Similar changes in cardiac morphology and DNA synthesis induced by doxorubicin and 4'-epi-doxorubicin.

ABSTRACT

Doxorubicin is an antineoplastic agent whose clinical administration is limited by dose-dependent irreversible cardiomyopathy. Doxorubicin inhibits the rate of DNA synthesis in cultured rat myocardial cells after 1 h incubation with 16 microM, as is demonstrated by a decreased incorporation of [methyl-3H]thymidine. An analogue of doxorubicin, 4'-epi-doxorubicin, also inhibits the rate of DNA synthesis within 1 h after treatment with 16 microM, to the same extent as doxorubicin-treatment of myocardial cells. Furthermore, similarity between doxorubicin and 4'-epi-doxorubicin in their effect on the myocardial thymidylate pool was also demonstrated by a significantly decreased incorporation of total [methyl-3H]thymidine. The effect of doxorubicin on the rate of DNA synthesis in cultured rat skeletal muscle cells treated for 1 h with 16 microM was quantitatively the same as in myocardial cells. Light microscopy of doxorubicin- and 4'-epi-doxorubicin-treated myocardial cells and doxorubicin-treated skeletal muscle cells showed distinct nucleolar fragmentation and revealed no differences between the two drugs in their effect on either myocardial or skeletal muscle cells. Electron microscopy of myocardial cells following doxorubicin treatment showed increased nuclear pleomorphism and invaginations, along with a striking and distinctive clumping of nuclear chromatin. Furthermore, an apparent high density of the mitochondria due to an increased matrix volume and a concomitant decrease in the intermembrane compartment were observed. The results of this study indicate that doxorubicin-induced inhibition of cardiac DNA synthesis in cultured myocardial cells is nonpredictive of cardiotoxicity. The mechanism is at least bimodal, and the apparent minor toxicity of 4'-epi-doxorubicin compared with that of doxorubicin in clinical trials cannot be distinguished by a difference in the inhibition of DNA synthesis in the rat heart.