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V Malatesta

Publications and source records attributed to V Malatesta.

14 recordsLinked to original sources
PubMed1991

Enhancement of antitumor drug cytotoxicity via laser photoactivation.

We investigate the efficacy of daunomycin, some imino- and amino-substituted daunomycin analogues and the disubstituted aminoanthracenedione, mitoxantrone, in photosensitizing short-term cell kill upon irradiation in the long wavelength visible range, during incubation of Fisher rat thyroid cells with the drugs. While all compounds exhibit similar cytocidal effects on our cell line, in the absence of irradiation, administering 86 J/cm2 at wavelengths either coincident or close to drug absorption peaks causes greater enhancement in cell mortality for the 4-demethoxydaunomycin analogues than either the parent drug or its 5-imino-derivative. A lower enhancement is observed with mitoxantrone. In particular, C50 doses (i.e. concentrations that would kill 50% cells) as low as approximately 10(-9) M are found for both 6- and 11-amino 4-demethoxydaunomycin, compared with the values obtained in the absence of light, which are 2.59 x 10(-4) and 0.43 x 10(-4) M, respectively. Our previous studies of the photophysical and photochemical properties of the excited states of these drugs, and ESR and spin trapping studies of photosensitized generation of singlet oxygen, which were extended in this work to include mitoxantrone, indicate that the cytocidal effects proceed via type I rather than type II mechanisms.

Animals↗
PubMed1991

Photocytotoxicity of anthracyclines upon laser excitation in their long-wavelength absorption bands.

Newly synthesized daunomycin derivatives with red-shifted absorption compared to the parent molecule are shown to be able to photosensitize cells in vitro upon excitation with either argon or argon-pumped dye laser. Administering 86 J/cm2 total fluence (1 h irradiation) to Fisher rat thyroid cells during 2 h incubation with either daunomycin (excitation wavelength: 488 nm) or 5-iminodaunomycin (595 nm) produced cell killing at doses (about 2.7 X 10(-7) M for 50% cell survival) which were not toxic if administered in the dark. Greater photocytotoxicity (about 7 X 10(-8) M for 50% cell survival) was obtained with 4-demethoxydaunomycin as well as with its 6- and 11-amino derivatives (514 nm) while no cell killing as a result of photosensitization was observed for either Adriamycin or its 4'-iodo derivative. Our results suggest that the photosensitizing efficacy correlates with the absence of the methoxy group in the anthraquinone chromophore but is rather independent of the occurrence of triplet-mediated photoreactions. Finally, the fact that the imino- or amino-substituted 4-demethoxy compounds exhibit red-shifted absorption spectra compared to the parent molecule might be exploited for in vivo applications of the photoactivated cytotoxicity reported in this work.

Animals↗
PubMed1990

Cardiotoxicity and antitumor activity of a copper(II)-doxorubicin chelate.

The cardiotoxic and cytotoxic effects of the Cu(II)-doxorubicin (DXR) complex [Cu(DXR)]n are compared with those of the parent drug. It is shown that 10(-4) M [Cu(DXR)]n has no depressant effects on isolated rat atria, in contrast with an equimolar concentration of the parent drug. No differences were found between the cytotoxic activities of the Cu(II) complex and free DXR on B16 melanoma and HeLa cells. A reduced penetration of the polymeric [Cu(DXR)]n into the myocardial cells as compared with the free drug was invoked to account for the absence of cardiotoxicity of the DXR complex. On the other hand, the observation that copper-complexation does not affect the cytotoxicity of the drug suggests that extracellular as well as intracellular mechanisms may be involved in the development of its antitumor activity.

Animals↗
PubMed1989

Cell photosensitization by 5-iminodaunomycin activated with red light.

