CLINICAL TRIAL: PHASE II STUDY OF TAMOXIFEN FOR PROGRESSIVE TRANSITIONAL CELL CA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们已经证明，雌激素受体(ER)-B在RT-4、5637、T-24、TSU-PR1和TCC-SUP细胞系中都有表达，而ER-a的表达水平很低。选择性雌激素受体调节剂雷洛昔芬在体外以剂量依赖的方式诱导RT-4、T-24和5637细胞株的凋亡并降低其存活率。组织芯片分析显示，ER-B在210例膀胱肿瘤中表达133例(63.3%)，而ER-a仅在2例肿瘤中表达。ER-B的表达与肿瘤的分期和分级有关。我们建立了一种荷人膀胱癌的异种移植模型，以评价SERMS在动物模型中的疗效。将105637个人移行细胞癌细胞接种于6~8周龄雌性裸鼠乳房脂肪垫的一个部位。只有在两周内发生可测量的皮下肿瘤(一维至少3毫米)的小鼠被选为进一步研究。每组小鼠6-8只，每组6-8只，分别给予不治疗、帕雷西博(仅用溶媒)、雷洛昔芬0.01 mg/d、雷洛昔芬0.1 mg/d和雷洛昔芬1 mg/d灌胃，每周5天，共8周。雷洛昔芬各剂量组均能显著抑制肿瘤生长(p&lt；0.05)。在第二个实验中，四组可测量肿瘤的小鼠每组10只，分别植入皮下60天缓释微丸(美国创新研究公司，萨拉索塔，佛罗里达州)，分别提供安慰剂、他莫昔芬0.008 mg/天、他莫昔芬0.125 mg/天和他莫昔芬1.25 mg/天。同样，观察到所有剂量的他莫昔芬对肿瘤有显著的抑制作用(p&lt；0.01)。在单独的第三个验证性实验中，四组小鼠每组10只(具有统计上相似的肿瘤体积)被植入60天皮下缓释微丸(美国萨拉索塔创新研究公司，佛罗里达州萨拉索塔)，分别提供安慰剂、他莫昔芬0.008毫克/天(低剂量)、他莫昔芬0.125毫克/天(中剂量)和雷洛昔芬0.1 mg/天。与安慰剂相比，他莫昔芬或雷洛昔芬治疗的小鼠肿瘤明显较小(P&lt；0.05)。雌激素受体在人膀胱癌中的表达，以及SERM在体外和在荷人膀胱癌细胞的小鼠移植模型中的抗肿瘤活性，为评估他莫昔芬作为膀胱癌患者的靶向治疗提供了理论基础。 他莫昔芬是一种选择性雌激素受体调节剂(SERM)，可能通过表达雌激素受体(ER)-B受体而对人移行细胞癌具有抗肿瘤活性。 主要目的：评估进展期移行细胞癌铂类药物治疗后4个月他莫昔芬的无进展时间(FFP)。 次要目标： 确定目标应答率 探讨FFP与肿瘤ER-B状态的关系 评估该方案的毒性/安全性 评估总体生存(OS)

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 (p<0.05). 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 (p<0.01). 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 (P<0.05). 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. 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. 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)