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

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Abstract
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, I 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.