Low-dose metronomic oral dosing of a prodrug of gemcitabine (LY2334737) causes antitumor effects in the absence of inhibition of systemic vasculogenesis.
Low-dose metronomic oral dosing of a prodrug of gemcitabine (LY2334737) causes antitumor effects in the absence of inhibition of systemic vasculogenesis.
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DOI：
10.1158/1535-7163.mct-11-0659
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发表时间：
2012-03
影响因子：
5.7
通讯作者：
Kerbel RS
中科院分区：
文献类型：
--
作者：
Francia G;Shaked Y;Hashimoto K;Sun J;Yin M;Cesta C;Xu P;Man S;Hackl C;Stewart J;Uhlik M;Dantzig AH;Foster FS;Kerbel RS
节拍化疗是指以相对较低的最低毒性剂量密切、规律地给予常规化疗药物，且没有长时间的停顿期；目前，它在各种 II 期临床试验中显示出令人鼓舞的结果，目前正在进行 III 期试验评估。人们认为它主要通过抗血管生成机制产生抗肿瘤作用，局部通过靶向肿瘤新血管系统的内皮细胞，以及通过对骨髓衍生细胞（包括循环内皮祖细胞（CEP））的影响而全身发挥作用。先前的研究表明，通过节拍性施用多种不同的化疗药物，包括长春花碱、环磷酰胺、紫杉醇、拓扑替康和替加氟加尿嘧啶 (UFT)，可以减少 CEP。然而，除了抗血管生成作用之外，甚至代替抗血管生成作用，节拍化疗还可能通过其他机制（例如刺激细胞毒性 T 细胞反应）或直接抗肿瘤作用来抑制肿瘤生长。在此，我们报告了在非荷瘤小鼠以及人卵巢癌 (SKOV3-13) 和乳腺癌 (LM2-4) 异种移植物的临床前模型中评估吉西他滨 LY2334737 (LY) 口服前药节拍给药特性的结果。通过每日灌胃（6mg/kg/天），测试的方案没有毒性并具有抗肿瘤作用；然而，没有检测到对 CEP 的抑制作用。出乎意料的是，节拍式 LY 给药导致荧光素酶标记的 LM2-4 肿瘤异种移植物中的血流量增加；这种效应与肿瘤生物发光的相对增加同时发生。这些结果强调了一些化疗药物的节拍性给药介导的显着抗肿瘤作用的可能性，而不同时抑制全身血管生成。
Metronomic chemotherapy refers to the close, regular administration of conventional chemotherapy drugs at relatively low minimally toxic doses with no prolonged break periods; it is now showing encouraging results in various phase II clinical trials, and is currently undergoing phase III trial evaluation. It is thought to cause anti-tumor effects primarily by antiangiogenic mechanisms, both locally by targeting endothelial cells of the tumor neovasculature and systemically by effects on bone marrow derived cells, including circulating endothelial progenitor cells (CEPs). Previous studies have shown reduction of CEPs by metronomic administration of a number of different chemotherapeutic drugs, including vinblastine, cyclophosphamide, paclitaxel, topotecan, and tegafur plus uracil (UFT). However in addition to, or even instead of, anti angiogenic effects, metronomic chemotherapy may cause suppression of tumor growth by other mechanisms such as stimulating cytotoxic T cell responses, or by direct anti-tumor effects. Here we report results evaluating the properties of metronomic administration of an oral prodrug of gemcitabine LY2334737 (LY) in non tumor-bearing mice, and in preclinical models of human ovarian (SKOV3-13) and breast cancer (LM2-4) xenografts. Through daily gavage (at 6mg/kg/day) the schedules tested were devoid of toxicity and caused anti-tumor effects; however, a suppressive effect on CEPs was not detected. Unexpectedly metronomic LY administration caused increased blood flow in luciferase-tagged LM2-4 tumor xenografts; and this effect coincided with a relative increase in tumor bioluminescence. These results highlight the possibility of significant anti-tumor effects mediated by metronomic administration of some chemotherapy drugs without a concomitant inhibition of systemic angiogenesis.