Association between chemotherapeutic effect and apotosis-related gene in gastrointestinal cancer

1.化疗敏感性与细胞凋亡相关蛋白表达的关系我们对5-FU联合小剂量顺铂(FP)治疗的胃癌患者的胃镜活检标本进行了免疫组织化学染色。在18例p53阳性(突变型)癌中，有3例对FP治疗有效。相反，12例p53阴性肿瘤(野生型)中有10例化疗有效(P=0.04)。提示野生型P53胃癌患者可能是FP治疗的应答者。结果：1.在bax阳性患者中，bc1-2阳性患者化疗耐药程度明显高于bc1-2阴性患者(P=0.036)，且预后较差(P=0.008)。人胃癌细胞对化疗药物敏感性与白介素1-β转换酶(ICE)活性的关系已有报道，ICE可能是最终常见的细胞凋亡途径。我们观察到了ga…冰激活度的峰值。顺铂作用3h后，OCUM-2M、OCUM-2M/DDP、KATO-III和MKN-28细胞株数量增加。IC50与顺铂和ICE活性比值(ICE活性/未处理细胞的ICE活性)之间的回归系数为0.66。提示ICE可能是顺铂作为早期反应蛋白化疗敏感性的预测指标。此外，顺铂耐药细胞OCUM-2M7DDP经顺铂作用后ICE活性和凋亡指数明显低于其亲本细胞OCUM-2M，提示ICE活性与细胞凋亡的关系。应用SSCP和DNA直接测序技术对8例FP治疗的胃肠癌进行化疗敏感相关的p53突变位点和DNA测序分析。6例应答者(部分应答者)中4例携带野生型P53基因，2例无应答者(无变化)为突变型P53基因。部分缓解型肿瘤第7外显子第259位密码子发生点突变，而7号外显子241-245位密码子缺失13bP。结果表明，需要DNA直接测序才能确定与化疗敏感有关的p53突变位点。我们分析了另外22例接受口服5-FU衍生物治疗的胃肠癌患者的P53基因。我们正在观察这些患者的预后，以此作为化疗效果的指标，以完成与化疗敏感性相关的P53突变位点的分析。较少

1. Association between chemosensitivity and apoptosis related protein expressionWe studied immunohistochemical staining for the endoscopic biopsy specimens of the patients with gastric cancer treated with 5-FU+low dose cisplatin (FP) therapy. Among 18 patients with p53 positive (mutant type) carcinomas, 3 patients were responders of FP therapy. On the contrary, 10 of 12 patients with p53 negative tumors (wild type) showed the response to chemotherapy (P=0.04). The results suggested the patients with wild type p53 gastric carcinomas may be responders to FP therapy. Among the Bax-positive cases, the patients with Bc1-2-positive tumors were significantly more chemoresistant (P=0.036) and had worse prognosis (P=0.008) than Bc1-2-negative cases.2. Association between chemosensitivity and interleukin 1-beta converting enzyme (ICE) activity in human gastric cancer cell lineIt has been reported ICE may represent a final common pathway of apoptosis. We observed the peaks of ICE activities of ga … More stric cancer cell lines, OCUM-2M, OCUM-2M/DDP, Kato-III, and MKN-28 at 3hrs after exposure to cisplatin. The regression value was 0.66 between the IC_<50> to cisplatin and ICE activity ratio (ICE activity at 3hrs after exposure cisplatin/that of no treatment cells). It suggested ICE may be a predictor of chemosensitivity to cisplatin as a early response protein. Moreover, the significant lower levels of ICE activity and apoptotic index in the cisplatin resistant cell, OCUM-2M7DDP after exposure to cisplatin than those of its parent cell, OCUM-2M.The result indicated the relation between ICE activity and apoptosis.3. p53 mutation site associated with chemosensitivityp53 gene analyses were performed with SSCP and DNA direct sequencing for 8 gastrointestinal carcinomas treated with FP therapy. Foru of 6 responders (partial response) had wild type p53 gene whereas 2 non-responders (no change) had mutant p53 gene. A partial response tumor had point mutation at codon 259 of exon 7, while a no change tumor had 13bp deletion at codon 241-245 of exon 7. The result showed DNA direct se1quencing was required to identify p53 mutation site related with chemosensitivity. We analyzed p53 genes in other 22 gastrointestinal carcinomas which are treating with oral 5-FU derivatives. We are observing the prognosis of these patients as indicator of chemotherapeutic effect to accomplish the analysis of p53 mutation site associated with chemosensitivity. Less