).

The toxicity of H2O2 in Escherichia coli wild type and superoxide dismutase mutants was investigated under different experimental conditions. Cells were either grown aerobically, and then treated in M9 salts or K medium, or grown anoxically, and then treated in K medium. Results have demonstrated that the wild type and superoxide dismutase mutants display a markedly different sensitivity to both modes of lethality produced by H2O2 (i.e. mode one killing, which is produced by concentrations of H2O2 lower than 5 mM, and mode two killing which results from the insult generated by concentrations of H2O2 higher than 10 mM). Although the data obtained do not clarify the molecular basis of H2O2 toxicity and/or do not explain the specific function of superoxide ions in H2O2-induced bacterial inactivation, they certainly demonstrate that the latter species plays a key role in both modes of H2O2 lethality. A mechanism of H2O2 toxicity in E. coli is proposed, involving the action of a hypothetical enzyme which should work as an O2-. generating system. This enzyme should be active at low concentrations of H2O2 (less than 5 mM) and high concentrations of the oxidant (greater than 5 mM) should inactivate the same enzyme. Superoxide ions would then be produced and result in mode one lethality. The resistance at intermediate H2O2 concentrations may be dependent on the inactivation of such enzyme with no superoxide ions being produced at levels of H2O2 in the range 5-10 mM. Mode two killing could be produced by the hydroxyl radical in concert with superoxide ions, chemically produced via the reaction of high concentrations of H2O2 (greater than 10 mM) with hydroxyl radicals. The rate of hydroxyl radical production may be increased by the higher availability of Fe2+ since superoxide ions may also reduce trivalent iron to the divalent form.

Aerobiosis↗
PubMed1989

Adenosine receptors linked to adenylate cyclase activity in human neuroblastoma cells: modulation during cell differentiation.

In IMR32 neuroblastoma cells, the two adenosine receptor agonists N6-R-phenylisopropyladenosine and 5'-N-ethylcarboxamidoadenosine dose-dependently stimulated membrane adenylate cyclase activity with potencies consistent with the presence of adenosine receptors of the A2-subtype. The S enantiomer of N6-R-phenylisopropyladenosine induced a significantly lower stimulation of adenylate cyclase, accordingly to its lower ability to activate adenosine receptors. These effects were selectively counteracted by the adenosine receptor antagonist theophylline and, conversely, were not affected by the A1-adenosine receptor selective blocker 8-cyclopentyl-1,3-dipropylxanthine. No adenosine receptors belonging to the A1-subtype seem, therefore, to be present in this cell line, as also shown by the lack of inhibitory activity of N6-R-phenylisopropyladenosine on both basal and forskolin-stimulated adenylate cyclase activity. Activation of A2-receptors did not modify intracellular basal calcium levels, did not influence calcium influx through voltage-dependent calcium channels and did not modify calcium influx and redistribution induced by muscarinic receptor activation. Prolonged exposure of cells to either N6-R-phenylisopropyladenosine or 5'-N-ethylcarboxamidoadenosine was associated with a small but significant degree of morphological differentiation, comparable to that induced by dibutyryl cAMP, and therefore presumably related to the prolonged increase of intracellular cAMP levels elicited by the two adenosine agonists. After cellular differentiation induced with either dibutyryl cAMP or 5-bromodeoxyuridine, a selective desensitization of A2-receptor stimulated adenylate cyclase activity was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1989

Identification of 4 ataxia telangiectasia cell lines hypersensitive to gamma-irradiation but not to hydrogen peroxide.

The effect of hydrogen peroxide on the rate of semi-conservative DNA synthesis in ataxia telangiectasia (AT) and normal human lymphoblastoid cells was investigated. The rate of DNA synthesis in AT cells was not depressed to a lesser extent than in normal cells, as might have been expected since H2O2 is a radiomimetic agent. On the contrary, 4 AT cell lines displayed a higher sensitivity to the inhibitory effect of H2O2 on DNA synthesis than 2 normal cell lines. Comparable levels of cytotoxicity were detected in cell viability studies. Furthermore, neither the level of DNA breakage produced by H2O2, nor the rate of repair of these lesions was significantly different in normal and AT cells. Together, these results indicate that the AT cell lines utilized in this study are not hypersensitive to the oxidant. It is suggested that H2O2 may not induce lethality via the direct action of the hydroxyl radical (OH.).

Ataxia Telangiectasia↗
PubMed1989

Morphological changes in Escherichia coli cells exposed to low or high concentrations of hydrogen peroxide.

