Detection of the cytochrome P450 enzyme in lung cancer may be useful for cancer screening

【引言】细胞色素P450（CYP 450）与肿瘤的发生、发展以及抗癌前药的活化及其代谢清除有关。最近，已经发现一些CYP，特别是CYP 3A亚家族的酶（CYP 3A 4、CYP 3A 5和CYP 3A 7）在许多抗癌药物的代谢中起作用。CYP 3A不仅使主要抗癌药物如他莫昔芬、紫杉醇和长春花生物碱失活，而且还使主要抗癌前药如环磷酰胺和异环磷酰胺活化。为了更好地管理肺癌，了解CYP的作用以及它们的表达与个体肺癌临床特征之间的关系是至关重要的。本研究检测了78例非小细胞肺癌（NSCLC）组织中4种CYP（CYP 1A 1、CYP 2A 6、CYP 2 E1和CYP 3A）的表达，并分析了它们之间的相互关系、肿瘤p53表达与患者临床特征的关系。[材料与方法]采用酶联免疫吸附法（ELISA）检测细胞色素P450和p53。 ...更多信息 在获得适当的知情同意后，在UOEH接受手术切除的78例日本NSCLC患者的免疫反应性。根据WHO分类进行肿瘤的组织学分型（腺癌; 48例，鳞状细胞癌; 30例）。采用LSAB（标记链霉亲和素生物素）法对78例NSCLC进行免疫组织化学染色（IHC）。当超过10%的肿瘤细胞被染色时，CYP和p53表达被确定为阳性。使用ABI 373 A DNA测序仪（Applied Biosystems）通过双脱氧链终止法对48个腺癌中的p53突变进行测序。[结果] 48例腺癌中CYP 1A 1、CYP 2A 6、CYP 2 E1和CYP 3A的阳性率分别为43.8%（21/48）、45.8%（22/48）、39.6%（19/48）和39.6%（19/48），而30例鳞状细胞癌中无CYPs阳性病例。女性腺癌中CYP阳性率高于男性腺癌。早期腺癌的CYP阳性率高于晚期腺癌。高、中分化腺癌的CYP阳性率高于低分化腺癌。CYP 1A 1、CYP 2 E1和Cyp 3A在腺癌中的表达呈正相关。腺癌中CYP的表达与肿瘤p53的改变无关。[结论]深入研究肿瘤组织中的表达对探讨肿瘤发生机制、作为肿瘤标志物、进行分子靶向治疗、筛选抗肿瘤药物具有重要意义。少

[Introduction] The cytochrome P450 (CYP) is associated with tumor development and progression as well as activation of anti-cancer prodrugs and their metabolic clearance. Recently, some CYPs, in particular enzymes of the CYP3A subfamily (CYP3A4, CYP3A5, and CYP3A7), have been found to play a role in the metabolism of many anticancer drugs. CYP3A not only inactivates major anticancer drugs, such as tamoxifen, taxol and vinca alkaloids, but also activates major anticancer prodrugs, such as cyclophosphamide and ifosphamide. For the better management of lung cancer, it is essential to understand the roles of CYPs and the relationships between their expression and the clinical feature of individual lung cancers. In this study, we investigate the expression of four CYPs (CYP1A1, CYP2A6, CYP2E1 and CYP3A) in 78 non-small cell lung cancer (NSCLC) and their relationships to each other, tumor p53 expression, and clinical features of the patients.[Materials and Methods] We examined CYPs and p53 i … More mmunoreactivities in 78 Japanese patients with NSCLC who underwent surgical resection at UOEH after obtaining appropriate informed consent. Histological typing of the tumors was performed according to the WHO classification (adenocarcinoma ; 48 cases, squamous cell carcinoma ; 30 cases). Immunohistochemical staining (IHC) of 78 NSCLC was performed by the LSAB (labelled streptavidine biotin) method. CYPs and p53 expression was determined as positive when more than 10% of tumor cells were stained. The p53 mutations in 48 adenocarcinomas were sequenced by the dideoxy chain termination method using an ABI 373A DNA Sequencer (Applied Biosystems).[Results] The CYP1A1, CYP2A6, CYP2E1 and CYP3A positive rates in 48 adenocarcinomas were 43.8% (21/48), 45.8% (22/48), 39.6% (19/48) and 39.6% (19/48), respectively, although there was no CYPs positive cases in 30 squamous cell carcinomas. The CYPs positive rates in female adenocarcinoma were higher than those in male adenocarcinoma. The CYPs positive rates in early adenocarcinoma were higher than those in advanced adenocarcinoma. The CYPs positive rates in well and moderately differentiated adenocarcinoma were higher than those in poorly differentiated adenocarcinoma. There were positive relationships among CYP1A1, CYP2E1 and Cyp3A expressions in adenocarcinoma. The CYPs expression in adenocarcinoma was independent of tumor p53 alterations.[Conclusions] Our results suggest that better understanding of CYP expression in tumors should be useful and essential, 1) to investigate the mechanism of carcinogenesis, 2) to apply CYP expression as tumor marker, 3) to use the knowledge of CYP expression for molecular targeting therapy, 4) for selection of anti-cancer drug. Less