Cross resistance and cellular uptake of 4'-O-methyldoxorubicin in experimental tumors with acquired resistance to doxorubicin.

A new analog of doxorubicin, 4'-O-methyldoxorubicin, was previously reported to have a pronounced activity against L1210 leukemia, which shows a natural partial resistance to doxorubicin itself. In the present study, lines of P388 leukemia and Ehrlich ascites tumor with acquired resistance to doxorubicin were found to be cross-resistant to 4'-O-methyldoxorubicin, indicating that the natural and the acquired resistance to doxorubicin involve different mechanisms. In vitro studies on the uptake of 4'-O-methyldoxorubicin in the Ehrlich ascites tumor cells indicated that the observed cross-resistance was partly due to a decreased drug uptake in the resistant cells because of an increased extrusion of the drug, in accordance with previous findings on the mechanism of acquired resistance to doxorubicin.