Combination treatment significantly enhances the efficacy of antitumor therapy by preferentially targeting angiogenesis
Combination treatment significantly enhances the efficacy of antitumor therapy by preferentially targeting angiogenesis
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DOI：
10.1038/labinvest.3700272
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发表时间：
2005-06-01
影响因子：
5
通讯作者：
Polverini, P
中科院分区：
文献类型：
--
作者：
Kumar, P;Benedict, R;Polverini, P
放射治疗是最广泛使用的癌症治疗方法之一，但由于肿瘤细胞和肿瘤血管内壁的内皮细胞 (EC) 产生放射抗性，放射治疗常常不成功。我们之前已经证明，ECs 主要通过激活磷酸肌醇 3-激酶 (PI3 K)-Akt-Bcl-2 存活途径来免受电离辐射的影响。在此，我们报告，与单独使用每种药物（分别为 17%、17% 和 11%）相比，低剂量 PI3K 抑制剂 (LY294002)、顺铂和 γ 射线照射的联合治疗导致 EC 死亡率显着升高 (61%)。这种联合治疗在诱导肿瘤细胞死亡方面同样有效（72%）。与单独使用每种药物相比，联合治疗还显着抑制基质胶中 EC 管的形成 (75%)（LY294002、顺铂和伽玛射线照射分别为 8%、8% 和 18%）。在我们的人肿瘤生长和血管生成的体内严重联合免疫缺陷小鼠模型中，低剂量的LY294002、顺铂和放射联合治疗显着抑制了人口腔鳞状细胞癌（OSCC-3）以及前列腺癌（LnCap）的生长。联合疗法在抑制肿瘤血管生成方面也非常有效，新血管形成减少了 90% 以上。相比之下，联合治疗仅显示出 29% 的生理性血管生成抑制率。总而言之，这些结果表明了一种潜在的新策略来克服肿瘤血管内皮细胞的耐药性，从而提高放疗和化疗的有效性。此外，这种联合使用低剂量 PI3K/Akt 抑制剂、顺铂和放疗的策略有可能显着减少与最大耐受剂量的放疗和化疗相关的不良副作用，同时保持其治疗效果。
Radiotherapy is one of the most widely used cancer treatments, but it is often unsuccessful due to the development of radioresistance by tumor cells and endothelial cells (ECs) lining the tumor blood vessels. We have previously shown that ECs are protected against ionizing irradiation primarily via the activation of the phosphoinositide 3-kinase (PI3 K)-Akt-Bcl-2 survival pathway. Here we report that combination treatment with low doses of PI3K inhibitor (LY294002), cisplatin and gamma-irradiation resulted in significantly higher (61%) EC death as compared to each agent used alone (17, 17 and 11%, respectively). This combination treatment was equally effective in inducing tumor cell death (72%). Combination treatment also significantly inhibited EC tube formation in Matrigel (75%) as compared to each of the agents used alone (8, 8 and 18% for LY294002, cisplatin and gamma-irradiation, respectively). In our in vivo severe combined immunodeficient mouse model of human tumor growth and angiogenesis, combination treatment with low doses of LY294002, cisplatin and irradiation significantly inhibited the growth of human oral squamous carcinoma (OSCC-3) as well as prostate cancer (LnCap). The combination therapy was also very effective in inhibiting tumor angiogenesis where it showed a greater than 90% decrease in neovascularization. In contrast, combination treatment showed only a 29% inhibition of physiological angiogenesis. Taken together, these results suggest a potentially novel strategy to overcome the resistance in ECs lining tumor blood vessels, thereby enhancing the effectiveness of the radiation and chemotherapy. Moreover, this strategy of using a combination of low doses of PI3K/Akt inhibitor, cisplatin and radiation has the potential of significantly decreasing untoward side effects associated with the maximum tolerated doses of radiation and chemotherapy while maintaining their therapeutic efficacy.