Establishment of a novel mouse model for studying prostate cancer metastasis to human bone and new therapeutic strategies.

前列腺癌有一种特殊的骨转移倾向。我们利用Hubone-NOD-SCID小鼠进行了一系列旨在抑制人类血管生成的实验，以开发骨转移的治疗策略。肿瘤细胞产生血管生成因子，如血管内皮细胞生长因子和血管生成素-1，与其受体(Flt-2和Tek/Fit-2)结合。将可溶性嵌合分子(Flt-1/Fc和Tek/Fc)导入逆转录病毒载体。这些载体被感染入人乳腺癌、神经母细胞瘤、前列腺癌细胞系。可溶性嵌合受体分子的表达表明NOD-SCID小鼠的肿瘤重量和体积减少。在表达嵌合分子的肿瘤中，人类血管生成显著减少。我们探讨了血清抗酒石酸酸性磷酸酶(tracp，破骨细胞标记物)在co…中预测未经治疗的前列腺癌患者骨转移的临床价值。骨转移患者血清TRACP、PACP、ALP和PSA水平显著升高。Logistic回归分析显示，TRACP是骨转移的显著预测因子，PSA和ALP也是骨转移的预测因子。我们评估了一种新的策略，该策略依赖于反义bcl2寡核苷酸以及谷胱甘肽清除剂联合己烯雌酚(DES)治疗激素非依赖性前列腺癌。BCL-2反义寡核苷酸可显著增强DES对激素非依赖性前列腺癌细胞的细胞毒作用，其作用途径不依赖于增加的活性氧产生，而谷胱甘肽去除剂则可增强细胞毒作用和增加活性氧的产生。一种新的NFkappaB激活抑制剂DHMEQ对三种人激素不耐药的前列腺癌DU145、JCA-1和PC-3细胞株具有显著的生长抑制作用，并显著诱导了细胞的凋亡。此外，IP。给予DHMEQ可显著抑制预先建立的JCA-1 S.C.裸体肿瘤生长。我们的结果表明，NFkappaB激活抑制剂有可能成为激素耐药前列腺癌的一种新的治疗策略。较少

Tumors arising from the prostate possess a special propensity to metastasize to bone. We have carried out a series of experiments aimed at inhibition of human angiogenesis for the development of a therapeutic strategy to bone metastasis using HuBone-NOD-SCID mice. Tumor cells produce angiogenetic factors such as VECF and angiopoetin-1 that bind to their receptors (Flt-2 and Tek/Fit-2). The soluble chimeric molecules (Flt-1/Fc and Tek/Fc) were incorporated into retroviral vectors. The vectors were infected into human breast cancer, neuroblastoma, prostate cancer cell lines. Expression of the soluble chimeric receptor molecules demonstrated a reduction of tumor weight and volume in NOD-SCID mice. Human angiogenesis was significantly decreased in the tumors expressing the chimeric molecules. We have investigated the clinical value of serum tartrate-resistant acid phosphatase (TrACP, osteoclastic marker) for the prediction of bone metastasis in patients with untreated prostate cancer in co … More mparison with PSA, ALP, and PACP Serum TrACP, PACP, ALP, and PSA levels were significantly elevated in patients with bone metastases. Logistic regression analysis demonstrated that TrACP was a significant predictor of bone metastases as well as PSA and ALP. We assessed the efficacy of a novel strategy that relies on antisense bcl-2 oligodeoxynucleotides as well as a glutathione depletor combined with diethylstilbestrol (DES) for hormone independent prostate cancer. Antisense bcl-2 oligodeoxynucleotides significantly enhanced DES induced cytotoxicity in hormone independent prostate cancer cells through the apoptotic pathway independent of augmented reactive oxygen species generation, whereas the glutathione depletor augmented cytotoxicity and reactive oxygen species generation. Statistically significant growth inhibition was achieved by a novel NFkappaB activation inhibitor, DHMEQ, in three human hormone-refractory prostate cancer cell lines, DU145, JCA-1, and PC-3, and marked levels of apoptosis were induced by DHMEQ. Furthermore, i.p. administrations of DHMEQ significantly inhibited pre-established JCA-1 s.c. tumor growth in nude. Our result indicates the possibility of a NFkappaB activation inhibitor as a new treatment strategy against hormone-refractory prostate cancer. Less