5-Iminodaunomycin, an anthracycline antitumor drug exhibiting an absorption peak at 595 nm, is shown to photosensitize in vitro cell kill. The photoactivation is performed irradiating the culture dishes during the incubation with the drug for 2 h with 34 mW/cm2 intensity, that is with light doses of up to 245 J/cm2. Long-term effects of administering 50 ng/ml and light for 2 h are studied in terms of growth curves. We show that photoactivation enhances the dark toxicity by a factor of about 10. Immediate cell death is produced by irradiating the cells in the presence of higher drug concentrations (e.g., 1000 ng/ml) which, however, are not toxic in the short term if administered in the dark. The viable cell percentage decreases at increasing light doses, being about 0.6% at the maximum dosage. Administering lower light doses, such as 30 J/cm2, which corresponds to an exposure duration of 15 min, has a short-term effect on the cell survival that strongly depends on the timing of the exposures within the incubation period.

Animals↗
PubMed1989

Triplet state characteristics and singlet oxygen generation properties of anthracyclines.

The triplet states of adriamycin (Ad), daunomycin (D) and two daunomycin analogues, daunomycinone (Dc) and daunomycin N-trifluoroacetamide (DAc), have been studied using laser flash photolysis and pulse radiolysis techniques. Triplet lifetimes, molar absorption coefficients, energy levels and quantum yields have been obtained for Dc and DAc, and estimated for D and Ad. Time-resolved near-infrared singlet oxygen luminescence measurements have been carried out on D, Ad and 5-iminodaunomycin (5-ID) in 2H2O solution and Dc in benzene solution at room temperature. Singlet oxygen quenching by the water-soluble anthracyclines was observed and a second-order rate constant of approx. 10(8) M-1.s-1 obtained. Electron spin resonance experiments have demonstrated that D photoexcited at lambda less than or 365 nm gives rise to singlet oxygen as shown by its reaction with 2,2,6,6-tetramethyl-4-piperidone to give the corresponding nitroxyl radical. Although all the anthracyclines studied have the ability to photosensitize the formation of singlet oxygen, the quantum yields are very low (phi delta approximately 0.02-0.03), suggesting that these anthracyclines would be poor photodynamic sensitisers.

Acetamides↗
PubMed1989

Laser time-resolved fluorescence study of the interaction between anthracyclines and cardiolipin.

The molecular interaction between cardiolipin vesicles and two representative anthracyclines, daunomycin and 5-iminodaunomycin, has been studied at pH 7.1 by laser time-resolved fluorescence, for a cardiolipin-to-anthracycline ratio r ranging from 0.02 to 5. The fluorescence lifetime of daunomycin is 1.03 ns. For r = 0.3 - 5 a longer-lived transient (1.91 - 1.49 ns) is present and originates from the excitation of daunomycin bound on a single phosphate group of cardiolipin. At r = 0.3 two lifetimes are observed, the second one being due, partially, to free daunomycin and bound drug molecules embedded in the lipid bilayer. The fastest-decaying species is present for r = 0.5 - 2.0 and identified as two adjacent, stacked-up daunomycin molecules bound onto the two phosphate groups of the cardiolipin. In the case of 5-iminodaunomycin, a less cardiotoxic analogue, three-exponential decay is never observed and a fast-decaying component, pi approximately 0.2 ns, is already present at low r and vanishes for r greater than 0.5. The constancy of the lifetimes of the longer-lived species may originate from the reorientation of the bound drug from the hydrophilic to the lipid domain.

Antibiotics, Antineoplastic↗
PubMed1988

Role of daunosamine and hydroxyacetyl side chain in reaction with iron and lipid peroxidation by anthracyclines.

