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.