Hashimoto Y, Ueda K, Minami K, Watatani M
First Department of Surgery, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.
Int J Clin Oncol. 2001 Apr;6(2):90-6. doi: 10.1007/pl00012089.
Adjuvant chemotherapy with 5-fluorouracil (5-FU) and mitomycin C (MMC) has commonly been used after resection of colorectal cancer. The aim of this study was to determine the predictive value of p53 mutation or the expression of GML, a target of p53, for sensitivity to 5-FU and MMC.
We analyzed p53 mutations and the expression of GML in six colorectal cancer cell lines (SW837, DLD-1, RPMI4788, WiDr, HT-29, and HCT116), and examined the correlation between genetic changes and in-vitro chemosensitivity to MMC and 5-FU by measuring the colony-forming ability in these cell lines. We also introduced GML cDNA into a cell line that lacked endogenous GML expression to investigate changes in sensitivity to MMC and 5-FU.
The sensitivity to MMC was highest in HCT116, which had no p53 gene abnormalities and expressed endogenous GML, and lowest in RPMI4788 cells, which had neither p53 gene abnormalities nor expression of endogenous GML. For 5-FU treatment with 24-h exposure, HCT116 showed the highest sensitivity, and SW837, which had p53 mutations without expression of GML, showed the lowest sensitivity. The introduction of GML cDNA to RPMI4788 (RPMI4788-GML) showed that the sensitivity of RPMI4788-GML to MMC was enhanced almost to the level of HCT116 cells. However, when RPMI4788-GML were exposed to 5-FU for 24 h, the sensitivity of RPMI4788-GML was slightly increased compared with that of the parental cells, but was slightly lower than that of HCT116.
GML expression and p53 mutation in colorectal cancer may be useful predictive genetic markers for sensitivity to MMC and 5-FU, respectively.
5-氟尿嘧啶（5-FU）和丝裂霉素C（MMC）辅助化疗常用于结直肠癌切除术后。本研究的目的是确定p53突变或p53靶点GML的表达对5-FU和MMC敏感性的预测价值。
我们分析了六种结直肠癌细胞系（SW837、DLD-1、RPMI4788、WiDr、HT-29和HCT116）中的p53突变和GML表达，并通过测量这些细胞系中的集落形成能力，研究基因变化与对MMC和5-FU的体外化疗敏感性之间的相关性。我们还将GML cDNA导入缺乏内源性GML表达的细胞系中，以研究对MMC和5-FU敏感性的变化。
对MMC敏感性最高的是没有p53基因异常且表达内源性GML的HCT116细胞系，最低的是既没有p53基因异常也没有内源性GML表达的RPMI4788细胞。对于24小时暴露的5-FU治疗，HCT116显示出最高的敏感性，而有p53突变且无GML表达的SW837显示出最低的敏感性。将GML cDNA导入RPMI4788（RPMI4788-GML）表明，RPMI4788-GML对MMC的敏感性几乎提高到了HCT116细胞的水平。然而，当RPMI4788-GML暴露于5-FU 24小时时，RPMI4788-GML的敏感性与亲代细胞相比略有增加，但略低于HCT116。
结直肠癌中的GML表达和p53突变可能分别是对MMC和5-FU敏感性的有用预测性遗传标志物。
