DETECTION OF ADRIAMYCIN-INDUCED CARDIOTOXICITY IN CULTURED HEART-CELLS WITH TECHNETIUM-99M-SESTAMIBI

Adriamycin, a broad-spectrum cytotoxic agent useful in cancer chemothe rapy, is limited by a dose-dependent cardiomyopathy mediated in part b y disruption of mitochondrial energetics. Hexakis(2-methoxyisobutyl is onitrile)technetium(I) (Tc-99m-SESTAMIBI) is a gamma-emitting radiopha rmaceutical with myocellular accumulation properties dependent on mito chondrial membrane potential. To test the hypothesis that Tc-99m-SESTA MIBI could monitor Adriamycin-induced alterations in cardiac energetic s, cultured chick heart cells were treated with Adriamycin and Tc-99m- SESTAMIBI tracer kinetics were determined. Concentration- and time-dep endent depression of Tc-99m-SESTAMIBI accumulation was evident within 60 min of treatment. The apparent K(i) for acute Adriamycin inhibition of tracer accumulation was 82 muM. After 24 h of treatment, Adriamyci n concentrations as low as 0.1 muM demonstrated detectable inhibitory effects. The apparent K(i) for this subchronic Adriamycin inhibition o f Tc-99m-SESTAMIBI accumulation was 18 muM. Subchronic concentration-d ependent increases in adriamycin-induced myocellular injury as reflect ed by lactate dehydrogenase (LDH) release correlated inversely with de creases in Tc-99m-SESTAMIBI accumulation. These data further support a contribution from altered mitochondrial energetics to Adriamycin-indu ced injury and establish a pharmacological foundation for pursuing the possibility of noninvasive imaging of chronic Adriamycin cardiotoxici ty in cancer patients using Tc-99m-SESTAMIBI.