Comparative effectiveness of mitoxantrone and doxorubicin in overcoming experimentally induced drug resistance in murine and human tumour cell lines in vitro.

Using a range of cell lines of murine and human tumour origin in which relatively modest levels (2- to 17-fold) of drug resistance have been selected in vitro by exposure to a range of standard antitumour drugs, we compared the cytotoxic effects of doxorubicin (DOX) and mitoxantrone (MITO). In general, significantly lower concentrations of MITO than of DOX were required to achieve comparable cytotoxicity, confirming previously published data. MITO appears more generally effective against the murine L5178Y drug-resistant sublines than DOX, although there was no expression of collateral sensitivity to this newer agent. In the various human tumour lines there was a lack of cross-resistance to both DOX and MITO in two 5-fluorouracil (FU)-resistant lines and one of two cisplatin (CDDP)-resistant cells, but cross-resistance was expressed in one subline resistant to vincristine (VCR) and two etoposide (VP-16)-resistant sublines. One murine and two human DOX-resistant sublines were effectively killed by MITO, whilst DOX proved effective against the human MITO-resistant subline. This apparent lack of cross-resistance between DOX and MITO in these resistant sublines expressing low levels of resistance in vitro therefore appears to contrast with previous reports involving highly multidrug-resistant DOX-selected sublines. However, since the latter lines generally exhibited profound cross-resistance to VCR and definite cross-resistance to VP-16, this may at least in part dictate their responses to MITO. Therefore, attempts to use experimentally derived drug-resistant sublines for preclinical drug screening should be approached with caution, since patterns of drug response appear to be influenced by the level of drug resistance expressed. The need remains to determine which type of model system provides the most relevant clinical information.