Triozzi Pierre L, Aldrich Wayne, Dombos Christopher
Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio
Melanoma Res. 2008 Dec;18(6):420-30. doi: 10.1097/CMR.0b013e3283194118.
Uveal melanoma is refractory to chemotherapy. The receptor tyrosine kinase inhibitor, imatinib mesylate, has demonstrated antiproliferative effects against uveal melanoma cells in vitro. The effects of imatinib mesylate, alone and combined with the alklyating agent, temozolomide, were examined in vivo as well as in vitro. Proliferation and angiogenic factor production of human uveal melanoma cell lines in response to imatinib mesylate and temozolomide were examined in vitro. Tumor growth, angiogenic factor production, tumor interstitial fluid pressure, and stroma constituents in response to imatinib mesylate and temozolomide were examined in vivo in mice bearing human uveal melanoma xenografts. Imatinib mesylate in vitro antagonized the antiproliferative effects of temozolomide and increased the production of angiogenic factors. In contrast, pretreatment with imatinib mesylate in vivo could improve the antitumor activity of temozolomide. Imatinib mesylate in vivo decreased the production of angiogenic factors in the tumor stroma and tumor interstitial fluid pressure. These effects were transient. Increases in angiogenic factors, interstitial fluid pressure, and tumor infiltrating macrophages were observed with continued imatinib mesylate treatment in vivo. The antitumor effects of imatinib mesylate can vary in vivo when compared with in vitro. Imatinib mesylate can both positively and negatively modify host-tumor interactions in uveal melanoma.
葡萄膜黑色素瘤对化疗具有耐药性。受体酪氨酸激酶抑制剂甲磺酸伊马替尼在体外已显示出对葡萄膜黑色素瘤细胞的抗增殖作用。本文对甲磺酸伊马替尼单独使用以及与烷化剂替莫唑胺联合使用的效果进行了体内和体外研究。体外检测了人葡萄膜黑色素瘤细胞系对甲磺酸伊马替尼和替莫唑胺的增殖及血管生成因子产生情况。在携带人葡萄膜黑色素瘤异种移植瘤的小鼠体内检测了甲磺酸伊马替尼和替莫唑胺对肿瘤生长、血管生成因子产生、肿瘤间质液压力和基质成分的影响。甲磺酸伊马替尼在体外拮抗了替莫唑胺的抗增殖作用并增加了血管生成因子的产生。相反，在体内用甲磺酸伊马替尼预处理可提高替莫唑胺的抗肿瘤活性。甲磺酸伊马替尼在体内降低了肿瘤基质中血管生成因子的产生和肿瘤间质液压力。这些作用是短暂的。在体内持续使用甲磺酸伊马替尼治疗时，观察到血管生成因子、间质液压力和肿瘤浸润巨噬细胞增加。与体外相比，甲磺酸伊马替尼的抗肿瘤作用在体内可能有所不同。甲磺酸伊马替尼可对葡萄膜黑色素瘤中的宿主 - 肿瘤相互作用产生正向和负向的影响。
