This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT We have demonstrated that estrogen receptor (ER)-B is expressed in RT-4, 5637, T-24, TSU-PR1 and TCC-SUP human bladder cancer cell lines, while ER-a is expressed at verylow levels. Raloxifene, a SERM (selective estrogen receptor modulator) induced apoptosis and decreased the viability of RT-4, T-24, and 5637 cell-lines in-vitro in a dose dependent manner. Using tissue microarray analysis, ER-B was expressed in 133 (63.3%) of 210 bladder tumors, while ER-a was expressed in only 2 tumors. The expression of ER-B was associated withhigher stage and grade. We constructed a muring xenograft model bearing human bladder cancer to evaluate the efficacy of SERMs in an animal model. A total of 10 5637 human transitional cell carcinoma cells were injected into one site at a mammary fat pad of 6-8 week old female athymic BALB/c nu/nu mice. Only mice that developed measurable subcutaneous tumor (at least 3 mm in one dimension) within 2 weeks were chosen for further study. Five cohorts of mice consisting of 6-8 mice per cohort were administered no therapy, palcebo (solvent only), raloxifene 0.01 mg/day, raloxifene 0.1 mg/day and raloxifene 1 mg/day for 5 days a week by oral gavage for 8 weeks. All of the doses of raloxifene significantly inhibited the growth of tumor (p0.05). In a second experiment, four cohorts of mice with measurable tumors with 10 mice per cohort were implanted withsubcutaneous 60-day time-release pellets (innovative Research of America, Sarasota, FL) delivering placebo, tamoxifen 0.008 mg/day, tamoxifen 0.125 mg/day and tamoxifen 1.25 mg/day, respectively. Again, significant inhibition of tumor was observed with all of the doses of tamoxifen (p0.01). In a separate third confirmatory experiment, four cohorts of mice with 10 mice per cohort (with statistically similar tumor volumes) were implanted with subcutaneous 60-day time-release pellets (Innovative Research of America, Sarasota, FL) delivering placebo, tamoxifen 0.008 mg/day (low dose), tamoxifen 0.125 mg/day (medium dose) and raloxifene 0.1 mg/day, respectively. The tamoxifen or raloxifene treated mice demonstrated significantly smaller tumors compared to placebo (P0.05). The expression of estrogen receptors in human bladder cancers in conjunction with the anti-tumor activity of SERMs both in vitro and in a murine xenograft model bearing human bladder cancer cells provides the rationale for evaluating tamoxifen as a targeted therapeutic for patients with bladder cancer. HYPOTHESIS Tamoxifen, a selective estrogen receptor modulator (SERM), may have anti-tumor activity against human transitional cell carcinoma owing to estrogen receptor (ER)-B receptor expression by this malignancy.
SPECIFIC AIMS Primary objective: To assess the 4 month freedom fromprogression (FFP) from tamoxifen in progressive transitional cell cancer following platinum-based therapy Secondary objectives: To determine ojbective response rate To assess the association of FFP with ER-B status of the tumor To assess the toxicity/safety profile of this regimen To assess overall survival (OS)
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