IN-VIVO MODEL SYSTEMS IN P-GLYCOPROTEIN-MEDIATED MULTIDRUG-RESISTANCE

In this article we review the in vivo model systems that have been dev eloped for studying P-glycoprotein-mediated multidrug resistance (MDR) in the preclinical setting. Rodents have two mdr genes, both of which confer the MDR phenotype: mdrla and mdrlb. At gene level they show st rong homology to the human MDR1 gene and the tissue distribution of th eir gene product is very similar to P-glycoprotein expression in human s. In vivo studies have shown the physiological roles of P-glycoprotei n, including protection of the organism from damage by xenobiotics. Tu mors with intrinsic P-glycoprotein expression, induced MDR or transfec ted with an mdr gene, can be used as syngeneic or xenogenic tumor mode ls. Ascites, leukemia, and solid MDR tumor models have been developed. Molecular engineering has resulted in transgenic mice that express th e human MDR1 gene in their bone marrow and in knockout mice missing a murine mdr gene. The data on pharmacokinetics, efficacy, and toxicity of chemosensitizers of P-glycoprotein in vivo are described. Results f rom studies using monoclonal antibodies directed against P-glycoprotei n and other miscellaneous approaches for modulation of MDR are mention ed. The importance of in vivo studies prior to clinical trials is bein g stressed and potential pitfalls due to differences between species a re discussed.