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Enhanced Sensitivity of the Rat Hepatoma Cell to the Daunorubicin Analogue 4-Demethoxydaunorubicin Associated with Induction of DNA Damage

Departments of Pharmacology/Toxicology and Medicine, Medical College of Virginia, Richmond, Virginia 23298

The H-35 rat hepatoma, a cell line which is relatively resistant to the classical anthracycline antibiotics such as Adriamycin [the concentration of drug which inhibits cell proliferation by 5090 (IC₅₀) = 2.5 µM] and daunorubicin (IC₅₀ of 0.5 µM), is markedly more sensitive to the 4-demethoxydaunorubicin derivative, idarubicin (IC₅₀ of 0.025 µM). In contrast to daunorubicin, which has previously been shown to inhibit hepatoma cell proliferation in the absence of perceptible DNA cleavage, idarubicin induces concentration-dependent DNA damage which may account for its enhanced capacity to inhibit proliferation of the rat hepatoma. Free radical scavengers fail to interfere with inhibition of cell proliferation induced by idarubicin. Damage to the cell membrane or alterations in mitochondrial integrity do not appear to represent components of idarubicin toxicity in this tumor cell line. Inhibition of DNA synthesis by idarubicin prallels inhibition of cell growth; however, sensitivity of DNA synthesis to idarubicin is significantly less than that for cell proliferation (IC₅₀ values of 0.5 µM and 0.025 µM, respectively). It is postulated that the antiproliferative effects of idarubicin in the H-35 rat hepatoma model may be a consequence of alterations in DNA integrity which ultimately result in the inhibition of cellular biosynthetic processes.

¹ Supported by a grant from the American Heart Association Virginia Affiliate. To whom requests for reprints should be addressed, at Departments of Pharmacology/Toxicology and Medicine, Medical College of Virginia, Box 230, MCV Station, Richmond, VA 23298.

Received 12/13/88. Revised 4/10/89. Accepted 6/ 8/89.