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

STI571 靶向 PDGF/PDGFR 信号通路在胃癌和乳腺癌肿瘤进展和血管生成中的化疗增敏作用

基本信息

批准号：
15591345
负责人：
KIM Ryungsa
金额：
$ 2.18万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591345/
关键词：
gastric carcinoma breast carcinoma STI571 PDGFR anticancer drug molecular targeting PDGFR

项目摘要

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.

目的：PDGF/ pdgfr信号通路介导的自分泌和旁分泌生长在实体瘤的进展中起重要作用。我们评估了STI571联合5-氟尿嘧啶（5-FU）、紫杉醇（TXL）或多西紫杉醇（TXT）靶向PDGF/ pdgfr信号通路对胃癌和乳腺癌肿瘤生长的影响。实验设计：以MKN-45胃癌细胞和MDA-MB-231乳腺癌细胞为实验对象，采用MTT法评价其细胞毒作用，裸鼠异种移植观察其体内抗肿瘤作用。STI571和一种抗癌药物均腹腔注射。Western blot和免疫组化染色检测基因表达。TUNEL法观察凋亡细胞死亡情况，微血管密度法观察肿瘤血管生成情况。结果：体外仅用STI571治疗无效，IC_<50>分别为24.3和9.2微M。当STI571在MKN-45细胞中的浓度增加到10 μ M时，STI571与5-FU或TXL联合作用，细胞毒作用有所增强。相比之下，STI571与5-FU或TXL联合治疗可显著增强抗肿瘤药物的体内抗肿瘤作用。增强的抗肿瘤作用与增加的凋亡细胞死亡和抑制肿瘤血管生成有关。用STI571治疗可下调肿瘤细胞中PDGF-BB和pdgfr - β的表达，减少ppdgfr - β和pAkt的产生。此外，STI571抑制了间质细胞中pdgfr - β的表达。MDA-MB-231在体内细胞中也观察到类似的结果。结论：STI571靶向肿瘤和基质细胞进展和血管生成过程中的PDGF/ pdgfr信号通路，是5-FU、TXL、TXT等抗癌药物治疗胃癌和乳腺癌的有效化学增敏剂。