药物诱导的体内乳腺癌组织及体外成纤维细胞中的细胞凋亡以及p53、BCL-2和BAX表达。

Drug-induced apoptosis and p53, BCL-2 and BAX expression in breast cancer tissues in vivo and in fibroblast cells in vitro.

作者信息

Suzuki K, Kazui T, Yoshida M, Uno T, Kobayashi T, Kimura T, Yoshida T, Sugimura H

机构信息

First Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan.

出版信息

Jpn J Clin Oncol. 1999 Jul;29(7):323-31. doi: 10.1093/jjco/29.7.323.

DOI:10.1093/jjco/29.7.323

PMID:10470656

Abstract

BACKGROUND

Chemotherapeutic management of breast cancers is a difficult task as they show significant differences in chemosensitivity. The present study was undertaken to determine the usefulness of the apoptosis-related factors as indicators of tumor sensitivity to 5'-deoxyfluorouridine (5'-DFUR) in breast cancers.

METHODS

(1) Forty-six breast cancer patients were randomly assigned to a group in which oral 5'-DFUR (1200 mg/day) was administered for more than 5 days before operation (24 patients) and a control group who received no preoperative chemotherapy (22 patients). Surgical specimens were examined for the frequency of apoptotic cells [apoptotic index (AI)] by a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling method and for the expression of p53, BCL-2 and BAX by immunohistochemical staining. (2) Normal human diploid fetal lung fibroblast, IMR90 and SV40 transformed IMR90 were exposed to 5-FU. Apoptotic cells were detected by flow cytometry and BCL-2 and BAX mRNAs by real-time quantitative RT-PCR analysis.

RESULTS

(1) No significant difference in the AIs or in BCL-2 and BAX scores was observed between the 5'-DFUR-treated and control groups. However, in the p53 negative subgroup (n = 36), AI and BAX scores were higher and BCL-2 scores lower in the 5'-DFUR group than in the control group (P = 0.006, 0.008 and 0.050, respectively). (2) The sensitivity of IMR90 was significantly decreased by SV40 transformation and the 5-FU-induced cytotoxicity was mainly due to induction of apoptosis. The BCL-2/BAX mRNA ratio was decreased in response to 5-FU in IMR90. These results correlated with our clinical data.

CONCLUSIONS

Preoperative treatment with 5'-DFUR induced apoptosis and changes in BCL-2 and BAX expression in p53 negative breast cancers. p53 status, AI and the BCL-2/BAX ratio may be useful information for the choice of postoperative chemotherapy for breast cancer.

摘要

背景

乳腺癌的化疗管理是一项艰巨的任务，因为它们在化疗敏感性方面存在显著差异。本研究旨在确定凋亡相关因子作为乳腺癌对5'-脱氧氟尿苷（5'-DFUR）肿瘤敏感性指标的有用性。

方法

（1）46例乳腺癌患者被随机分为两组，一组在手术前口服5'-DFUR（1200mg/天）超过5天（24例患者），另一组为未接受术前化疗的对照组（22例患者）。通过末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记法检测手术标本中凋亡细胞的频率[凋亡指数（AI）]，并通过免疫组织化学染色检测p53、BCL-2和BAX的表达。（2）将正常人二倍体胎儿肺成纤维细胞IMR90和SV40转化的IMR90暴露于5-氟尿嘧啶。通过流式细胞术检测凋亡细胞，通过实时定量RT-PCR分析检测BCL-2和BAX mRNA。

结果

（1）5'-DFUR治疗组和对照组之间的AI以及BCL-2和BAX评分没有显著差异。然而，在p53阴性亚组（n = 36）中，5'-DFUR组的AI和BAX评分高于对照组，BCL-2评分低于对照组（分别为P = 0.006、0.008和0.050）。（2）SV40转化显著降低了IMR90的敏感性，5-氟尿嘧啶诱导的细胞毒性主要是由于诱导凋亡。IMR90中BCL-2/BAX mRNA比值因5-氟尿嘧啶而降低。这些结果与我们的临床数据相关。