Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Free Radic Biol Med. 2011 Jun 1;50(11):1610-9. doi: 10.1016/j.freeradbiomed.2011.03.007. Epub 2011 Mar 12.
Conventional treatment approaches have had little impact on the course of pancreatic cancer, which has the highest fatality rate among cancers. Gemcitabine, the primary therapeutic agent for pancreatic carcinoma, produces minimal survival benefit as a single agent. Therefore, numerous efforts have focused on gemcitabine combination treatments. Using a ratio design, this study established that combining pharmacologically achievable concentrations of ascorbate with gemcitabine resulted in a synergistic cytotoxic response in eight pancreatic tumor cell lines. Sensitization was evident regardless of inherent gemcitabine resistance and epithelial-mesenchymal phenotype. Our analysis suggested that the promiscuous oxidative actions of H(2)O(2) derived from pharmacologic ascorbate can culminate in synergism independent of the cancer cell's underlying phenotype and resistance to gemcitabine monotherapy. Gemcitabine-ascorbate combinations administered to mice bearing pancreatic tumor xenografts consistently enhanced inhibition of growth compared to gemcitabine alone, produced 50% growth inhibition in a tumor type not responsive to gemcitabine, and demonstrated a gemcitabine dose-sparing effect. These data support the testing of pharmacologic ascorbate in adjunctive treatments for cancers prone to high failure rates with conventional therapeutic regimens, such as pancreatic cancer.
传统的治疗方法对胰腺癌的病程几乎没有影响，胰腺癌的死亡率在所有癌症中最高。吉西他滨是胰腺癌的主要治疗药物，作为单一药物使用时，其生存获益最小。因此，人们进行了大量研究来探索吉西他滨联合治疗。本研究采用比率设计，发现将具有药理作用的浓度的抗坏血酸与吉西他滨联合使用，可在 8 种胰腺肿瘤细胞系中产生协同的细胞毒性反应。无论内在的吉西他滨耐药性和上皮-间充质表型如何，都有明显的增敏作用。我们的分析表明，来源于药理学抗坏血酸的 H2O2 的混杂氧化作用可能导致协同作用，而与癌细胞的潜在表型和对吉西他滨单药治疗的耐药性无关。与单独使用吉西他滨相比，吉西他滨-抗坏血酸联合治疗在携带胰腺肿瘤异种移植物的小鼠中，对肿瘤生长的抑制作用始终增强，在一种对吉西他滨无反应的肿瘤类型中产生 50%的生长抑制作用，并显示出吉西他滨的剂量节省效应。这些数据支持在常规治疗方案失败率高的癌症（如胰腺癌）的辅助治疗中测试药理学抗坏血酸。
