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.
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.
Department of Clinical Pharmacology and Pharmacoepidemiology; University of Heidelberg; Heidelberg, Germany.
Dirk
D
Theile
Experimental Neurosurgery Research; Department of Neurosurgery; University of Heidelberg; Heidelberg, Germany.
Zoltan
Z
Gal
Experimental Neurosurgery Research; Department of Neurosurgery; University of Heidelberg; Heidelberg, Germany; Molecular Cell Biology Group; Department of Otorhinolaryngology, Head and Neck Surgery; University of Heidelberg; Heidelberg, Germany.
Rolf
R
Warta
Department of Clinical Pharmacology and Pharmacoepidemiology; University of Heidelberg; Heidelberg, Germany.
Juan Pablo
JP
Rigalli
Hamamatsu Tissue Imaging and Analysis Center (TIGA); BIOQUANT; University of Heidelberg; Heidelberg, Germany; Institute of Pathology; University of Heidelberg; Heidelberg, Germany.
Bernd
B
Lahrmann
Hamamatsu Tissue Imaging and Analysis Center (TIGA); BIOQUANT; University of Heidelberg; Heidelberg, Germany; National Center of Tumor Diseases; Medical Oncology; University of Heidelberg; Heidelberg, Germany.
Niels
N
Grabe
Experimental Neurosurgery Research; Department of Neurosurgery; University of Heidelberg; Heidelberg, Germany; Molecular Cell Biology Group; Department of Otorhinolaryngology, Head and Neck Surgery; University of Heidelberg; Heidelberg, Germany.
Christel
C
Herold-Mende
Molecular Cell Biology Group; Department of Otorhinolaryngology, Head and Neck Surgery; University of Heidelberg; Heidelberg, Germany.
Gerhard
G
Dyckhoff
Department of Clinical Pharmacology and Pharmacoepidemiology; University of Heidelberg; Heidelberg, Germany.
Johanna
J
Weiss
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D000077195:Squamous Cell Carcinoma of Head and Neck
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002945:Cisplatin; D005472:Fluorouracil; D019394:Ki-67 Antigen; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel
P-glycoprotein; cytostatics; head and neck squamous cell carcinoma; multidrug resistance; murine xenograft model; paclitaxel; pregnane-x-receptor