Minimizing long-term tumor burden: The logic for metronomic chemotherapeutic dosing and its antiangiogenic basis
Minimizing long-term tumor burden: The logic for metronomic chemotherapeutic dosing and its antiangiogenic basis
复制标题
DOI：
10.1006/jtbi.2003.3162
复制
发表时间：
2003-02-21
影响因子：
2
通讯作者：
Hlatky, L
中科院分区：
文献类型：
--
作者：
Hahnfeldt, P;Folkman, J;Hlatky, L
最大耐受剂量（MTD）范式（一种旨在优化总肿瘤细胞根除机会的策略）的普遍实用性在这里受到质疑。迄今为止的证据表明，对于许多肿瘤来说，根除的可能性实际上很遥远，在具有根除意图的 MTD 治疗后，患者始终表现出肿瘤细胞的存在。未能根除很大程度上归因于肿瘤的异质性。异质细胞群表现出对预先剂量递送的短期不应性，但作为剂量恢复的一部分而“重新敏感”，当递送更均匀间隔时，显示出对给定系列剂量的总体敏感性增加。事实证明：（1）最小化总肿瘤负荷而不是完全根除往往可能是更实际的目标； (2) 定期“节拍”给药是实现这一目标的最佳方法。作为推论，发现肿瘤内皮细胞在给药后重新敏化的更有效能力预示着当采用节律给药时对肿瘤内皮区室的靶向偏差。这为最近的实证研究提供了理论支持，该研究表明，没有延长休息时间的定期给药方案具有更强的抗血管生成作用，从而延迟或避免获得性耐药的发生。 (C) 2003 Elsevier Science Ltd. 保留所有权利。
The general utility of the maximum tolerated dose (MTD) paradigm, a strategy aimed at optimizing the chance of total tumor cell eradication, is here questioned. Evidence to date suggests that for many tumors the potential for eradication is in fact remote, with patients consistently demonstrating tumor cell presence subsequent to MTD treatments having eradicative intent. The failure to eradicate is attributed largely to the heterogeneous nature of the tumor. Heterogeneous cell populations demonstrate short-term refractoriness to up-front dose delivery, but "resensitize" as part of dose recovery, showing increased overall susceptibility to a given series of doses when delivered more evenly spaced. It is demonstrated: (1) that the minimization of total tumor burden, rather than complete eradication, may often be the more practical objective; and (2) that regularly spaced, "metronomic" dosing is the best way to achieve it. As a corollary, it is found that the more efficient ability of the tumor endothelial cells to resensitize following dosing predicts a targeting bias towards the endothelial compartment of a tumor when metronomic dosing is employed. This lends theoretical support to recent empirical studies showing that regularly spaced dosing schedules with no extended rest periods act more antiangiogenically, thereby delaying or avoiding the onset of acquired resistance. (C) 2003 Elsevier Science Ltd. All rights reserved.