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.
Petrylak
D P
DP
Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, N.Y.
Scher
H I
HI
Reuter
V
V
O'Brien
J P
JP
Cordon-Cardo
C
C
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