Differential effects of imatinib mesylate against uveal melanoma in vitro and in vivo

Abstract

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.

PDGFRα up-regulation mediated by sonic hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation

“…Treatment was initiated 10 days after cell inoculation when the tumor developed and had a diameter of around 0.4 cm. Doses of sunintib and imatinib were chosen based on data available in the literature [26, 27, 31, 33]. To test vemurafenib and sunitinib combination, mice were randomly divided into 4 groups of 5 mice each.…”

The reduction of tumor interstitial fluid pressure by liposomal imatinib and its effect on combination therapy with liposomal doxorubicin

“…The effect of free IMA or SSL-IMA on tumor IFP was initially investigated by a consecutive dosing regimen as previously reported [12,13,21]. Oral dose of free IMA was 100 mg/kg according to previous researches [15,22], while the dose of free IMA and SSL-IMA for i.v.…”

Abstract 3703: PDGFRα up-regulation mediated by Sonic Hedgehog Pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation

“…The IC50 doses of sunitinib, imatinib and crenolanib were found to be 2, 15 and 1.5 µM, respectively (Supplementary Figure 3). In line with the data in the literature [25][26][27][28][29][30][31][32][33][34][35], the doses of 1.5 and 3 µM for sunitinib, 10 and 20 µM for imatinib and 1 and 2 µM for crenolanib, were tested in combination with vemurafenib for their anti-proliferative effect and induction of apoptosis. As shown in Figure 4A and Supplementary Figure 4, vemurafenib and PDGFRα-I combination inhibited the proliferation of Colo38 and M21 cells to a significantly greater extent (P<0.05) than each agent alone.…”