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 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. Furthermore, 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 model with which to analyze the relationship between expression of P-glycoprotein and the metastatic phenotype of prostatic carcinoma cells.
Bashir
I
I
Department of Clinical Oncology, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.
Sikora
K
K
Abel
P
P
Foster
C S
CS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D002277:Carcinoma / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D066298:In Vitro Techniques; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000473:pathology*; D051381:Rats; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D004317:Doxorubicin