Escherichia coli cells challenged with low or high concentrations of hydrogen peroxide are killed via two different mechanisms and respond with morphological changes which are also dependent on the extracellular concentration of the oxidant. Treatment with low concentrations (less than 2.5 mM) of H2O2 is followed by an extensive cell filamentation which is dependent on the level of H2O2 or the time of exposure. In particular, addition of 1.75 mM H2O2 results in a growth lag of approximately 90 min followed by partial increase in optical density, which was mainly due to the onset of the filamentous response. In fact, microscopic analysis of the samples obtained from cultures incubated with the oxidant for various time intervals has revealed that this change in morphology becomes apparent after 90 min of exposure to H2O2 and that the length of the filaments gradually increases following longer time intervals. Analysis of the ability of these cells to form colonies has indicated a loss in viability in the first 90 min of exposure followed by a gradual recovery in the number of cells capable of forming colonies. Measurement of lactate dehydrogenase in culture medium (as a marker for membrane damage) has revealed that a small amount of this enzyme was released from the cells at early times (less than 150 min) but not after longer incubation periods (300 min). Cells exposed to high concentrations of H2O2 (greater than 10 mM) do not filament and their loss of viability is associated with a marked reduction in cell volume. In fact, treatment with 17.5 mM H2O2 resulted in a time-dependent decrease of the optical density, clonogenicity, and cellular volume. In addition, these effects were paralleled by a significant release in the culture medium of lactate dehydrogenase thus suggesting that the reduced cell volume may be dependent on membrane damage followed by loss of intracellular material. This hypothesis is supported by preliminary results obtained in electron microscopy studies. In conclusion, this study further demonstrates that the response of E. coli to hydrogen peroxide is highly dependent on the concentration of H2O2 and further stresses the point that low or high concentrations of the oxidant result in the production of different species leading to cell death via two different mechanisms and/or capable of specifically affecting the cell shape.

Dose-Response Relationship, Drug↗
PubMed1989

Role of hydroxyl radicals in Escherichia coli killing induced by hydrogen peroxide.

Escherichia coli lethality by hydrogen peroxide is characterized by two modes of killing. In this paper we have found that hydroxyl radicals (OH.) generated by H2O2 and intracellular divalent iron are not involved in the induction of mode one lethality (i.e. cell killing produced by concentrations of H2O2 lower than 2.5 mM). In fact, the OH radical scavengers, thiourea, ethanol and dimethyl sulfoxide, and the iron chelator, desferrioxamine, did not affect the survival of cells exposed to 2.5 mM H2O2. In addition cell vulnerability to the same H2O2 concentration was independent on the intracellular iron content. In contrast, mode two lethality (i.e. cell killing generated by concentrations of H2O2 higher than 10 mM) was markedly reduced by OH radical scavengers and desferrioxamine and was augmented by increasing the intracellular iron content. It is concluded that OH. are required for mode two killing of E. coli by hydrogen peroxide.

Deferoxamine↗
PubMed1989

Molecular mechanisms of hydrogen peroxide cytotoxicity.

The molecular mechanisms of H2O2 toxicity have been investigated in both mammalian or bacterial cells. DNA breakage mediates cytotoxicity by low concentrations of H2O2 in mammalian cells, but DNA lesions do not appear as a direct consequence of the action of the hydroxyl radical; rather, these radicals may disturb intracellular Ca2+ homeostasis, which results in secondary reactions ultimately leading to DNA strand breakage and cytotoxicity. Studies that have used Escherichia coli (E. coli) as a cellular system have indicated that the two modes of killing detectable in cells exposed to increasing concentrations of H2O2 are mediated by different radical species. Mode-one killing seems to be produced by the superoxide anion whereas mode-two killing seems to be a consequence of the hydroxyl radical attack.

Animals↗
PubMed1989

Synthesis and dopamine receptor affinities of 6-amino-5,6,7,8-tetrahydroquinoline derivatives.

Some N,N-dialkylderivatives of 6-amino-5,6,7,8-tetrahydroquinoline were synthesized. The affinity of new compounds for dopamine binding sites was measured in a test involving displacement of [3H]SCH 23390 (D-1 selective) and [3H]spiperone (D-2 selective) from homogenized rat striatal tissue. While no compound was effective in displacing [3H]SCH 23390, in the binding assays on the D-2 receptor all tetrahydroquinolines displaced [3H]spiperone from specific binding sites, the compounds with a N-n-propyl-N-phenylethylamino group (18) or N,N-di n-propylamino group (16) being the most potent.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Randomly distributed DNA single strand breaks are not lethal for mammalian cells.

1. The primary objective of this study was to assess whether randomly distributed DNA single strand breaks result in cytotoxicity. 2. The experimental approach was exposure of cultured Chinese hamster ovary cells to hydroxyl radicals generated either by X-rays (via water radiolysis) or from H2O2 (via the Fenton reaction). 3. An excellent inverse correlation was observed with X-rays: the higher the level of DNA breakage, the lower the cloning efficiency of the cells. 4. In the case of H2O2 the same correlation was found, however, single strand breaks produced by this agent appeared less toxic than those generated by X-irradiation. 5. Since considerable evidence indicates DNA damage as the major cause of X-ray-and H2O2-induced lethality, it is concluded that randomly distributed single strand breaks have hardly any effect in cell killing.

Animals↗
PubMed1988

Synthesis and dopamine receptors binding affinity of 2-(3-fluoro-4-hydroxyphenyl)ethylamine and its N-alkyl derivatives.

