Expression of the kidney-associated differentiation glycoprotein gp160 and resistance to the antitumor effects of interferon alpha in renal cell carcinomas.
BACKGROUND
Alpha interferon (IFN-alpha) is commonly used to treat patients with advanced renal cell carcinoma (RCC). We previously reported that resistance of RCCs to IFN-alpha in vitro correlated with the expression of a cell-surface glycoprotein of 160,00 kD molecular weight (gp160) which we subsequently identified as aminopeptidase A.


METHODS
To directly test the role of gp160/APA in IFN-resistance, we stably introduced the gp160/APA cDNA into IFN-sensitive SK-RC-49 cells resulting in the expression of an enzymatically active gp160/APA protein. In addition, to determine if gp160/APA expression could function as a marker of IFN-resistance in vivo, we assessed gp160/APA protein levels in autologous normal kidney and primary renal cancer specimens from 29 patients half of which were randomized to receive adjuvant IFN-alpha therapy following nephrectomy.


RESULTS
Four clones which possessed varying amounts of gp160/APA specific enzyme activity were assayed for sensitivity to the antiproliferative effects of IFN-alpha. All four clones exhibited sensitivity to IFN-alpha similar to that observed with parental SK-RC-49 cells. The analysis of tumor tissue detected no significant difference between the mean level of gp160/APA in tissue from control and IFN-alpha treated patients (1.33 A.U. versus 0.9981 A.U., p = 0.23); however, the mean gp160/APA level was significantly less in tumor tissue (mean = 1.15 A.U.) compared to normal tissue (mean = 2.15 A.U.; p < 0.00001). Within the IFN-alpha treated group, tumor gp160/APA levels did not correlate with the development of metastases or survival (p = 0.469).


CONCLUSIONS
These data indicate that gp160/APA does not directly convey IFN-resistance to RCC cells and suggest that expression of gp160/APA in primary RCCs does not predict the benefit of IFN-alpha therapy.
Geng
Y
Y
Genitourinary Oncology Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Biffi
A
A
Engelstein
D
D
Ronch
E
E
Faustini
M
M
Lai
H K
HK
Albino
A P
AP
Di Fronzo
G
G
Nanus
D M
DM
D000368:Aged; D000626:Aminopeptidases / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology*; D002454:Cell Differentiation; D002460:Cell Line; D004351:Drug Resistance; D005260:Female; D043384:Glutamyl Aminopeptidase; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D007668:Kidney / Q000201:enzymology / Q000276:immunology*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D000626:Aminopeptidases; D043384:Glutamyl Aminopeptidase