Modulation of Doxorubicin sensitivity and level of p-glycoprotein expression in human colon-carcinoma cells by ectopic and orthotopic environments in nude-mice.
Modulation of Doxorubicin sensitivity and level of p-glycoprotein expression in human colon-carcinoma cells by ectopic and orthotopic environments in nude-mice.
复制标题
裸鼠异位和原位环境对人结肠癌细胞阿霉素敏感性和 p-糖蛋白表达水平的调节。
DOI：
10.3892/ijo.3.3.413
复制
发表时间：
1993
影响因子：
5.2
通讯作者：
I. Fidler
中科院分区：
文献类型：
--
作者：
C. Wilmanns;D. Fan;C. O'brian;R. Radinsky;C. Bucana;R. Tsan;I. Fidler
这项研究的目的是确定器官环境是否会影响结肠癌细胞对化疗的反应。将先前选择用于在裸鼠中产生肝转移的高转移性人结肠癌细胞系KM 12 L4注射到盲肠壁和脾脏中以产生肝转移，并注射到裸鼠的皮下组织中。在肿瘤细胞注射后第7天和第16天，静脉内注射10 mg/kg的多柔比星（DOX）或盐水（对照）。在盲肠、肝脏和皮下（s.c.）位点以及从肝和s.c.肿瘤进行比较。结肠癌皮下生长裸鼠盲肠壁或肝脏中的肿瘤对DOX更敏感。s.c.肿瘤（敏感性）和肝肿瘤（抗性）的差异不是由于选择了对DOX具有不同敏感性的细胞群或DOX分布的差异。PKC活性在肝和盲肠肿瘤中低于皮下。肿瘤的从不同器官的病变中收集的肿瘤细胞的流式细胞术分析所确定的P-糖蛋白的表达与其对DOX的敏感性呈负相关。北方分析表明，P-糖蛋白水平升高与mdr-1、mdr-3 mRNA表达相关。总的来说，数据显示器官环境影响人结肠癌细胞对DOX的反应，并推荐用于实验治疗研究的该疾病的动物模型采用肿瘤细胞的原位植入。
The purpose of the study was to determine whether the organ environment can influence the response of colon cancer cells to chemotherapy. The highly metastatic human colon cancer cell line KM12L4, previously selected for production of liver metastases in nude mice, was injected into the cecal wall and into the spleen to produce liver metastases, and into the subcutis of nude mice. Doxorubicin (DOX) at 10 mg/kg or saline (control) was injected intravenously on days 7 and 16 after tumor cell injection. The in vivo response of tumors growing in the cecum, liver, and subcutaneous (s.c.) sites as well as the DOX sensitivity of cell lines established from liver and s.c. tumors were compared. Colon cancers growing s.c. were more sensitive to DOX than tumors growing in the cecal wall or liver of nude mice. The difference in response to DOX between s.c. tumors (sensitive) and liver tumors (resistant) was not due to selection of cell populations with different sensitivity to DOX, or differences in DOX distribution. PKC activity was lower in tumors of the liver and the cecum than in s.c. tumors. The expression of P-glycoprotein as determined by flow cytometric analysis of tumor cells harvested from lesions in different organs correlated inversely with their sensitivity to DOX. Increased levels of P-glycoprotein correlated with mdr-1, mdr-3 mRNA expression as determined by Northern analysis. Collectively, the data show that the organ environment influences the response of human colon carcinoma cells to DOX and recommend that animal models of this disease for experimental therapeutic studies employ orthotopic implantation of tumor cells.