Synergistic Antivascular and Antitumor Efficacy with Combined Cediranib and SC6889 in Intracranial Mouse Glioma.
Synergistic Antivascular and Antitumor Efficacy with Combined Cediranib and SC6889 in Intracranial Mouse Glioma.
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DOI：
10.1371/journal.pone.0144488
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Pike MM
中科院分区：
文献类型：
--
作者：
Lobo MR;Kukino A;Tran H;Schabel MC;Springer CS Jr;Gillespie GY;Grafe MR;Woltjer RL;Pike MM
恶性神经胶质瘤的预后仍然极差。靶向治疗方法，包括单药抗血管生成和蛋白酶体抑制策略，尚未产生持续的抗神经胶质瘤临床疗效。我们测试了抗血管生成受体酪氨酸激酶抑制剂西地尼布和新型蛋白酶体抑制剂 SC68896 联合使用和单独使用的抗神经胶质瘤功效。为了评估抗血管生成作用和疗效，我们采用 4C8 颅内小鼠神经胶质瘤和双推注灌注 MRI 方法来测量 Ktrans、相对脑血流量和体积（rCBF、rCBV）以及相对平均通过时间（rMTT），并结合肿瘤生长的解剖 MRI 测量。虽然单一药物西地尼布或 SC68896 治疗不会改变肿瘤生长或存活，但与未治疗相比，西地尼布/SC68896 联合治疗显着延迟了肿瘤生长，并将中位存活率提高了 2 倍。西地尼布/SC68896 组的肿瘤坏死显着增加 (p<0.01)，而单药治疗则未观察到这一情况。与未治疗组相比，西地尼布/SC68896联合治疗组的平均血管密度显着降低，平均血管管腔面积显着升高。与我们之前的发现一致，单独使用西地尼布并没有显着改变平均肿瘤 rCBF、rCBV、rMTT 或 Ktrans。相比之下，与未治疗相比，SC68896 减少了 rCBF，但 rCBV、rMTT 或 Ktrans 没有同时减少。重要的是，西地尼布/SC68896 组合显着降低了 rCBF、rCBV。 rMTT 和 Ktrans。对 Ktrans/rCBV 的一项新分析表明，Ktrans 随时间和/或治疗的变化与总血管表面积的改变有关。数据表明，西地尼布/SC68896 组合可诱导有效的抗血管生成作用，从而提高血管效率并减少外渗，这与血管正常化的过程一致。该研究首次证明西地尼布与蛋白酶体抑制剂的组合可显着提高单独使用任一药物产生的抗血管生成功效，并协同减缓神经胶质瘤肿瘤的生长并延长生存期，这表明这是一种有前途的治疗方法，值得进一步研究。
Prognosis remains extremely poor for malignant glioma. Targeted therapeutic approaches, including single agent anti-angiogenic and proteasome inhibition strategies, have not resulted in sustained anti-glioma clinical efficacy. We tested the anti-glioma efficacy of the anti-angiogenic receptor tyrosine kinase inhibitor cediranib and the novel proteasome inhibitor SC68896, in combination and as single agents. To assess anti-angiogenic effects and evaluate efficacy we employed 4C8 intracranial mouse glioma and a dual-bolus perfusion MRI approach to measure Ktrans, relative cerebral blood flow and volume (rCBF, rCBV), and relative mean transit time (rMTT) in combination with anatomical MRI measurements of tumor growth. While single agent cediranib or SC68896 treatment did not alter tumor growth or survival, combined cediranib/SC68896 significantly delayed tumor growth and increased median survival by 2-fold, compared to untreated. This was accompanied by substantially increased tumor necrosis in the cediranib/SC68896 group (p<0.01), not observed with single agent treatments. Mean vessel density was significantly lower, and mean vessel lumen area was significantly higher, for the combined cediranib/SC68896 group versus untreated. Consistent with our previous findings, cediranib alone did not significantly alter mean tumor rCBF, rCBV, rMTT, or Ktrans. In contrast, SC68896 reduced rCBF in comparison to untreated, but without concomitant reductions in rCBV, rMTT, or Ktrans. Importantly, combined cediranib/SC68896 substantially reduced rCBF, rCBV. rMTT, and Ktrans. A novel analysis of Ktrans/rCBV suggests that changes in Ktrans with time and/or treatment are related to altered total vascular surface area. The data suggest that combined cediranib/SC68896 induced potent anti-angiogenic effects, resulting in increased vascular efficiency and reduced extravasation, consistent with a process of vascular normalization. The study represents the first demonstration that the combination of cediranib with a proteasome inhibitor substantially increases the anti-angiogenic efficacy produced from either agent alone, and synergistically slows glioma tumor growth and extends survival, suggesting a promising treatment which warrants further investigation.