Metronomic Gemcitabine in Combination with Sunitinib Inhibits Multisite Metastasis and Increases Survival in an Orthotopic Model of Pancreatic Cancer
Metronomic Gemcitabine in Combination with Sunitinib Inhibits Multisite Metastasis and Increases Survival in an Orthotopic Model of Pancreatic Cancer
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DOI：
10.1158/1535-7163.mct-10-0201
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发表时间：
2010-07-01
影响因子：
5.7
通讯作者：
Katz, Matthew H. G.
中科院分区：
文献类型：
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作者：
Cao, Hop S. Tran;Bouvet, Michael;Katz, Matthew H. G.
节拍化疗抑制原发性肿瘤和已建立的转移瘤的生长。然而，其对转移进展的影响基本上是未知的。我们报告了节拍吉西他滨和舒尼替尼治疗胰腺癌转移模型。在有或无舒尼替尼（SU）的情况下，以节律性（每日1 mg/kg，METG）或最大耐受剂量（每周两次，150 mg/kg，MTDG）给药吉西他滨治疗原位表达红色荧光蛋白的胰腺癌肿瘤移植物的小鼠。计算原发肿瘤生长率、转移率、腹水率和生存率。吉西他滨以2 mg或更高的日剂量在1个月内在无肿瘤的小鼠中导致毒性，但METG以1 mg/kg/d耐受良好。胰腺癌肿瘤移植小鼠死于转移性疾病的中位时间为25天。与对照组或单用METG/SU方案相比，METG/SU方案显著延长了中位总生存期（44天）（P < 0.05）。METG/SU（P = 0.03）抑制原发性肿瘤生长，但METG或舒尼替尼单独使用均不能抑制。相比之下，METG治疗抑制了多个部位的转移，舒尼替尼增强了这种效果。MTDG联合或不联合舒尼替尼对原发性肿瘤生长和生存期的影响最有利，但其抗转移疗效与METG/SU相似。METG可抑制von Willebrand因子的表达。使用METG，总剂量减少42倍，达到了接近MTDG的抗转移活性，舒尼替尼进一步增强了抗转移活性。我们的研究结果表明，这种治疗模式对胰腺癌的辅助和维持设置的潜力。Mol Cancer Ther; 9（7）; 2068-78. (C)2010年AACR。
Metronomic chemotherapy suppresses growth of primary tumors and established metastases. However, its effect on metastatic progression is essentially unknown. We report the treatment of a metastatically competent model of pancreatic cancer with metronomic gemcitabine and sunitinib. Mice with orthotopic, red fluorescent protein-expressing, pancreatic cancer tumorgrafts were treated with gemcitabine on a metronomic (1 mg/kg daily, METG) or maximum tolerated dose (150 mg/kg twice weekly, MTDG) schedule with or without sunitinib (SU). Rates of primary tumor growth, metastasis, ascites, and survival were calculated. Gemcitabine at a daily dose of 2 mg or greater led to toxicity within 1 month in mice without tumors but METG at 1 mg/kg/d was well tolerated. Mice with pancreatic cancer tumorgrafts died with metastatic disease at a median of 25 days. METG/SU significantly prolonged median overall survival (44 days) compared with control or either regimen alone (P < 0.05). Primary tumor growth was inhibited by METG/SU (P = 0.03) but neither METG nor sunitinib alone. In contrast, treatment with METG suppressed metastasis at multiple sites, an effect enhanced by sunitinib. MTDG with or without sunitinib had the most favorable effect on primary tumor growth and survival, but its antimetastatic efficacy was similar to that of METG/SU. von Willebrand factor expression was inhibited by METG. Antimetastatic activity approaching that of MTDG is achieved with a total dose reduced 42 times using METG and is further enhanced by sunitinib. Our results suggest the potential of this therapeutic paradigm against pancreatic cancer in the adjuvant and maintenance settings. Mol Cancer Ther; 9(7); 2068-78. (C) 2010 AACR.