Intermittent Metronomic Drug Schedule Is Essential for Activating Antitumor Innate Immunity and Tumor Xenograft Regression
Intermittent Metronomic Drug Schedule Is Essential for Activating Antitumor Innate Immunity and Tumor Xenograft Regression
复制标题
DOI：
10.1593/neo.131910
复制
发表时间：
2014-01-01
期刊：
影响因子：
4.8
通讯作者：
Waxman, David J.
中科院分区：
文献类型：
--
作者：
Chen, Chong-Sheng;Doloff, Joshua C.;Waxman, David J.
使用环磷酰胺 (CPA) 的节拍化疗与抗血管生成广泛相关。然而，最近的研究涉及其他基于免疫的机制，包括抗肿瘤先天免疫，它可以在植入的脑肿瘤模型中诱导肿瘤的主要消退。这项研究证明了药物时间表的至关重要性：当按照 6 天重复节拍时间表间歇性给药时，CPA 会诱导有效的抗肿瘤先天免疫反应和肿瘤消退，但与每 3 天时间表给药或使用每日口服方案（作为许多节拍化疗临床试验的基础）相同的活性 CPA 总暴露量不同。值得注意的是，更频繁的节律性 CPA 计划消除了抗肿瘤先天免疫和治疗反应。此外，先天免疫反应和抗肿瘤活性均表现出异常陡峭的剂量反应曲线，并且不伴随抗血管生成。 6 天重复 CPA 方案对先天免疫细胞的强烈募集并未持续，并且通过适度减少 (25%) CPA 剂量，肿瘤消退被消除。此外，CPA 剂量增加约 20% 消除了在每 6 天治疗的肿瘤的一部分中观察到的部分肿瘤消退和较弱的先天免疫细胞募集。因此，节律性药物治疗必须采用足够高的剂量，但也必须及时间隔足够远，以诱导强烈持续的抗肿瘤免疫细胞募集。当前许多临床节拍化疗方案采用每日口服低剂量方案，但不满足这些要求，这表明它们可能受益于旨在最大化抗肿瘤免疫反应的优化。
Metronomic chemotherapy using cyclophosphamide (CPA) is widely associated with antiangiogenesis; however, recent studies implicate other immune-based mechanisms, including antitumor innate immunity, which can induce major tumor regression in implanted brain tumor models. This study demonstrates the critical importance of drug schedule: CPA induced a potent antitumor innate immune response and tumor regression when administered intermittently on a 6-day repeating metronomic schedule but not with the same total exposure to activated CPA administered on an every 3-day schedule or using a daily oral regimen that serves as the basis for many clinical trials of metronomic chemotherapy. Notably, the more frequent metronomic CPA schedules abrogated the antitumor innate immune and therapeutic responses. Further, the innate immune response and antitumor activity both displayed an unusually steep dose-response curve and were not accompanied by antiangiogenesis. The strong recruitment of innate immune cells by the 6-day repeating CPA schedule was not sustained, and tumor regression was abolished, by a moderate (25%) reduction in CPA dose. Moreover, an similar to 20% increase in CPA dose eliminated the partial tumor regression and weak innate immune cell recruitment seen in a subset of the every 6-day treated tumors. Thus, metronomic drug treatment must be at a sufficiently high dose but also sufficiently well spaced in time to induce strong sustained antitumor immune cell recruitment. Many current clinical metronomic chemotherapeutic protocols employ oral daily low-dose schedules that do not meet these requirements, suggesting that they may benefit from optimization designed to maximize antitumor immune responses.