Drug-selected cell line panels for evaluation of the pharmacokinetic consequences of multidrug resistance proteins.

Through the selection with five chemotherapeutics of diverse chemical structures and modes of action (cis-diamminedichloroplatinum, doxorubicin, etoposide, methotrexate and vincristine), four multidrug-resistant cell line panels were developed. Cancer cell lines of different species (human and murine) as well as tissue/organ (skin, colon) origin, characterized by low endogenous expression of multidrug resistance (MDR) proteins and high sensitivity to anticancer agents, were used as parental cell lines. A selection process resulted in the upregulation of several ABC transporters (ABCB1/Abcb1a, ABCC1/Abcc1 and ABCG2/Abcg2), which was confirmed by a number of molecular and cell biology methods. The MDR protein expression pattern seemed to be mainly dependent on the drug used for the selection and not on the species or tissue origin of the cell line. We postulate that such cell panels can be used as a research model to assess the role of MDR proteins in the pharmacokinetics of novel drugs or drug formulations.