Doxorubicin (Adr), daunorubicin (Dnr), and analogs of Adr modified in daunosamine (4'-epi-Adr and 3'-N-acetyl-Adr) were investigated with respect to their reaction with Fe(III) and analyzed for the ability of the corresponding iron complexes to sustain lipid peroxidation of isolated human platelet membranes. When the proportion of iron [25 microM Fe(III)] to Adr was 1:4, almost 50% of the metal was reduced following 1 hour of anaerobic reaction, while only approximately equal to 14% of the bound iron could be extracted as Fe(II) in the reactions of the Dnr complexes. The reaction of Adr was associated with formation of two main novel anthracyclines. One of the products had lost the C14 atom of the C9 chain and displayed chromatographic features and visible UV light spectra identical to those of authentic 9-dehydroxyacetyl-9-carboxyl-Adr. In complexes of iron and Dnr, no significant anthracycline degradation was observed. Reduction of anthracycline-bound Fe(III) by 4'-epi-Adr (38%) and 3'-N-acetyl-Adr (21.2%) was consistently less than that by Adr. Complexes of the anthracyclines investigated had different abilities to sustain lipid peroxidation, which was blocked (a) by the iron chelators deferoxamine and bathophenanthroline, indicating that Fe(III) and Fe(II) were needed for the reaction, and (b) by ICRF-198, the chelating product that forms intracellularly by hydrolysis of razoxane, which can prevent Adr cardiotoxicity. Peroxidation was not affected by scavengers of reduced oxygen radicals (superoxide dismutase, catalase, and mannitol). The isolated membranes contributed to the reduction of anthracycline-bound Fe(III) and probably represented the main determinant of lipid peroxidation by iron-Dnr. Lipid peroxidation was significantly less for complexes of iron with 4'-epi-Adr or 3'-N-acetyl-Adr than for complexes of iron with Adr. The observed differences may be relevant to the different biologic properties of Adr and its analogs, in particular their different degrees of cardiotoxicity.

Antibiotics, Antineoplastic↗
PubMed1988

Direct detection of paramagnetic species in adriamycin perfused rat hearts.

Direct detection of paramagnetic species in control and adriamycin-perfused rat hearts has been carried out. Depending on the flow rate of the perfusion solution (8,4,2 and 1 ml/min) different paramagnetic species were observed: Fe(III)(g = 2.12) at 4 ml/min; three types of oxygen centered radicals of which two in control hearts (g = 2.05 g = 2.038 g = g = 2.008) and the third one (g = 2.03 g = 2.005) in adriamycin perfused hearts, at 2 ml/min. The latter radical was the only one observed at perfusion rate of 1 ml/min both in control and adriamycin treated systems. A relationship between the intracellular enzymatic reductive activation of the anthracycline and the occurrence of ischemic conditions (4,2 and 1 ml/min) in myocardial tissues is proposed basing on the relative amounts of the paramagnetic species above mentioned.

Animals↗
PubMed1986

Knee arthrography: effects of various contrast media and epinephrine on synovial fluid.

Changes in synovial fluid leukocytes, total protein, and total complement were studied in 58 patients after they underwent single contrast material-enhanced knee arthrography with ionic (sodium iothalamate, sodium meglumine diatrizoate, meglumine iothalamate) and nonionic (iopamidol, iohexol) contrast media. In 30 of 58 cases, 0.3 mg epinephrine was also injected. In patients examined without epinephrine, a significant increase in the number of leukocytes was observed when sodium iothalamate and sodium meglumine diatrizoate were used. When administered with epinephrine all ionic compounds produced significant leukocytosis; articular reactions were most evident in patients examined with sodium salts. No inflammatory changes in the synovial fluid were observed when nonionic compounds were used. These data suggest that sodium-containing compounds produce a greater reaction in the joint compared with other contrast media, nonionic compounds are better tolerated by the joint, and epinephrine increases the articular reaction to ionic contrast media.

Adolescent↗
PubMed1985

[Ioexol in arthrography].

Single contrast knee arthrography was performed in a group of 50 patients, using either Urografin or Ioexol as contrast agents. Both contrast media were well tolerated clinically and no significant difference was found to exist as far as image quality is concerned. However, while Urografin produced a significant increase of the white cells in the synovial fluid, no inflammatory change was observed in the synovial fluid after Ioexol. So we believe that Ioexol is a significantly preferable contrast medium in arthrography, especially in patients with inflammatory joint diseases.

Adolescent↗