Control of the Metastatic Progression of Prostate cancer

描述(由申请人提供)： 目前还没有控制前列腺癌转移的有效治疗方法。对这种癌症和其他转移性癌症的研究发现，间质诱导因素会产生“获得性耐药”。在前列腺癌中，间质因子诱导肿瘤细胞产生促炎细胞因子、IL-1β、IL-6和IL-8。这与对细胞毒性/抗转移药物，如阿霉素和CMT-3(一种新的细胞毒性和抗转移四环素类似物)的耐药性增加不谋而合。阻断IL-1β和IL-6的产生可以提高肿瘤细胞对化疗药物的敏感性，而阻断IL-8的产生则会降低肿瘤细胞的侵袭潜能。细胞毒性药物和抗炎药物的结合可减少这些细胞因子的表达。因此，在对化疗的炎症反应中抑制细胞因子产生的联合疗法应该会提高细胞毒和抗转移药物的疗效。该方案的目标是：1.建立肿瘤细胞相关细胞因子的产生与获得性耐药以及肿瘤进展之间的因果关系。(2)评价细胞毒与抗炎药物联合治疗转移性前列腺癌的疗效。通过研究表达绿色荧光蛋白的前列腺癌细胞(PC-3ML和LNCaP)的生长和转移，以及IL-1β、IL-6或IL-8的正义和反义构建，将建立细胞因子产生与肿瘤进展之间的因果关系。将通过鉴定表达IL-1β反义/IL-6和IL-1β正义/IL-8反义cDNA的PC-3m1双转基因细胞来研究这3种细胞因子的可能连锁作用(目标1)。在选择性改变细胞因子产生的PC-3ML和LNCaP转染体中，药物诱导的细胞毒性的变化将通过细胞毒性分析、基因芯片分析、随后的RT-PCR和蛋白质ELISA来研究。还将检查引起药物敏感性改变的基质因子的药物引起的变化(目标2)。一种细胞毒性/抗转移药物(即CMT-3)和一种抗炎药物(即塞来昔布)的联合疗效将在异种移植的PC-3ML和LNCaP细胞因子转基因细胞中进行测试。(目标3)。这项拟议的研究应该揭示细胞因子在获得性耐药和前列腺癌进展中的作用。它还将确定细胞毒性和抗炎联合治疗在控制转移性前列腺癌方面是否会更有效。

DESCRIPTION (provided by applicant): Effective treatments for controlling prostate cancer metastasis are not yet available. Investigations of this and other metastatic cancers have revealed stromal-induced factors that confer "acquired drug resistance". In prostate cancer, stromal factors induce pro-inflammatory cytokines, IL-1beta, IL-6 and IL-8 production in tumor cells. This coincides with increased resistance to cytotoxic/anti-metastatic drugs, such as doxorubicin, and CMT-3 (a novel cytotoxic and anti-metastatic tetracycline analog). Blocking IL-1beta and IL-6 production by antisense cDNA transfection sensitizes tumor cells to chemodrugs, whereas, blocking IL-8 production decreases their invasive potential. A combination of cytotoxic and anti-inflammatory drugs reduces the expression of these cytokines. Thus, a combination therapy that inhibits cytokine production during an inflammatory response to chemotherapy should improve the efficacy of cytotoxic and anti-metastatic drugs. The goals of this proposal are: 1. To establish a cause and effect relationship between tumor cell-associated cytokine production and acquired drug resistance, as well as, tumor progression. (2) Evaluate the efficacy of combined cytotoxic and anti-inflammatory drugs to control metastatic prostate cancer. A cause-effect relationship between cytokine production and tumor progression will be established by investigating, in xenografts, the growth and metastasis of prostate cancer cells (PC-3ML and LNCaP), expressing green fluorescence protein and cDNA -sense and anti-sense constructs of IL-1beta, IL-6 or IL-8. Possible interlinked roles of these 3 cytokines will be investigated by characterizing double transfectants of PC-3ML expressing IL-1beta antisense/IL-6sense and IL-1beta sense/IL-8antisense cDNAs (Aim 1). Alterations in drug-induced cytotoxicity in PC-3ML and LNCaP transfectants, selectively altered in cytokine production, will be studied by cytotoxicity assays, cDNA microarray analysis, followed by RT-PCR and protein ELISAs. Drug-induced changes in stromal factors responsible for altering drug sensitivity will also be examined (Aim 2). The efficacy of a combination of a cytotoxic/anti-metastatic drug (i.e., CMT-3) and an anti-inflammatory drug (i.e., Celecoxib) will be tested in PC-3ML and LNCaP cytokine transfectants in xenografts. (Aim 3). The proposed study should reveal the role of cytokines in acquired drug resistance and prostate cancer progression. It will also establish whether a combined cytotoxic and anti-inflammatory therapy will be more effective in controlling metastatic prostate cancer.