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Effects of gamma interferon on tumour cell lines resistant to doxorubicin
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Pharmacological Research, Vol. 26, Supplement 1, 1992
PROTECTIVE EFFECT OF a-PHENYL N-tert-BUTYLNITRONE EARLY AND DELAYED EFFECTS OF DOXORUBICIN (DXR). A. Jotti, E. Monti, L. Paracchini, F.Piccinini Institute of Pharmacology, University of Milano, Italy.
(PBN) AGAINST THE
The effect of the spin-trapping agent a-phenyl N-tert-butyl nitrone (PBN) againstdoxorubicin (DXR)-induced cardiomyopathy wasassessedinaratmodel. DXR was administered as 3 closely spaced i.v. injections, resulting in a cumulative dose of 9 mg/kg. In this model DXR produced impairment in body weight gain; bone marrow toxicity, as assessed by WBC count, reverting within 4 weeks after treatment; ECG alterations characterized by a biphasic time course;impairment of contractile properties of the myocardium, as assessed on isolated Langendorff-perfused hearts 1, 2 and 9 wks after drug treatment. An involvement of free radical reactions in the early effects of DXR has been demonstrated,whereas the mechanisms of the delayed effects are still debated. Osmotic pumps releasing PBN at a constant rate of 3.7 pmoles/kg/hr, were implanted i.p. 3 days before DXR administration, yielding a steady state PBN plasma concentration of 182 pM for approximately 14 days. The administration of PBN during the first two weeks after DXR treatment significantly improved all the parameterstested,in both the early and delayed phases of DXRtoxicity. The present results suggest that free radicals produced shortly after DXR administration also play a role in the delayed myocardial pathology. Supported by MURST 40%, 1990.
EFFECTSOF GAMMAINTERFERON ON TUMOLJR CELL LINES RESISTANTTO DOXORLJBICIN M.Crescimanno, N.Borsellino, V.Leonardi, C.Flandina, L.Rausa, M.Ciaccio" e N.D'Alessandro? Istituti di Farmacologia e "Biochimica, Facolta diMedicina, Palermo e *Istituto diFarmacologia, Facolta di Medicina, Messina. We have studied the in vitro effects of gammainterferon (ifn) on themouse B16 melanoma (B16) and the human K562 erythroleukemia (K562), both as Doxg rubicin (DXR)-sensitive or -resistant (with a MDRphenotype) variants. The antiproliferative effects of ifn were marked in B16 and quite modest in K562, without differences between the DXR-sensitive and -resistant lines. In fact, the concentration of ifn inhibiting the growth of 50% was 5 U/ml in B16, irrespectively of its state of sensitivity or resistance to DXR, whiledosesup to 10.000 U/ml produced only marginal inhibitions in the DXR-sensitive or -resistant K562. Slightly cytotoxic concentrations of ifn added their antiproliferative effects to those of DXR in B16 and K562 as DXR-sensitive variants and did not modify the activity of DXR in the DXR-resistant tumours. In addition, we are trying to identify the major factors which account for cell sensitivity to ifn. In B16, both as DXR-sensitive or -resistant varL effects of ifn were associated with an increase ant, the antiproliferative in CAMPcell content and with an elevation of the MHCclass I antigens. 1~ stead, they were not related with changes in tryptophan oxidation or with the status of the cell defenses against free radicals, especially of the glutathione content. This work was partially supported by AIRC.
Pharmacological Research, Vol. 26, Supplement 1, 1992
PROTECTIVE EFFECT OF a-PHENYL N-tert-BUTYLNITRONE EARLY AND DELAYED EFFECTS OF DOXORUBICIN (DXR). A. Jotti, E. Monti, L. Paracchini, F.Piccinini Institute of Pharmacology, University of Milano, Italy.
(PBN) AGAINST THE
The effect of the spin-trapping agent a-phenyl N-tert-butyl nitrone (PBN) againstdoxorubicin (DXR)-induced cardiomyopathy wasassessedinaratmodel. DXR was administered as 3 closely spaced i.v. injections, resulting in a cumulative dose of 9 mg/kg. In this model DXR produced impairment in body weight gain; bone marrow toxicity, as assessed by WBC count, reverting within 4 weeks after treatment; ECG alterations characterized by a biphasic time course;impairment of contractile properties of the myocardium, as assessed on isolated Langendorff-perfused hearts 1, 2 and 9 wks after drug treatment. An involvement of free radical reactions in the early effects of DXR has been demonstrated,whereas the mechanisms of the delayed effects are still debated. Osmotic pumps releasing PBN at a constant rate of 3.7 pmoles/kg/hr, were implanted i.p. 3 days before DXR administration, yielding a steady state PBN plasma concentration of 182 pM for approximately 14 days. The administration of PBN during the first two weeks after DXR treatment significantly improved all the parameterstested,in both the early and delayed phases of DXRtoxicity. The present results suggest that free radicals produced shortly after DXR administration also play a role in the delayed myocardial pathology. Supported by MURST 40%, 1990.
EFFECTSOF GAMMAINTERFERON ON TUMOLJR CELL LINES RESISTANTTO DOXORLJBICIN M.Crescimanno, N.Borsellino, V.Leonardi, C.Flandina, L.Rausa, M.Ciaccio" e N.D'Alessandro? Istituti di Farmacologia e "Biochimica, Facolta diMedicina, Palermo e *Istituto diFarmacologia, Facolta di Medicina, Messina. We have studied the in vitro effects of gammainterferon (ifn) on themouse B16 melanoma (B16) and the human K562 erythroleukemia (K562), both as Doxg rubicin (DXR)-sensitive or -resistant (with a MDRphenotype) variants. The antiproliferative effects of ifn were marked in B16 and quite modest in K562, without differences between the DXR-sensitive and -resistant lines. In fact, the concentration of ifn inhibiting the growth of 50% was 5 U/ml in B16, irrespectively of its state of sensitivity or resistance to DXR, whiledosesup to 10.000 U/ml produced only marginal inhibitions in the DXR-sensitive or -resistant K562. Slightly cytotoxic concentrations of ifn added their antiproliferative effects to those of DXR in B16 and K562 as DXR-sensitive variants and did not modify the activity of DXR in the DXR-resistant tumours. In addition, we are trying to identify the major factors which account for cell sensitivity to ifn. In B16, both as DXR-sensitive or -resistant varL effects of ifn were associated with an increase ant, the antiproliferative in CAMPcell content and with an elevation of the MHCclass I antigens. 1~ stead, they were not related with changes in tryptophan oxidation or with the status of the cell defenses against free radicals, especially of the glutathione content. This work was partially supported by AIRC.