Chemosensitization by STI571 targeting the PDGF/PDGFR-signaling pathway in the tumor progression and angiogenesis of gastric and breast carcinoma

目的：PDGF/PDGF信号通路介导的自分泌和旁分泌生长在实体瘤的发生发展中起重要作用。我们评估了STI 571与靶向PDGF/PDGF信号通路的5-氟尿嘧啶（5-FU）、紫杉醇（TXL）或多西他赛（TXT）联合对胃癌和乳腺癌肿瘤生长的影响。实验设计：采用MTT法检测其对胃癌细胞MKN-45和乳腺癌细胞MDA-MB-231的细胞毒作用;采用裸鼠移植瘤模型检测其体内抗肿瘤作用。STI 571和一种抗癌药物均经腹膜内施用。通过Western印迹分析和免疫组织化学染色评估基因表达。TUNEL法检测细胞凋亡，微血管密度（MVD）检测肿瘤血管生成。结果：单独用STI 571处理在体外是无效的，通过<50>分别为24.3和9.2 μ M的IC值评估。当STI 571的浓度增加到10 μ M时，STI 571与5-FU或TXL的组合处理在一定程度上增强了MKN-45细胞中的细胞毒性效应。相反，STI 571与5-FU或TXL的组合治疗显著增强了抗癌药物的体内抗肿瘤作用。增强的抗肿瘤作用与细胞凋亡增加和肿瘤血管生成抑制有关。用STI 571处理下调肿瘤细胞中PDGF-BB和PDGFR-β的表达，并减少pPDGFR-β和pAkt的产生。此外，用STI 571处理抑制基质细胞中PDGFR-β的表达。MDA-MB-231体内细胞观察到类似的结果。结论：STI 571是一种有效的化疗增敏剂，用于胃癌和乳腺癌的抗癌药物，如5-FU、TXL和TXT，靶向肿瘤和基质细胞的PDGF/PDGF信号通路，促进血管生成。

Purpose : Autocrine and paracrine growth mediated by the PDGF/PDGFR-signaling pathway plays an important role in the progression of solid tumors. We assessed the effect of STI571 on the tumor growth of gastric and breast carcinoma in combination with 5-fluorouracil (5-FU), paclitaxel (TXL) or docetaxel (TXT) targeting the PDGF/PDGFR-signaling pathway. Experimental Design : In MKN-45 gastric and MDA-MB-231 breast carcinoma cells, the cytotoxic effect was evaluated by MTT assay and the in vivo antitumor effect was evaluated by the nude mice xenograft. Both STI571 and one anticancer drug were administered intraperitoneally. Gene expression was assessed by Western blot analysis and immunohistochemical staining. Apoptotic cell death was evaluated by the TUNEL assay and tumor angiogenesis was evaluated by microvessel density (MVD). Results: Treatment with STI571 alone was not effective in vitro, assessed by an IC_<50> value of 24.3 and 9.2 micro M, respectively. Combination treatment with STI571 and 5-FU or TXL somewhat enhanced the cytotoxic effect when the concentration of STI571 was increased to 10 micro M in MKN-45 cells. In contrast, combination treatment with STI571 and 5-FU or TXL significantly enhanced the antitumor effect of the anticancer drug in vivo. The enhanced antitumor effect was associated with increased apoptotic cell death and inhibition of tumor angiogenesis. Treatment with STI571 downregulated the expression of PDGF-BB and PDGFR-beta in tumor cells and decreased the production of pPDGFR-beta and pAkt. Furthermore, treatment with STI571 inhibited the expression of PDGFR-beta in stromal cells. Similar results for MDA-MB-231 in vivo cells were observed. Conclusions : STI571 is an effective chemosensitizer of anticancer drugs such as 5-FU, TXL, and TXT for gastric and breast carcinoma, targeting the PDGF/PDGFR-signaling pathway of tumor and stromal cells in progression and angiogenesis.