Antiproliferative efficacies but minor drug transporter inducing effects of paclitaxel, cisplatin, or 5-fluorouracil in a murine xenograft model for head and neck squamous cell carcinoma
Antiproliferative efficacies but minor drug transporter inducing effects of paclitaxel, cisplatin, or 5-fluorouracil in a murine xenograft model for head and neck squamous cell carcinoma
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DOI：
10.4161/cbt.27632
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发表时间：
2014-04-01
影响因子：
3.6
通讯作者：
Weiss, Johanna
中科院分区：
文献类型：
--
作者：
Theile, Dirk;Gal, Zoltan;Weiss, Johanna
体外头颈部鳞状细胞癌（HNSCC）中药物诱导的多药耐药（MDR）与药物转运蛋白的过表达有关。这项工作的目的是在小鼠异种移植模型中重新评估这些发现。移植了10(6)个HNO97细胞的NOD-SCID小鼠连续4周接受每周紫杉醇、双周顺铂（均腹腔注射）或5-氟尿嘧啶（5-FU，通过渗透泵给药）治疗。每周记录肿瘤体积和体重。采用实时定量聚合酶链反应和/或免疫组织化学检测药物转运体和Ki-67标志物的表达。2-3周后，紫杉醇和顺铂均显著减小肿瘤体积。5- fu治疗的动物在化疗2周或4周后体重明显降低。没有药物在mRNA水平上影响药物转运蛋白的表达。而紫杉醇组P-糖蛋白（Pgp）蛋白表达升高（P < 0.01）。无论使用何种药物，Ki-67的表达在治疗期间均无变化。紫杉醇和顺铂在HNSCC小鼠异种移植模型中是有效的肿瘤减容药物。紫杉醇在蛋白水平上增强了Pgp的表达，但在mRNA水平上没有，这表明转录诱导的相关性较小。相反，转录后机制或内在药物转运体过表达MDR细胞的达尔文选择可能导致HNSCC的医源性化疗耐药。
Drug-induced multidrug resistance (MDR) has been linked to overexpression of drug transporting proteins in head and neck squamous cell carcinoma (HNSCC) in vitro. The aim of this work was to reassess these findings in a murine xenograft model.NOD-SCID mice xenotransplanted with 10(6) HNO97 cells were treated for four consecutive weeks with weekly paclitaxel, biweekly cisplatin (both intraperitoneal), or 5-fluorouracil (5-FU, administered by osmotic pump). Tumor volume and body weight were weekly documented. Expression of drug transporters and Ki-67 marker were examined using quantitative real-time polymerase chain reaction and/or immunohistochemistry.Both paclitaxel and cisplatin significantly reduced tumor volumes after 2-3 weeks. 5-FU-treated animals had significantly lower body weights after 2 or 4 weeks of chemotherapy. None of the drugs affected expression of drug transporters at the mRNA level. However, P-glycoprotein (Pgp) protein expression was increased by paclitaxel (P < 0.01). Ki-67 expression did not change during treatment irrespective of the drug applied.Paclitaxel and cisplatin are effectively tumor volume reducing drugs in a murine xenograft model of HNSCC. Paclitaxel enhanced Pgp expression at the protein level, but not at the mRNA level suggesting transcriptional induction to be of minor relevance. In contrast, posttranscriptional mechanisms or Darwinian selection of intrinsically drug transporter overexpressing MDR cells might lead to iatrogenic chemotherapy resistance in HNSCC.