EFFECT OF CONCENTRATION ON THE CYTOTOXIC MECHANISM OF DOXORUBICIN-APOPTOSIS AND OXIDATIVE DNA-DAMAGE

Anthracycline derivatives such as doxorubicin are part of many chemoth erapeutic regimens and reach peak plasma concentrations of 5 mu M. We investigated the cytotoxic mechanisms of various doxorubicin concentra tions in MOLT-4 ALL-cells. Concentrations of up to 100 mu M doxorubici n achieved similar cytotoxic effects in cultures of MOLT-4 cells, but acted via different mechanisms. Doxorubicin induced apoptosis (maximum effect at 1 mu M), which was dependent on RNA synthesis and involved oxidative stress. Concentrations higher than 3 mu M did not induce apo ptosis, but significantly inhibited RNA synthesis. DNA strand breaks i n MOLT-4 cells occurred in the presence of 1 to 5 mu M doxorubicin to a similar extent, but showed a dose-dependence at higher concentration s. There was no GC/MS-detectable oxidation of DNA bases in apoptotic c ells and only 1 out of 13 DNA base oxidation products, 8-hydroxyguanin e, increased significantly in the presence of as much as 100 mu M doxo rubicin. These results suggest that at pharmacologically relevant conc entrations apoptosis and not oxidative DNA damage is the main killing mechanism of doxorubicin against ALL cells. (C) 1997 Academic Press