ESTABLISHMENT AND IN-VIVO CHARACTERIZATION OF MULTIDRUG-RESISTANT DUNNING R3327 RAT PROSTATE-CARCINOMA CELL-LINES

We describe the selection of 3 new multidrug-resistant cell lines deri ved from tumor cells of different metastatic phenotypes within the Dun ning R3327 model of rat prostatic carcinoma. Cell lines of weak (AT2) and strong (AT3 and MAT-LyLu) metastatic behaviour were culture in vit ro and challenged with doxorubicin at progressively increasing concent rations. Chemosensitivity was determined colorimetrically by release o f precipitated formazan pigment (MTT assay). Expression of the multidr ug-resistance glycoprotein (P-170) was monitored immunocytochemically and by Western blottig using monoclonal antibody C219. The behaviour o f the parental and resultant drug-resistant cells was assessed by thei r growth in syngeneic rats. Doxorubicin challenge of the initially dru g-sensitive parental prostatic carcinoma cell lines resulted in the ra pid development of multidrug resistance together with simultaneous exp ression of P-glycoprotein. While lung and lymph-node metastases develo ped in host animals inoculated with parental AT3 and MAT-LyLu cells, n o metastases developed in the multidrug-resistant progeny of these cel l lines. This study has shown that Dunning rat prostate-carcinoma cell lines, previously sensitive to different cytotoxic agents, rapidly be come multidrug-resistant and express P-glycoprotein following exposure to doxorubicin. Furthermore, development of multidrug resistance is a ssociated with a less aggressive tumor phenotype and loss of metastati c potential. Nevertheless, it is unlikely that the non-metastatic phen otype of Dunning rat prostatic carcinoma cells is solely associated wi th expression of P-glycoprotein. These new multidrug-resistant cell li nes exhibiting an altered behavioral phenotype will provide a valuabhl e model with which to analyze the relationship between expression of P -glycoprotein and the metastatic phenotype of prostatic carcinoma cell s. (C) 1994 Wiley-Liss, Inc.