P-glycoprotein expression and activity of resistance modifying agents in primary cultures of human renal and adrenocortical carcinoma cells.
Tumor cells from patients with renal or adrenocortical carcinomas were tested in vitro for sensitivity to doxorubicin (Dox) and vincristine (Vcr), as well as for the modulation of this sensitivity by resistance modifiers and the immunohistochemical expression of the multidrug resistance associated P-glycoprotein (Pgp). Normal adrenocortical cells from one patient and Pgp-expressing cells of Dox-resistant myeloma RPMI 8226 sublines were included for comparison. The normal adrenocortical cells and cells from one adrenocortical carcinoma showed high Pgp expression, comparable to the most Dox-resistant myeloma cell line, whereas the other tumor samples showed variable but lower expression. The normal adrenocortical as well as the adrenocortical and renal tumor cells were highly resistant to Dox and Vcr. Whereas the cytotoxic effect of Dox was considerably increased by verapamil, cyclosporin A and its non-immunosuppressive analogue SDZ PSC 833 in the Pgp-expressing Dox-resistant sublines, comparatively small effects on the Dox and Vcr sensitivity were observed in the patient samples, irrespective of their Pgp expression. The results indicate that the Dox and Vcr resistance in human adrenocortical and renal carcinomas is mediated by mechanisms other than Pgp and that resistance modulating agents targeting Pgp may be much less efficient in the clinic than in Pgp-expressing cell lines, at least for the tumor types described in the present study.
Fridborg
H
H
Division of Clinical Pharmacology, University Hospital, Uppsala University, Sweden.
Larsson
R
R
Juhlin
C
C
Rastad
J
J
Akerström
G
G
Backlin
K
K
Nygren
P
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000306:Adrenal Cortex Neoplasms / Q000737:chemistry* / Q000473:pathology; D002352:Carrier Proteins / Q000032:analysis*; D016572:Cyclosporine / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000737:chemistry* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000032:analysis*; D009363:Neoplasm Proteins / Q000032:analysis*; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D003524:Cyclosporins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D004317:Doxorubicin; D016572:Cyclosporine; D014700:Verapamil; C070272:valspodar