- Email: [email protected]
Doxorubicin uptake by isolated sarcoplasmic reticulum
J Mol Cell Cardi
(Supplement
II) (1989)
262
DOXORUBICIN UPTAKE BY ISOLATED SARCOPLASMIC RETICULUM. L. Gailis. Department of Medicine and Institut de Cardiologie de Qusbec, Lava1 University, Quebec, Que., Canada GlV 465. Doxorubicin, an antineoplastic drug, also damages normal tissues, in particular the heart. Since its mode of flux in non-neoplastic tissues is not established we studied doxorubicin uptake by sarcoreticulum plasmic vesicles isolated from rabbit leg muscles. The vesicles were loaded with 100 mM glucose and 100 mM Na glutamate, pH 7.0, to provide a driving potential. At 24OC, doxorubicin (17 NM) was taken up from the external medium (300 mM glucose, pH 7.0) for up to 40 min. At this time, 38 f 4% (Mean -I SE, n = 5) of total doxorubicin taken up. was Previous estimates of vesicular volume suggest that this represents a lOOO-fold concentration. The addition of 100 mM which would abolish the driving potential, resulted in the loss NaCl, of 92 + 2% of the vesicular doxorubicin within 20 min. The results suggest that a driving potential is essential for doxorubicin accumulation; however, the alternative explanations of decreased binding to proteins or vesicle permeabilization remain to be eliminated.
263
EFFECTS OF DOXORUBICIN HEART BY P-31 NMR AND
ON ESR
THE ENERGY ANALYSIS.
METABOLISM S. Bradamante,
OF
THE PERFUSED F. Morazzoni,
RAT F.
Piccinini, E. Monti. Chemistry and Pharmacology Depts., University of Milan, Italy. Development of dose-dependent cardiotoxicity is the major sideeffect promoted by the anthracicline doxorubicin (DXR). We used P-31 NMR spectroscopy to quantify variations on energy metabolism induced antitumor drug on the Langendorff perfused rat heart. by the Perfusion with DXR (SO mg/l) over 15 min in conditions of spontaneous flow does not produce significant changes in high energy phosphates relative to control, while changes in functions (RPP) were statistically significant. DXR administration in condition of low flow ischemia (half of the spontaneous flow) caused both functional and metabolic changes: variation of ATP concentration relative to th2+semiishomeochemic control, have been related to an alteration of the Ca stasis: we investigated by NMR and ESR spectroscopy the mechanisms of interaction between the drug and the metal ions as for free radicals generation and for metal enzyme inhibition.
264
CHRONIC
CARDI~TOXICITY
OF
ADRIAMYCIN.
T.
Dekker,
C.J.A.
van
Echteld,
W.H.
J.H. Schornagel, Interuniversity Cardiology Institute of Jon& J.H. Kirkels, of Cardiology, University Hospital Utrecht, Netherlands and Department
de the the
Netherlands. Chronic cardiotoxicity of adriamycin was investigated in a rat model using 31Pintravenously at a dose of 1 mg/kg up to a NMR. Adriamycin was administered in a period of 9 weeks. Control rats received cumulative dose of 13 mg/kg physiological saline. Experiments were performed after cumulative doses of 6, 8, 10. 12 and 13 mg/kg. Hearts were excised and perfused according to Langendorff. 31PNMR spectra were obtained subsequently from hearts a) without pacing, b) at 360 beats/minute, c) at 480 beats/minute and back from c to a. After a cumulative dose of 12 mg/kg, the creatine phosphate (CP)/ATP ratio without pacing was significantly lower than in controls (1.40 + 0.35 (SD) vs 2.25 + 0.41, p
S.88
(Supplement
II) (1989)
262
DOXORUBICIN UPTAKE BY ISOLATED SARCOPLASMIC RETICULUM. L. Gailis. Department of Medicine and Institut de Cardiologie de Qusbec, Lava1 University, Quebec, Que., Canada GlV 465. Doxorubicin, an antineoplastic drug, also damages normal tissues, in particular the heart. Since its mode of flux in non-neoplastic tissues is not established we studied doxorubicin uptake by sarcoreticulum plasmic vesicles isolated from rabbit leg muscles. The vesicles were loaded with 100 mM glucose and 100 mM Na glutamate, pH 7.0, to provide a driving potential. At 24OC, doxorubicin (17 NM) was taken up from the external medium (300 mM glucose, pH 7.0) for up to 40 min. At this time, 38 f 4% (Mean -I SE, n = 5) of total doxorubicin taken up. was Previous estimates of vesicular volume suggest that this represents a lOOO-fold concentration. The addition of 100 mM which would abolish the driving potential, resulted in the loss NaCl, of 92 + 2% of the vesicular doxorubicin within 20 min. The results suggest that a driving potential is essential for doxorubicin accumulation; however, the alternative explanations of decreased binding to proteins or vesicle permeabilization remain to be eliminated.
263
EFFECTS OF DOXORUBICIN HEART BY P-31 NMR AND
ON ESR
THE ENERGY ANALYSIS.
METABOLISM S. Bradamante,
OF
THE PERFUSED F. Morazzoni,
RAT F.
Piccinini, E. Monti. Chemistry and Pharmacology Depts., University of Milan, Italy. Development of dose-dependent cardiotoxicity is the major sideeffect promoted by the anthracicline doxorubicin (DXR). We used P-31 NMR spectroscopy to quantify variations on energy metabolism induced antitumor drug on the Langendorff perfused rat heart. by the Perfusion with DXR (SO mg/l) over 15 min in conditions of spontaneous flow does not produce significant changes in high energy phosphates relative to control, while changes in functions (RPP) were statistically significant. DXR administration in condition of low flow ischemia (half of the spontaneous flow) caused both functional and metabolic changes: variation of ATP concentration relative to th2+semiishomeochemic control, have been related to an alteration of the Ca stasis: we investigated by NMR and ESR spectroscopy the mechanisms of interaction between the drug and the metal ions as for free radicals generation and for metal enzyme inhibition.
264
CHRONIC
CARDI~TOXICITY
OF
ADRIAMYCIN.
T.
Dekker,
C.J.A.
van
Echteld,
W.H.
J.H. Schornagel, Interuniversity Cardiology Institute of Jon& J.H. Kirkels, of Cardiology, University Hospital Utrecht, Netherlands and Department
de the the
Netherlands. Chronic cardiotoxicity of adriamycin was investigated in a rat model using 31Pintravenously at a dose of 1 mg/kg up to a NMR. Adriamycin was administered in a period of 9 weeks. Control rats received cumulative dose of 13 mg/kg physiological saline. Experiments were performed after cumulative doses of 6, 8, 10. 12 and 13 mg/kg. Hearts were excised and perfused according to Langendorff. 31PNMR spectra were obtained subsequently from hearts a) without pacing, b) at 360 beats/minute, c) at 480 beats/minute and back from c to a. After a cumulative dose of 12 mg/kg, the creatine phosphate (CP)/ATP ratio without pacing was significantly lower than in controls (1.40 + 0.35 (SD) vs 2.25 + 0.41, p
S.88