P-glycoprotein expression in primary and metastatic transitional cell carcinoma of the bladder.
BACKGROUND
To determine the expression of P-glycoprotein in pre- and post-chemotherapy tumor tissue samples from patients with transitional cell carcinomas treated with M-VAC (methotrexate, vinblastine, adriamycin and cisplatin).


METHODS
Fresh frozen tissue sections of primary and metastatic urothelial tumors were stained with mouse monoclonal antibody HYB-241 which recognized an external epitope of P-glycoprotein, using an avidin-biotin immunohistochemical technique. Immunoreactivity was scored separately in tumor cells and endothelial cells.


RESULTS
Untreated primary lesions showed immunostaining in 6 of 46 cases (13%), while 6 of 16 (38%) post-therapy primary tumors were immunoreactive. None of the untreated metastases (0 of 17) were positive, however, 6 of 11 (55%) post-therapy specimens showed varied percentages of positivity for p-glycoprotein (p = 0.002). The highest percentage, 50%-70% of tumor cells stained, was observed in metastatic lesions from patients who had received 6 or more chemotherapy cycles. No difference in the proportion of endothelial cells stained was observed in pre- and post-therapy specimens. However, 3 of 6 post-therapy samples obtained from 5 individual patients showed MDR1 up-regulation on endothelial cells.


CONCLUSIONS
The data show that an increase in the proportion of cells expressing P-glycoprotein occurs after exposure to a combination chemotherapy program containing drugs known to select for P-glycoprotein expression in vitro. The observation of increased immunoreactive endothelial cells suggests transactivation of the MDR1 in these cells. While data are preliminary, P-glycoprotein expression in capillary endothelial cells may contribute to drug resistance. Taken together, these mechanisms may contribute to therapeutic failure in patients with bladder tumors treated with chemotherapy.
Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, N.Y.
D P
DP
Petrylak
H I
HI
Scher
V
V
Reuter
J P
JP
O'Brien
C
C
Cordon-Cardo
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002295:Carcinoma, Transitional Cell / Q000737:chemistry* / Q000188:drug therapy / Q000556:secondary; D002945:Cisplatin / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D018432:Drug Resistance, Multiple; D006801:Humans; D007150:Immunohistochemistry; D008727:Methotrexate / Q000008:administration & dosage; D001749:Urinary Bladder Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000473:pathology; D014747:Vinblastine / Q000008:administration & dosage
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014747:Vinblastine; D004317:Doxorubicin; D002945:Cisplatin; D008727:Methotrexate