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Structural and Functional Effects of Adriamycin on Cardiac Cells in Vitro¹

Division of Medical Oncology [T. J. L., I. C. H., G. P. C.] and Pharmacology [M. I.], Sidney Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115

The effects of Adriamycin (ADR) on the heart, seen clinically as transient electrocardiographic changes and cardiomyopathy, have been simulated in an in vitro cardiac cell system. Structural and functional alterations in cultured heart cells can be dissociated based upon ADR dose and length of exposure. At high ADR doses (100 to 200 µg/ml), cessation of beating was rapid, and structural changes consistent with the in vivo cardiomyopathic picture (vacuolization and nucleolar fragmentation) were observed. At low ADR doses (0.1 to 0.5 µg/ml), arrhythmias were produced in the absence of ultrastructural changes (within 48 hr); the incidence and severity of the arrhythmias were demonstrated to be dose dependent. Continued treatment of cultures at low dose levels for sustained periods of time (up to 17 days) resulted in a striking loss of muscle fiber without concomitant vacuolization and nucleolar fragmentation. An intermediate ADR dose of 10 µg/ml for 1 hr exposure caused vacuolization and cessation of beating, with lysis of cells within 72 hr. The parallel between the effects of ADR on in vitro cardiac cell structure and function with those seen in vivo suggests that this simple system may have value in studies directed towards the mechanism of ADR-induced cardiac toxicity and in the screening of anthracycline analogs for their potential effects on the heart.

¹ This work was supported in part by Research Grants CA 09172, CA 19118, and CA 24771 from the National Cancer Institute and by funds provided by Adria Laboratories, Inc., Columbus, Ohio.

² To whom requests for reprints should be addressed, at Sidney Farber Cancer Institute, 44 Binney Street, Boston, Mass. 02115.

Received 5/ 5/80. Accepted 7/23/80.

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