Detection of adriamycin-induced cardiotoxicity in cultured heart cells with technetium 99m-SESTAMIBI.
Adriamycin, a broad-spectrum cytotoxic agent useful in cancer chemotherapy, is limited by a dose-dependent cardiomyopathy mediated in part by disruption of mitochondrial energetics. Hexakis(2-methoxyisobutyl isonitrile)technetium(I) (99mTc-SESTAMIBI) is a gamma-emitting radiopharmaceutical with myocellular accumulation properties dependent on mitochondrial membrane potential. To test the hypothesis that 99mTc-SESTAMIBI could monitor Adriamycin-induced alterations in cardiac energetics, cultured chick heart cells were treated with Adriamycin and 99mTc-SESTAMIBI tracer kinetics were determined. Concentration- and time-dependent depression of 99mTc-SESTAMIBI accumulation was evident within 60 min of treatment. The apparent Ki for acute Adriamycin inhibition of tracer accumulation was 82 microM. After 24 h of treatment, Adriamycin concentrations as low as 0.1 microM demonstrated detectable inhibitory effects. The apparent Ki for this subchronic Adriamycin inhibition of 99mTc-SESTAMIBI accumulation was 18 microM. Subchronic concentration-dependent increases in adriamycin-induced myocellular injury as reflected by lactate dehydrogenase (LDH) release correlated inversely with decreases in 99mTc-SESTAMIBI accumulation. These data further support a contribution from altered mitochondrial energetics to Adriamycin-induced injury and establish a pharmacological foundation for pursuing the possibility of noninvasive imaging of chronic Adriamycin cardiotoxicity in cancer patients using 99mTc-SESTAMIBI.
Piwnica-Worms
D
D
Department of Radiology, Harvard Medical School, Brigham and Women's Hospital, Boston, Mass. 02115.
Chiu
M L
ML
Kronauge
J F
JF
D000704:Analysis of Variance; D000818:Animals; D002642:Chick Embryo; D046508:Culture Techniques; D004317:Doxorubicin / Q000009:adverse effects*; D006321:Heart / Q000000981:diagnostic imaging / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D011877:Radionuclide Imaging; D017256:Technetium Tc 99m Sestamibi
D004317:Doxorubicin; D017256:Technetium Tc 99m Sestamibi; D007770:L-Lactate Dehydrogenase