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

Abstract

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 10⁶ 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.

Keywords: :

• cytostatics
• P-glycoprotein
• head and neck squamous cell carcinoma
• multidrug resistance
• murine xenograft model
• paclitaxel
• pregnane-x-receptor

10.4161/cbt.27632

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

This project was funded by grant WE 4135/3-1 und HE 2357/2-1 from the German Research Foundation. The authors thank Corina Mueller, Stephanie Rosenzweig, Natalia Heinzelbecker, and Melanie Greibich for excellent technical assistance.