科研之友
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摘要
Background: Gastric cancer is a highly chemoresistant tumor. Previous studies suggest that cancer cells can be sensitized to standard chemotherapy, and especially, alkylating agents, by inhibition of mammalian target of rapamycin (mTOR) signaling. The work presented here shows that the mTOR inhibitor everolimus, in combination with cyclophosphamide, exhibits synergistic antitumor activity in gastric cancer xenografts. Materials and Methods: Treatment with everolimus at the minimal effective dose was studied in combination with cyclophosphamide at maximum tolerated dose in a human gastric cancer severe combined immunodeficient (SCID) mouse xenograft model. Besides tumor size, biomarker expression for proliferation (Ki-67), hypoxia (HIF-1 alpha), apoptosis (activated caspase 3), angiogenesis (microvascular density, MVD) and levels of circulating endothelial progenitors (CEPs) were assessed. Results: Everolimus single agent treatment significantly inhibited tumor growth relative to control and cyclophosphamide treatment (TIC 19%, p<0.01). This antitumor activity was linked to a significant decrease in tumor cell proliferation (p<0.01) and a trend towards lower tumor MVD, HIF-1 alpha expression and levels of CEPs. Notably, the combination of everolimus with cyclophosphamide resulted in synergistic anti-tumor activity (TIC 9%, p<0.01). This antitumor activity coincided with a statistically significant decrease in MVD (p<0.01). Whereas treatment with everolimus-was well tolerated, cyclophosphamide at maximum tolerated dose (MTD) showed significant toxicity both as monotherapy and in combination with everolimus. Conclusion: The antiangiogenic activity of everolimus combined with a high dose of cyclophosphamide shows synergistic antitumor activity, against gastric cancer in vivo. In potential future clinical trials, the toxicity of cyclophosphamide in combination regimens with everolimus deserves careful evaluation.
- 出版日期2008-12
