Simultaneous blockade of platelet-derived growth factor-receptor and epidermal growth factor-receptor signaling and systemic administration of paclitaxel as therapy for human prostate cancer metastasis in bone of nude mice
Simultaneous blockade of platelet-derived growth factor-receptor and epidermal growth factor-receptor signaling and systemic administration of paclitaxel as therapy for human prostate cancer metastasis in bone of nude mice
复制标题
DOI：
10.1158/0008-5472.can-03-3763
复制
发表时间：
2004-06-15
期刊：
影响因子：
11.2
通讯作者：
Fidler, IJ
中科院分区：
文献类型：
--
作者：
Kim, SJ;Uehara, H;Fidler, IJ
一旦前列腺癌转移到骨骼，常规化疗在很大程度上是无效的。我们假设抑制肿瘤细胞和肿瘤相关内皮细胞上表达的表皮生长因子受体（EGF - R）和血小板衍生生长因子受体（PDGF - R）的磷酸化（这种磷酸化与肿瘤进展相关），再结合紫杉醇，将抑制实验性前列腺癌的骨转移并保护骨骼结构。我们使用人PC - 3MM2前列腺癌细胞在裸鼠中验证了这一假设。在骨组织附近生长的PC - 3MM2细胞以及这些病变内的内皮细胞在其表面表达磷酸化的EGF - R以及PDGF - Rα和 - β。阳性内皮细胞的百分比以及受体表达的强度与距骨组织的接近程度直接相关。口服PKI166抑制EGF - R的磷酸化，但不抑制PDGF - R的磷酸化，而口服STI571抑制PDGF - R的磷酸化，但不抑制EGF - R的磷酸化。口服PKI166和STI571并联合腹腔注射紫杉醇的联合疗法在肿瘤血管内皮细胞和肿瘤细胞中诱导了高水平的细胞凋亡，同时抑制了骨内肿瘤的生长，保护了骨骼结构，并减少了淋巴结转移。总之，这些数据表明，阻断EGF - R和PDGF - R的磷酸化并结合紫杉醇给药可显著抑制实验性人前列腺癌的骨转移。
Once prostate cancer metastasizes to bone, conventional chemotherapy is largely ineffective. We hypothesized that inhibition of phosphorylation of the epidermal growth factor receptor (EGF-R) and platelet-derived growth factor receptor (PDGF-R) expressed on tumor cells and tumor-associated endothelial cells, which is associated with tumor progression, in combination with paclitaxel would inhibit experimental prostate cancer bone metastasis and preserve bone structure. We tested this hypothesis in nude mice, using human PC-3MM2 prostate cancer cells. PC-3MM2 cells growing adjacent to bone tissue and endothelial cells within these lesions expressed phosphorylated EGF-R and PDGF-Ralpha and -beta on their surfaces. The percentage of positive endothelial cells and the intensity of receptor expression directly correlated with proximity to bone tissue. Oral administration of PKI166 inhibited the phosphorylation of EGF-R but not PDGF-R, whereas oral administration of STI571 inhibited the phosphorylation of PDGF-R but not EGF-R. Combination therapy using oral PKI166 and STI571 with i.p. injections of paclitaxel induced a high level of apoptosis in tumor vascular endothelial cells and tumor cells in parallel with inhibition of tumor growth in the bone, preservation of bone structure, and reduction of lymph node metastasis. Collectively, these data demonstrate that blockade of phosphorylation of EGF-R and PDGF-R coupled with administration of paclitaxel significantly suppresses experimental human prostate cancer bone metastasis.