ACADEMIC RESEARCH ENHANCEMENT AWARD

描述：这项工作的广泛、长期目标是a)到 确定抗骨溶解药物的特定细胞和分子机制 治疗可预防某些肿瘤的骨转移；b) 确定允许其他骨转移瘤细胞 逃避这种抑制作用。利塞膦酸盐等强效生物磷酸盐 抑制破骨细胞性骨吸收，可用于治疗溶骨症 骨转移。除了减少病变大小外，双膦酸类药物 治疗有时会降低骨转移的发生率。 导致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，这一应用的第一个特定目标是 评估早期形态学事件在建立皮损中的作用 未治疗或利塞膦酸盐治疗的大鼠。利塞膦酸盐治疗可降低 其中一种肿瘤克隆的骨转移发生率 研究，但对其他患者的病变大小或发病率影响不大。这个 目标将通过执行时间点实验和 定位于LacZ的肿瘤细胞病变发展的监测 组织切片进行组织化学染色。这种方法可以允许 骨转移瘤发生发展过程中具体步骤的识别 双膦酸类药物治疗引起的病变，提示有可能 治疗效果的作用机制。这项研究的第二个具体目标 目的是评价不同的ENU1564肿瘤克隆对肿瘤细胞的直接杀伤能力 溶解未经处理和利塞膦酸盐处理的骨；其次，测定 在趋化或有丝分裂反应上是否存在差异 肿瘤细胞对吸收释放产物的处理和未处理 骨头。而双膦酸盐治疗有效地抑制了骨破坏 经破骨细胞、组织学切片明确显示骨转移灶 表明肿瘤细胞经常对骨进行一定程度的直接溶解 在这个模型系统中继续发生。直接溶骨的能力 可能因肿瘤的不同而不同，并可能是残骨的原因 对生物磷酸盐的破坏和不满意的治疗反应 发生在一些骨转移瘤中。当产品从 骨吸收已被证明可以刺激趋化和增殖。 一些肿瘤细胞，尚不清楚这些因子是否会释放或它们的 双膦酸骨处理后对肿瘤细胞的影响发生改变。这个 最终确定肿瘤细胞特性的能力 对抗骨溶解治疗的不满意反应将使选择 可能从替代治疗中受益的患者的比例。

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.