Establish the chemopreventive strategy using PPAR gamma ligands for colorectal cancer

激活PPARy的合成配体，如吡格列酮和罗格列酮，常用于糖尿病患者的治疗，以改善胰岛素抵抗。已有研究表明，PPARy配体可抑制结直肠癌细胞生长，诱导细胞凋亡。另一方面，胰岛素抵抗或高胰岛素血症被认为是结直肠癌的主要危险因素之一。如果高胰岛素血症单独或合并胰岛素抵抗综合征的其他特征与结直肠癌风险增加相关，PPARy的激活可能在结肠癌的发生中发挥有益的作用。具有PPARy配体的结直肠癌的临床试验结果并不明显，这意味着将PPARy作为特异性抗肿瘤靶点是不太可能成功的，因为PPARy配体不是治疗晚期或转移性结直肠癌的有效药物。最近，我们在小鼠结肠癌发生的早期阶段证明了PPARy配体对结肠癌发生的实质性抑制作用，这表明PPARy配体作为化学防癌药物具有潜在的应用前景。此外，在人类研究中，PPARy配体治疗显著减少了结直肠癌癌前病变--异常隐窝病灶的数量。PPARy配体使用安全，有可能作为早期结直肠癌的抗癌药物应用于临床。这些结果表明，PPARy配体是一种很有前途的结直肠癌化学预防药物。

Activating synthetic ligands for PPARY, such as pioglitazone and rosiglitazone, are commonly used to treat patients with diabetes mellitus (DM) in order to improve insulin resistance. Several reports have clearly demonstrated that PPARY ligands, could inhibit colorectal cancer cell growth and induce apoptosis. On the other hands, the insulin resistance or hyper insulinemia are thought to be the one of the major risk factors of colorectal cancer (CRC). If hyper insulinemia, alone or in combination with other features of the insulin resistance syndrome, is associated with increased risk of CRC, activation of PPARY may play a benefited role in colon carcinogenesis. The results of clinical trials for CRC with PPARY ligands have shown modest This implies that aiming at PPARY as a specific anti-tumor target is not likely to be successful, because PPARY ligands are not an active agent for the treatment of advanced or metastatic CRC. Recently, we have demonstrated the substantial suppressive effects of PPARY ligands on colon carcinogenesis in mouse model in the early stage of carcinogenesis, suggesting a potential application as the chemopreventive agents against carcinogenesis. Furthermore, number of aberrant crypt foci, pre cancerous lesion of colorectal, was significantly decreased by PPARY ligand treatment in human study. PPARY ligands are used with safety benefit and may be a clinical application as anti-cancer drug in early stage of CRC. These results suggest that PPARY ligand is a promising candidate as a chemopreventive agent for CRC.