The 2-(3-fluoro-4-hydroxyphenyl)ethylamine and its N,N-dialkyl derivatives were synthesized. The affinity of new compounds for dopamine binding sites was measured in a test involving displacement of [3H]SCH 23390 (D-1 selective) and [3H]spiperone (D-2 selective) from homogenized rat striatal tissue. No compound proved effective in displacing [3H]SCH 23390. Two derivatives are selective displacers of [3H]spiperone.

Animals↗
PubMed1988

Gas chromatographic-mass spectrometric determination of levodropropizine plasma levels in healthy volunteers.

A gas chromatographic-mass spectrometric method for the qualitative and quantitative analysis of levodropropizine (S(-)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol, DF 526) in plasma is described. The method proved to be highly selective and sensitive. Drug concentrations as low as 5 ng/ml could be measured. Levodropropizine plasma levels were measured in 6 healthy volunteers after administration of an acute 60 mg dose. Peak concentrations were reached between 40 and 60 min and measurable amounts of drug were present till 8 h after administration.

Administration, Oral↗
PubMed1987

The effect of deazaadenosine analogues on the proliferation rate of cultured Vero cells.

Five adenosine analogues resistant to adenosine deaminase were analyzed for their effects on the proliferation on cultured Vero cells. Cells were exposed for 48 hr to various concentrations of 1-deazaadenosine (c1Ado), 3-deazaadenosine (c3Ado), 7-deazaadenosine (c7Ado), 1,3-dideazaadenosine (c1,3Ado) or 1,7-dideazaadenosine (c1,7Ado) and then counted with a hemocytometer. Results indicate that 1) whereas c7Ado produced a marked decrease in cell growth, c3Ado was toxic only at the highest concentration tested (30 microM), 2) c1Ado and c1,7Ado did not affect cell replication and 3) c1,3Ado produced a significant stimulation of cell proliferation. Further studies have suggested that none of the compounds tested is incorporated in the DNA.

Animals↗
PubMed1987

Adenosine modulates the dopaminergic function in the nigro-striatal system by interacting with striatal dopamine dependent adenylate cyclase.

Behavioral and pharmacological evidences suggest that dopaminergic mechanisms in striatum might be counteracted by adenosine or potentiated by its pharmacological antagonists methylxanthines. To test whether adenosine modulation of the dopaminergic function could be, at least in part, due to an interaction at the level of the adenylate cyclase complex, we studied the effects of the adenosine analog R-Phenyl-isopropil-adenosine (R-PIA) on basal and dopamine-sensitive adenylate cyclase in rat striatum. R-PIA, which interacts with both adenosine A1-inhibitory and A2-stimulatory receptors, dose-dependently inhibited the stimulation induced by dopamine, and seemed to utilize the same pool of enzyme linked to dopaminergic D1 receptors. Two experimental approaches leading to supersensitivity of striatal dopaminergic receptors, (i.e., 6-hydroxy-dopamine injection in substantia nigra and reserpine administration) also induced upregulation of adenosine-dependent adenylate cyclase in striatum, and altered R-PIA modulation of dopamine-sensitive adenylate cyclase. Conversely, after subchronic treatment with neuroleptics such as haloperidol or sulpiride, upregulation of 3H-Spiroperidol binding in striatum was not associated with changes of R-PIA dependent adenylate cyclase in this area. It is concluded that adenosine might modulate post-synaptic responses to dopamine via adenosine receptors which functionally interact with dopaminergic D1 receptors in striatum.

Adenosine↗
PubMed1987

Selective activity of bamifylline on adenosine A1-receptors in rat brain.

The activity of the xanthine derivative bamifylline on central adenosine A1 and A2 receptors has been evaluated with radio-receptor binding in rat brain in comparison with other structure-related compounds. Bamifylline displaced 3H-Cyclo-hexyl-adenosine and 3H-Diethyl-8-phenyl-xanthine with a potency similar to that of 8-phenyl-theophylline, suggesting a high activity on A1-receptor subtype. In contrast, when 3H-N-Ethyl-carboxamido adenosine was used to label A2 adenosine receptors in rat striatum, bamifylline displayed a lower activity comparable to that of enprofylline, an alkyl- xanthine considered a very weak antagonist of adenosine receptors. By calculating for each xanthine derivative its relative potency at A1 and A2 receptors (A2/A1 ratio), bamifylline turned out being the most selective A1 adenosine receptor antagonist so far tested.

Animals↗
PubMed1987

The effect of temperature or anoxia on Escherichia coli killing induced by hydrogen peroxide.

The cytotoxicity of hydrogen peroxide in Escherichia coli was investigated after various conditions of drug exposure. Two modes of killing were detected following a 15-min challenge with H2O2 under either aerated or anoxic conditions. Mode one killing occurred at levels below 2.5 mM and mode two killing at concentrations higher than 10 mM. Whereas mode one killing was similar at the two conditions of drug exposure, mode two lethality differed in that aerated cells were more sensitive than anoxic cells. Independently of O2 tension the hydroxyl radical scavenger, thiourea, prevented mode two but not mode one killing by H2O2. Cells treated with the drug at ice temperature did not display mode one killing and mode two lethality occurred only at very high concentrations. We suggest that hydroxyl radicals mediate mode two but not mode one killing by H2O2.

Escherichia coli↗