CONTROL OF METASTATIC PROGRESSION OF PROSTATE CANCER

有效控制前列腺癌（CaP）转移进展的治疗方式尚未可用。 这部分是由于原发性和转移性CaP对化疗的不同反应。 CaP细胞对抗增殖和抗转移药物的应答可以通过肿瘤细胞和器官特异性基质细胞（例如，成纤维细胞和内皮细胞）。 新的联合治疗，可以有效地中和这些肿瘤间质相互作用的保护作用，应显着提高常规化疗的疗效。为了检验这些假设，器官特异性基质的贡献（例如，骨、肺）在调节CaP细胞对药物诱导的细胞毒性、细胞凋亡和多药耐药性的反应中的作用。 对于这些研究，已建立（例如，阿霉素，紫杉醇）和新的（例如，化学修饰的四环素（CMT））药物。 当肿瘤细胞单独生长、与基质细胞或与基质细胞外基质（ECM）共培养时，将使用人cDNA表达阵列系统研究基因表达模式的改变。 间隙连接蛋白的表达和多药耐药表型将与基质存在下肿瘤细胞对细胞毒性药物的增强的耐药性相关（Aim 1）。 肿瘤-间质相互作用在调节转移促进因子（例如，基质降解酶、它们的抑制剂和CD 44）进行鉴定（目的2）。 可以中和CaP细胞对细胞毒性药物的增强的抗性的组合药物治疗策略的功效将在两种CaP转移模型（例如，自发和诱导）。这些模型类似于人类的早期和晚期CaP。 联合治疗将涉及使用两种药物（例如，紫杉醇/多柔比星和CMT-3）。 此外，还将在联合治疗策略中检测一些克服肿瘤细胞耐药性增强（由于基质影响）的药物（目的3）。这项研究的结果不仅可以增强我们对肿瘤-间质相互作用在控制前列腺肿瘤化疗反应中的作用的理解，而且还可以提出新的联合治疗方法，可以有效地控制CaP的转移进展。

Treatment modalities that effectively control the metastatic progression of prostate cancer (CaP) are not yet available. This is due in part to the differential response of primary and metastatic CaP to chemotherapy. The response of CaP cells to anti-proliferative and anti-metastatic drugs may be modulated through bidirectional inductive interactions between tumor cells and organ specific stromal cells (e.g., fibroblast and endothelial cells). Novel combination therapies that can effectively neutralize the protective effect of these tumor- stroma interactions should significantly enhance the efficacy of conventional chemotherapy. To test these hypotheses, the contribution of organ specific stroma (e.g., bone, lung) in modulating the response of CaP cells to drug-induced cytotoxicity, apoptosis, and multi drug resistance will be investigated, using both CaP and stromal human primary cell cultures. For these studies, established (e.g., doxorubicin, taxol) and novel (e.g., chemically modified tetracyclins, (CMT)) drugs will used. Alterations in the pattern of gene expression, when tumor cells are grown alone, in co- cultures with stromal cells or with stromal extracellular matrix (ECM), will be investigated using a human cDNA expression array system. The expression of gap-junctional proteins and the multi drug resistance phenotype will be correlated to the enhanced resistance of tumor cells to cytotoxic drugs in the presence of stroma (Aim 1). The contribution of tumor-stroma interactions in modulating the production and activity of metastasis promoting factors (e.g., matrix degrading enzymes, their inhibitors and CD44) will be identified (Aim 2). The efficacy of a combination drug treatment strategy that can neutralize the enhanced resistance of CaP cells to cytotoxic drugs will be examined in two models of CaP metastasis (e.g., spontaneous and induced). These models resemble early and late stage CaP in human. The combination treatment will involve the use of two drugs (e.g., taxol/doxorubicin and CMT-3) that have cytotoxic and antimetastatic actions. In addition, some drugs that overcome the enhanced drug resistance of tumor cells, due to the stromal influence, will also be tested in the combination treatment strategy (Aim 3). The results of this proposed study should not only enhance our understanding of the contribution of tumor-stroma interactions in controlling the response of prostate tumor by chemotherapy but would also suggest novel combination therapies that can effectively control the metastatic progression of CaP.