Establishment and in vivo characterization of multidrug‐resistant dunning R3327 rat prostate‐carcinoma cell‐lines

Abstract

We describe the selection of 3 new multidrug‐resistant cell lines derived from tumor cells of different metastatic phenotypes within the Dunning R3327 model of rat prostatic carcinoma. Cell lines of weak (AT2) and strong (AT3 and MAT‐LyLu) metastatic behavior were cultured in vitro and challenged with doxorubicin at progressively increasing concentrations. Chemosensitivity was determined colorimetrically by release of precipitated formazan pigment (MTT assay). Expression of the multidrug‐resistance glycoprotein (P‐170) was monitored immunocytochemically and by Western blotting using monoclonal antibody C219. The behavior of the parental and resultant drug‐resistant cells was assessed by their growth in syngeneic rats. Doxorubicin challenge of the initially drug‐sensitive parental prostatic carcinoma cell lines resulted in the rapid development of multidrug resistance together with simultaneous expression of P‐glycoprotein. While lung and lymph‐node metastases developed in host animals inoculated with parental AT3 and MAT‐LyLu cells, no metastases developed in the multidrug‐resistant progeny of these cell lines. This study has shown that Dunning rat prostate‐carcinoma cell lines, previously sensitive to different cytotoxic agents, rapidly become multidrug‐resistant and express P‐glycoprotein following exposure to doxorubicin. Further more, development of multidrug resistance is associated with a less aggressive tumor phenotype and loss of metastatic potential. Nevertheless, it is unlikely that the non‐metastatic phenotype of Dunning rat prostatic carcinoma cells is solely associated with expression of P‐glycoprotein. These new multidrug‐resistant cell lines exhibiting an altered behavioral phenotype will provide a valuable mode with which to analyze the relationship between expression of P‐glycoprotein and the metastatic phenotype of prostatic carcinoma cells.