Antiangiogenic scheduling of lower dose cancer chemotherapy.
Antiangiogenic scheduling of lower dose cancer chemotherapy.
复制标题
低剂量癌症化疗的抗血管生成安排。
作者：
S. Gately;R. Kerbel
癌症化疗在最大耐受性、毒性剂量下使用，很少能导致持续的肿瘤完全根除，患者最终无法接受各种化疗方案。如果肿瘤有反应，组成癌细胞的细胞对化疗药物产生抗药性，这主要是由于巨大的遗传不稳定性。将这些药物的靶点改为肿瘤增殖的微血管系统，这是一种更稳定的遗传细胞，可能会提供重要的治疗优势。将周期程序和大剂量化疗药物修改为连续的、低剂量的“节律”方案，可提高靶向肿瘤微血管的疗效，并产生毒性较低的治疗活性。临床前，持续、低剂量化疗的抗血管生成特性可以通过同时给予选择性血管生成抑制剂来进一步增强。由于靶点不只是肿瘤细胞，这种抗血管生成联合策略提供了延缓或可能避免获得性耐药的机会。临床前和临床观察为将癌症作为慢性病来治疗提供了基础，使用长期、连续的剂量。由于合适的化疗药物和商业上可获得的抑制血管生成的化合物很容易获得，因此尽快启动临床试验以评估化疗的抗血管生成计划将是有益的。
Cancer chemotherapy utilized at maximum tolerated, toxic doses, rarely results in sustained total tumor eradication, with patients ultimately failing a variety of chemotherapeutic regimens. If tumors respond, the constituent cancer cells acquire resistance to chemotherapeutic agents, largely due to tremendous genetic instability. Changing the target of these agents to the tumor's proliferating microvasculature, a more genetically stable cell, may provide important therapeutic advantages. Modifying the cyclic schedule and high doses of chemotherapeutic agents to a continuous, lower dose, "metronomic" regimen increases the efficacy of targeting the tumor microvasculature, and produces therapeutic activity with decreased toxicity. Preclinically, the antiangiogenic properties of continuous, lower-dose chemotherapy can be further enhanced by the concurrent administration of a selective angiogenesis inhibitor. Because the target is not exclusively the tumor cell, this antiangiogenic combination strategy provides the opportunity to delay or possibly avoid acquired resistance. Preclinical and clinical observations provide a basis for treating cancer as a chronic disease, using protracted, continuous dosing. Because appropriate chemotherapeutic agents and commercially available compounds that inhibit angiogenesis are readily available, it would be beneficial to initiate clinical trials to evaluate the antiangiogenic scheduling of chemotherapy expeditiously.