Tamoxifen enhances the chemosensitivity of bladder carcinoma cells.
OBJECTIVE
Chemosensitizers, which enhance cellular chemosensitivity and reduce chemoresistance, are expected to substantially improve response rates of systemic chemotherapy for patients with metastatic bladder cancer. Tamoxifen is a nonsteroidal antiestrogen that has been shown to reverse drug resistance in vitro in some cancer models through pathways not related to its antiestrogenic effect. In this study we tried to evaluate its possible effect on chemosensitization of bladder cancer cells.


METHODS
In vitro chemosensitivity tests were done with 3 bladder cancer cell lines and 4 cytotoxic agents (methotrexate, vinblastine, doxorubicin and cisplatin) in the presence or absence of graded concentrations of tamoxifen. Verapamil was used in parallel experiments to compare the degrees of chemosensitization. The transcript and protein product [P-glycoprotein, (P-gp)] levels of the mdr-1 gene were also examined in the 3 cell lines by reverse-transcription polymerase chain reaction (RT-PCR) and flow cytometric assay, respectively.


RESULTS
Tamoxifen at 5 and especially 10 microM. concentrations, which were minimally toxic to the 3 bladder cancer cell lines used, enhanced the chemosensitivity of bladder cancer cells in most drug combinations in a dose-dependent manner. In some combinations 10 microM. tamoxifen did better than 5 microM. in chemosensitization. The effect of chemosensitization was more evident in cells treated with 10 microM. tamoxifen plus methotrexate and vinblastine in which 12.9 to 95.4-fold and 12.4 to 21.3-fold IC50 reduction was observed, respectively. A less prominent, but still significant, effect could be seen in doxorubicin- and cisplatin-treated cells. Verapamil, although used at concentrations up to 10 microM. which are higher than systemically tolerable, was not able to enhance chemosensitivity of the 3 bladder cancer cell lines. By flow cytometric analysis of the P-gp level and by RT-PCR assay of the mdr-1 gene transcript level, it was shown that little if any mdr-1 gene expression could be detected in the 3 cell lines. This implies that the mdr-1 gene function may play a minimal role in drug resistance mechanisms of bladder cancer cells and that tamoxifen exerts its chemosensitization effect through pathways other than mdr-1 gene function modulation.


CONCLUSIONS
Tamoxifen was shown to be a good chemosensitizer in a bladder cancer cell model and may well be tried in combination with systemic chemotherapy for metastatic human bladder cancers in the clinical setting.
Pu
Y S
YS
Department of Oncology and Urology, National Taiwan University Hospital, Taipei, Republic of China.
Hsieh
T S
TS
Tsai
T C
TC
Cheng
A L
AL
Hsieh
C Y
CY
Su
I J
IJ
Lai
M K
MK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D008969:Molecular Sequence Data; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000473:pathology*; D014747:Vinblastine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D013629:Tamoxifen; D014747:Vinblastine; D004317:Doxorubicin; D002945:Cisplatin; D008727:Methotrexate