Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
Neoplasia. 2011 Mar;13(3):187-97. doi: 10.1593/neo.101186.
Metronomic chemotherapy involves frequent, regular administration of cytotoxic drugs at nontoxic doses, usually without prolonged breaks. We investigated the therapeutic efficacies of metronomic S-1, an oral 5-fluorouracil prodrug, and vandetanib, an epidermal growth factor receptor and vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, in models of hepatocellular carcinoma (HCC).
We compared anti-HCC effects and toxicity in the six treatment groups: control (untreated), maximum tolerated dose (MTD) S-1, metronomic S-1, vandetanib, MTD S-1 with vandetanib, and metronomic S-1 with vandetanib. Tumor microvessel density (MVD) and tumor apoptosis were evaluated by immunohistochemistry. The expression of VEGF and thrombospondin-1, an endogenous inhibitor of angiogenesis, was analyzed by Western blot.
Metronomic S-1 significantly inhibited tumor growth, which was enhanced by combination with vandetanib. With respect to toxicities, MTD S-1 caused severe body weight loss and myelosuppression, whereas metronomic S-1 did not cause any overt toxicities. Moreover, metronomic S-1 or metronomic S-1 with vandetanib prolonged survival, the latter treatment providing the greatest benefit. Metronomic S-1 and metronomic S-1 with vandetanib decreased MVDs and increased apoptosis in tumor tissues. The expression of VEGF in tumor tissues was upregulated by vandetanib and metronomic S-1 with vandetanib, whereas the expression of thrombospondin-1 was upregulated by metronomic S-1 and metronomic S-1 with vandetanib.
Metronomic S-1 with an antiangiogenic agent seems to be an effective and safe therapeutic strategy for HCC.
节拍化疗是指频繁、规律地给予非毒性剂量的细胞毒性药物，通常没有长时间的停药期。我们研究了口服氟尿嘧啶前体药物 S-1 和血管内皮生长因子受体和表皮生长因子受体酪氨酸激酶抑制剂凡德他尼在肝癌（HCC）模型中的治疗效果。
我们比较了以下六组治疗方案的抗 HCC 效果和毒性：对照组（未治疗）、最大耐受剂量（MTD）S-1、节拍 S-1、凡德他尼、MTD S-1 联合凡德他尼和节拍 S-1 联合凡德他尼。通过免疫组织化学评估肿瘤微血管密度（MVD）和肿瘤细胞凋亡。通过 Western blot 分析血管内皮生长因子（VEGF）和血栓素-1 的表达，血栓素-1 是一种内源性血管生成抑制剂。
节拍 S-1 显著抑制肿瘤生长，与凡德他尼联合使用时增强。关于毒性，MTD S-1 导致严重的体重减轻和骨髓抑制，而节拍 S-1 没有引起任何明显的毒性。此外，节拍 S-1 或节拍 S-1 联合凡德他尼延长了生存时间，后者的治疗效果最佳。节拍 S-1 和节拍 S-1 联合凡德他尼降低了肿瘤组织中的 MVDs，增加了肿瘤组织中的细胞凋亡。凡德他尼和节拍 S-1 联合凡德他尼上调了肿瘤组织中 VEGF 的表达，而节拍 S-1 和节拍 S-1 联合凡德他尼上调了血栓素-1 的表达。
节拍 S-1 联合抗血管生成药物似乎是 HCC 的一种有效和安全的治疗策略。
