Comparison of doxorubicin-induced DNA damage in doxorubicin-sensitive and -resistant P388 murine leukemia cells.

Doxorubicin-induced DNA damage was studied in the P388 leukemia cell line and in a doxorubicin-resistant subline by alkaline elution techniques. DNA single-strand breaks and DNA-protein cross-links were determined. Whereas, in the sensitive line, 1 hr exposure to drug induced DNA damage in a concentration-dependent manner, in the resistant line only a marginal effect was observed at high drug concentrations. In contrast, elution kinetics of DNAs from cells irradiated with X-rays were similar in both lines. Although a reduced intracellular drug accumulation was found in resistant cells, this difference could not account for the marked reduction in doxorubicin-induced DNA damage. The degree of resistance of the P388 subline was reduced about 7-fold by verapamil, whereas the extent of DNA damage was unaffected. These results suggest the presence of alternative modes of resistance, independent of membrane changes, in highly resistant cells.