ACADEMIC RESEARCH ENHANCEMENT AWARD

描述：这项工作的广泛，长期目标是a） 确定抗溶骨性关节炎 治疗预防某些肿瘤的骨转移，和B） 确定允许其他骨转移性肿瘤细胞 摆脱这种抑制作用。 生物膦酸盐，如利塞膦酸盐 抑制骨细胞骨吸收，可用于治疗溶骨性 骨转移 除了减少病变大小，双膦酸盐 治疗有时导致骨转移发生率降低。 负责这种保护作用的具体机制， 骨转移尚未确定。 使用大鼠模型， 骨转移性乳腺癌，本申请的第一个具体目的是 评估在建立病变中的早期形态学事件， 未处理或利塞膦酸盐处理的大鼠。 利塞膦酸钠治疗降低了 用于本研究的肿瘤克隆之一的骨转移发生率 研究，但在其他病变的大小或发病率几乎没有影响。 的 将通过进行时间点实验来实现目标， 监测定位于肿瘤细胞中的lacZ转染的肿瘤细胞的病变发展， 组织切片进行组织化学染色。 该方法可以允许 确定骨转移瘤发展的具体步骤 双膦酸盐治疗改变的病变，并提示可能 治疗效果的机制。 研究的第二个具体目标是 是评估不同的ENU1564肿瘤克隆的能力， 溶解未处理和利塞膦酸盐处理的骨，其次， 是否存在趋化或促有丝分裂反应的差异， 肿瘤细胞释放的产物再吸收处理或未处理 骨头 虽然双膦酸盐治疗有效地抑制骨破坏， 破骨细胞，骨转移灶的组织学切片清楚 表明肿瘤细胞对骨一定程度直接溶解经常 在这个模型系统中继续发生。 直接溶解骨头的能力 可能因肿瘤而异， 对生物膦酸盐的破坏和不满意的治疗反应， 发生在一些骨转移瘤中。 虽然产品从 吸收骨已经显示出刺激趋化性和增殖， 在某些肿瘤细胞中，尚不清楚是否释放这些因子或其 在双膦酸盐处理的骨中改变了对肿瘤细胞的影响。 的 最终能够识别肿瘤细胞的特性， 对抗溶骨性治疗的不满意的反应将使选择 可能受益于替代治疗的患者。

DESCRIPTION: The broad, long-term objectives of this work are a) to identify specific cellular and molecular mechanisms by which antiosteolytic therapy prevents the skeletal metastasis of some neoplasms and b) to identify specific properties that allow other bone-metastatic tumor cells to escape this inhibitory effect. Biophosphonates such as risedronate strongly inhibit osteoclastic bone resorption and can be used to treat osteolytic bone metastasis. In addition to decreased lesion size, bisphosphonate treatment sometimes results in a decreased incidence of bone metastases. Specific mechanisms responsible for this protective effect on incidence of bone metastases have not been determined. Using a rat model of bone-metastatic breast cancer, the first specific aim of this application is to evaluate early morphologic events in the establishment of lesions in untreated or risedronate-treated rats. Risedronate treatment decreases the incidence of bone metastases of one of the tumor clones to be used in the study, but has little effect on lesion size or incidence in the other. The objective will be accomplished by performing a time-point experiment and monitoring lesion development of lacZ-transfected tumor cells localized in tissue sections by histochemical staining. This approach may allow identification of specific steps in the development of bone metastatic lesions that are altered by bisphosphonate treatment and suggest possible mechanisms for the treatment effect. The second specific aim of the study is to evaluate the capacity of different ENU1564 tumor clones to directly lyse untreated and risedronate-treated bone and secondly, to determine whether there are differences in the chemotactic or mitogenic responses of the tumor cells to products released from resorbing treated or untreated bone. While bisphosphonate treatment efficiently inhibits bone destruction by osteoclasts, histologic sections of bone metastatic lesions clearly indicate that some degree of direct lysis of bone by tumor cells frequently continues to occur in this model system. The capacity to directly lyse bone may vary from tumor to tumor and could account for the residual bone destruction and unsatisfactory treatment responses to biophosphonates that occur with some bone-metastatic tumors. While products released from resorbing bone have been shown to stimulate chemotaxis and proliferation of some tumor cells, it is not known whether release of these factors or their influence on tumor cells is altered in bisphosphonate treated bone. The eventual ability to identify tumor cell properties responsible for unsatisfactory responses to antiosteolytic therapies will enable selection of patients that may benefit from alternative treatments.