ACTIVITY OF N-BENZYL-ADRIAMYCIN-14-VALERATE (AD198), A NEW ANTHRACYCLINE DERIVATE, IN MULTIDRUG-RESISTANT HUMAN OVARIAN AND BREAST-CARCINOMA CELL-LINES

The new lipophilic anthracycline N-benzyl-adriamycin-14-valerate (AD19 8) was evaluated for its activity in comparison to doxorubicin in P-gl ycoprotein (Pgp)-positive and -negative cell lines. AD198 and doxorubi cin showed comparable antitumor activity in the Pgp-negative breast ca ncer cell line MCF-7 and the Pgp-negative ovarian carcinoma cell line A2780. By contrast, AD198 was significantly more active than doxorubic in in the Pgp-positive breast cancer cell line MCF7AD (IC50 values 2.5 and 0.15 mu M for 96 h continuous exposure) and the Pgp-positive ovar ian carcinoma cell line A2780 DX5 (IC50 values 0.6 and 0.07 mu M, resp ectively). Unlike doxorubicin, the activity of AD198 was not increased by concommittant application of cyclosporin A in cell line MCF7AD. Fl ow cytometry studies showed that, in contrast to doxorubicin, AD198 wa s not transported by Pgp and that verapamil did not change the intrace llular pharmakokinetics of this new anthracycline. These data provide evidence that AD198 possesses high activity in human solid tumor cell lines expressing the classical multidrug resistant phenotype. Its furt her clinical development appears to be warranted.