Biochemical lesions in DNA associated with the antiproliferative effects of mitoxantrone in the hepatoma cell.
The H-35 rat hepatoma cell was markedly more sensitive to the anthracenedione mitoxantrone (IC50, 0.05 microM) than to the anthracycline antibiotics daunorubicin (IC50, 0.5 microM) and Adriamycin (IC50, 2.5 microM). In the rat hepatoma cell, mitoxantrone inhibited DNA and protein syntheses, with minimal effects on RNA synthesis. In contrast to daunorubicin, mitoxantrone induced both DNA strand breaks and DNA-protein cross links. The capacity of mitoxantrone to induce more extensive DNA cleavage than anthracycline antibiotics such as daunorubicin may be related to the sustained cellular retention of mitoxantrone (62% of accumulated drug) as compared to that for daunorubicin (32% of accumulated drug). Protein-associated DNA cleavage is likely to be one of the primary lesions contributing to the antiproliferative activity of mitoxantrone in the hepatoma cell, although marked growth inhibition was observed without corresponding alterations in DNA integrity.
Ellis
A L
AL
Department of Pharmacology/Toxicology, Medical College of Virginia, Richmond 23298.
Randolph
J K
JK
Conway
B R
BR
Gewirtz
D A
DA
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000032:analysis; D003630:Daunorubicin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005609:Free Radicals; D006863:Hydrogen-Ion Concentration; D008942:Mitoxantrone / Q000494:pharmacology*; D014176:Protein Biosynthesis; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004277:DNA, Single-Stranded; D005609:Free Radicals; D004317:Doxorubicin; D004247:DNA; D008942:Mitoxantrone; D003630:Daunorubicin