节律性化疗联合靶向HIF-1α治疗结肠癌的研究

Adjuvant chemotherapy for colon cancer is one of the most active areas of clinical cancer research. However, despite extensive exploration for new anti-cancer drugs or therapeutic strategies, the success of current treatments is still unsatisfactory, and the side effects of chemotherapy can be particularly harsh. Recently, there have been considerable interests in the notion of exploiting chemotherapeutic drugs as angiogenesis inhibitors. The mode of action is thought to be explained by the interference of these agents with cycling and proliferating endothelial cells in the process of tumor angiogenesis. Continuous, low-dose chemotherapy, i.e. metronomic chemotherapy, targeting the endothelial cells directly is thought to have fewer side-effects as well as a lack of drug resistance. However, it is noteworthy that previous studies indicated that low-dose chemotherapy protocols sometimes were not effective on their own and, indeed, in some cases, actually stimulated tumor growth partially due to enhance tumor hypoxia. The hypoxia-inducible factor-1 (HIF-1) is a master regulator of cellular responses to low oxygen. We hypothesis that inhibiting HIF-1 may sensitize hypoxic cancer cells to antiangiogensis therapy and lead to a more profound antitumor efficacy. The present study aims to investigate whether metronomic chemotherapy of paclitaxel could synergize with knockdown of hypoxia-inducible factor-1α to suppress HT-29 human colon tumors in BALB/c nude mice.

结肠癌辅助化疗是肿瘤临床研究最活跃的领域之一。传统化疗药物针对的是异常增殖的肿瘤细胞，具有遗传不稳定性，易于发生突变而耐药，且毒副反应大。近来研究表明增殖的内皮细胞比肿瘤细胞对化疗药物更加敏感，应用低剂量化疗可特异性靶向于肿瘤内皮细胞，通过其抗血管生成活性起到间接抑制肿瘤生长的作用。同时，低剂量化疗对骨髓造血系统、胃肠粘膜等化疗敏感组织毒副作用小，可长期持续使用。这种连续规律低剂量的给药方式被称为节律性化疗。有研究发现，肿瘤抗血管生成治疗使肿瘤血管减少，导致肿瘤缺氧并加速肿瘤恶变、局部侵袭和远处转移。缺氧诱导因子-1可能在此起了关键作用，它作为肿瘤微环境中的一个至关重要的调节因子，在促进肿瘤血管生成和肿瘤的侵袭性方面起中心作用。本课题拟将节律性化疗与靶向HIF-1α联合治疗结肠癌，利用靶向HIF-1α增强节律性化疗的抗肿瘤效应，研究其治疗效果及可能机制，将节律性化疗研究带入一个新的领域。

结肠癌辅助化疗是临床研究最活跃的领域之一。传统化疗药物针对的是异常增殖的肿瘤细胞，具有遗传不稳定性，易于发生突变而耐药，且毒副反应大。近年来研究表明化疗药物低剂量治疗对骨髓造血系统、胃肠粘膜等化疗敏感组织毒副作用小，可长期持续使用。这种连续规律低剂量的给药方式被称为节律性化疗。已有报道发现，缺氧诱导因子-1（HIF-1α）在加速肿瘤恶变、局部侵袭和远处转移中起中心作用。本课题验证了节律性化疗（LDM）相较于常规化疗（MTD）有着更好的抑制体内肿瘤生长、抑制微血管生成和较低的毒副作用；并且在获得有效的HIF-1α干扰质粒的前提下，研究发现节律性化疗（LDM）联合HIF-1α对结肠癌疗效更佳，这一过程与VEGF的表达与分泌过程相关。本研究明确了节律性化疗的意义，将为临床用药提供指导，以及节律性化疗（LDM）靶向HIF-1α的结合将节律性化疗带入新的研究领域。