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首页> 外文期刊>Anticancer Research: International Journal of Cancer Research and Treatment >Tyrosine kinase inhibitor SU6668 inhibits peritoneal dissemination of gastric cancer via suppression of tumor angiogenesis.
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Tyrosine kinase inhibitor SU6668 inhibits peritoneal dissemination of gastric cancer via suppression of tumor angiogenesis.

机译：酪氨酸激酶抑制剂SU6668通过抑制肿瘤血管生成来抑制胃癌的腹膜扩散。

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BACKGROUND: Peritoneal dissemination of cancer involves several steps, including tumor cell attachment, invasion and growth in the peritoneum. Tumor angiogenesis is a prerequisite for the growth of disseminated tumor. Vascular endothelial growth factor (VEGF) and its receptor are major regulators of angiogenesis. PURPOSE: We examined the cytotoxic effects of SU6668, an inhibitor of VEGF tyrosine kinase receptors, on in vitro gastric cancer cell lines and human umbilical vascular endothelial cells (HUVEC); we also examined the antitumor effects of SU6668 on human gastric cancer cells administered intraperitoneally into nude mice. MATERIALS AND METHODS: Direct cytotoxicity to gastric cancer cells (TMK-1, MKN-45 and MKN-74) and normal cells (HUVEC) was determined by the MTT assay and the bromodeoxyuridine (BrdU) incorporation assay, with and without VEGF-evoked growth stimulation in vitro. TMK-1 cells were transplanted intraperitoneally into nude mice, followed by twice daily oral administration of SU6668(200 mg/kg/day) for two weeks starting on the first day after transplantation. Both the number and the wet weight of disseminated peritoneal tumor nodules were assessed. RESULTS: In the MTT assay, SU6668 demonstrated low-grade cytotoxicity to the cell growth of three gastric cancer cells, with a 50% inhibitory concentration (IC50) of 22.6 microg/ml for TMK-1, 31.8 microg/ml for MKN-45 and 26.7 microg/ml for MKN-74; HUVEC was sensitive to SU6668 with an IC50 of 8.9 microg/ml. In the BrdU assay, VEGF stimulated DNA synthesis in HUVEC, while the incorporation of BrdU was not affected by VEGF in gastric cancer cell lines. SU6668 inhibited VEGF-induced DNA synthesis in HUVEC, while BrdU incorporation of gastric cancer cell lines was inhibited by SU6668 without correlation to VEGF stimulation. Peritoneal dissemination of cancer in nude mice was significantly suppressed by SU6668 compared with a control group at the p<0.05 level. CONCLUSION: The mechanism of the antitumor activity of SU6668 may not involve direct toxicity to cancer cells, but may rather be an inhibitory effect on tumor angiogenesis, resulting in the inhibition of tumor dissemination in the peritoneum.
机译：背景：腹膜癌的扩散涉及几个步骤，包括肿瘤细胞的附着，腹膜的侵袭和生长。肿瘤血管生成是播散性肿瘤生长的前提。血管内皮生长因子（VEGF）及其受体是血管生成的主要调节剂。目的：我们研究了VEGF酪氨酸激酶受体抑制剂SU6668对体外胃癌细胞系和人脐血管内皮细胞（HUVEC）的细胞毒性作用;我们还研究了SU6668对裸鼠腹膜内施用的人胃癌细胞的抗肿瘤作用。材料与方法：通过MTT法和溴脱氧尿苷（BrdU）掺入法（有或无VEGF诱发）测定对胃癌细胞（TMK-1，MKN-45和MKN-74）和正常细胞（HUVEC）的直接细胞毒性。体外生长刺激。将TMK-1细胞腹膜内移植到裸鼠中，然后从移植后的第一天开始，每天两次口服SU6668（200 mg / kg /天），持续两周。评估了弥散性腹膜肿瘤结节的数量和湿重。结果：在MTT分析中，SU6668对三种胃癌细胞的细胞生长表现出低度的细胞毒性，其中TMK-1的50％抑制浓度（IC50）为22.6 microg / ml，MKN-45的抑制浓度为31.8 microg / ml。 MKN-74为26.7微克/毫升; HUVEC对SU6668敏感，IC50为8.9微克/毫升。在BrdU分析中，VEGF刺激HUVEC中的DNA合成，而在胃癌细胞系中BrdU的掺入不受VEGF的影响。 SU6668抑制HUVEC中VEGF诱导的DNA合成，而SU6668抑制胃癌细胞系的BrdU掺入，而与VEGF刺激无关。与对照组相比，SU6668显着抑制了裸鼠腹膜中癌症的扩散，p <0.05。结论：SU6668的抗肿瘤活性机制可能不涉及对癌细胞的直接毒性，而可能是抑制肿瘤血管生成的作用，从而抑制了肿瘤在腹膜中的扩散。

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