Department of Internal Medicine and WHO Collaborating for Reference and Research on Viral Hepatitis, The Catholic University of Korea, Seoul, Korea.
Cancer Chemother Pharmacol. 2010 May;65(6):1029-37. doi: 10.1007/s00280-009-1108-4. Epub 2009 Aug 23.
Recent studies have demonstrated that frequent, low-dose metronomic (MET) dosing of cytotoxic agents may not only be as efficient as conventional maximum tolerated dose (MTD) chemotherapy but also less toxic. In this study, we investigated the therapeutic effect and safety of MET chemotherapy using cyclophosphamide (CTX) in rats with chemically induced hepatocellular carcinoma (HCC).
Rats received weekly intraperitoneal (i.p.) injections of diethylnitrosamine during 16 weeks for induction of HCC. The rats were divided into three groups: MTD group received 40 mg/kg CTX i.p. injection on days 1, 3, and 5 of a 21-day cycle; Control and MET groups received saline and 20 mg/kg CTX i.p. injection twice a week, respectively. The growth-modulating effects and overall survival were compared between the groups. Anti-angiogenic effects were evaluated by a measurement of endothelial cell and VEGFR-2 expression.
At 6 weeks of therapy, MTD and MET chemotherapy resulted in a significant reduction in tumor number and size compared with Control group. MET chemotherapy showed more prolonged survival than MTD chemotherapy and Control groups (P < 0.05). MET chemotherapy resulted in a significant decrease in both the micro-vessel density and endothelial proliferation index (P < 0.01). Furthermore, MET chemotherapy led to a greater decrease in VEGFR-2 expression at the mRNA and protein levels (P < 0.01).
MET scheduling not only exhibits anti-tumor and anti-angiogenic effects, but also prolongs survival without major toxicities in a rat model of HCC. Our results suggest that MET chemotherapy has a high therapeutic value and should be considered for future clinical trials.
最近的研究表明，频繁、低剂量的节拍（MET）给药的细胞毒性药物不仅可能与传统的最大耐受剂量（MTD）化疗一样有效，而且毒性更小。在这项研究中，我们研究了使用环磷酰胺（CTX）对化学诱导的肝癌（HCC）大鼠进行 MET 化疗的治疗效果和安全性。
大鼠在 16 周内每周接受腹腔内（i.p.）注射二乙基亚硝胺，以诱导 HCC。大鼠分为三组：MTD 组在 21 天周期的第 1、3 和 5 天接受 40mg/kg CTX i.p.注射；对照组和 MET 组分别接受生理盐水和 20mg/kg CTX i.p.注射，每周两次。比较各组的生长调节作用和总生存情况。通过测量内皮细胞和 VEGFR-2 表达来评估抗血管生成作用。
在 6 周的治疗中，与对照组相比，MTD 和 MET 化疗显著减少了肿瘤数量和大小。与 MTD 化疗和对照组相比，MET 化疗显示出更长的生存时间（P < 0.05）。MET 化疗导致微血管密度和内皮增殖指数均显著降低（P < 0.01）。此外，MET 化疗导致 VEGFR-2 表达在 mRNA 和蛋白水平上的降低更为显著（P < 0.01）。
MET 方案不仅表现出抗肿瘤和抗血管生成作用，而且在 HCC 大鼠模型中无明显毒性延长了生存时间。我们的结果表明，MET 化疗具有很高的治疗价值，应考虑用于未来的临床试验。
