Inoue Yasuhiro, Shirane Masatoshi, Miki Chikao, Hiro Junichiro, Tanaka Koji, Kobayashi Minako, Mori Kazushige, Yanagi Hidenori, Kusunoki Masato
The Second Department of Surgery, Mie University School of Medicine, Tsu, Japan.
Int J Oncol. 2004 Dec;25(6):1641-9.
The combination of irinotecan and a fluoropyrimidine has been widely accepted as a treatment for advanced colorectal carcinoma. However, there have been no evaluable data on the feasibility of these combinations. To assess the significance of such combinations, we attempted to identify gene expression patterns in response to irinotecan and two different types of fluoropyrimidines. In 12 patients dispositioned to receive preoperative chemotherapy for colorectal carcinoma, pre-therapy tumor biopsies and final resected specimens were available for analysis. Patients were randomly assigned to receive one of the following four regimens: (I), oral doxifluridine; (II), intravenous infusion of 5-FU; (III), intravenous infusion of irinotecan; (IV), combination of doxifluridine and irinotecan (I+III). To identify genes whose expressions changed, we analyzed the gene expression profiles prior to and after these therapies using an oligonucleotide microarray consisting of 12,000 genes. Next, we focused on the genes that demonstrated similar kinetics of altered expression in all patients in each of the regimens. We identified two proto-oncogenes, nuclear receptor of T-cells (NOT) and c-fos, that were up-regulated in doxifluridine- and irinotecan-related regimens but unchanged in the 5-FU-related regimen. Moreover, group IV tumors showed the highest apoptotic rate and lowest proliferation activity following the combined chemotherapy. These results suggest that doxifluridine has a synergistic impact on the therapeutic effect of irinotecan by up-regulating proto-oncogenes such as NOT and c-fos, and thus justify the use of one of the irinotecan and fluoropyrimidine combinations.
伊立替康与氟嘧啶联合用药已被广泛认可为晚期结直肠癌的一种治疗方法。然而，关于这些联合用药的可行性尚无可评估的数据。为了评估此类联合用药的意义，我们试图确定对伊立替康和两种不同类型氟嘧啶产生反应的基因表达模式。在12例准备接受结直肠癌术前化疗的患者中，可获得治疗前的肿瘤活检标本和最终切除的标本用于分析。患者被随机分配接受以下四种治疗方案之一：（I）口服去氧氟尿苷；（II）静脉输注5-氟尿嘧啶；（III）静脉输注伊立替康；（IV）去氧氟尿苷与伊立替康联合用药（I + III）。为了鉴定表达发生变化的基因，我们使用由12000个基因组成的寡核苷酸微阵列分析了这些治疗前后的基因表达谱。接下来，我们关注在每种治疗方案的所有患者中表现出相似表达变化动力学的基因。我们鉴定出两个原癌基因，T细胞核受体（NOT）和c-fos，它们在与去氧氟尿苷和伊立替康相关的治疗方案中上调，但在与5-氟尿嘧啶相关的治疗方案中未发生变化。此外，联合化疗后，IV组肿瘤显示出最高的凋亡率和最低的增殖活性。这些结果表明，去氧氟尿苷通过上调NOT和c-fos等原癌基因对伊立替康的治疗效果具有协同作用，从而证明了伊立替康与氟嘧啶联合用药方案之一的使用合理性。
