Part of this study was presented at the 109th annual meeting of the Triological Society, Chicago, IL, May 19–22, 2006.
The predictive and therapeutic value of thymidine phosphorylase and dihydropyrimidine dehydrogenase in capecitabine (Xeloda)-based chemotherapy for head and neck cancer†
Article first published online: 31 DEC 2008
Copyright © 2009 The American Laryngological, Rhinological, and Otological Society, Inc.
Volume 119, Issue 1, pages 82–88, January 2009
How to Cite
Saito, K., Khan, K., Yu, S.-Z., Ronson, S., Rhee, J., Li, G., Van Echo, D., Suntharalingam, M., O'Malley, B. W. and Li, D. (2009), The predictive and therapeutic value of thymidine phosphorylase and dihydropyrimidine dehydrogenase in capecitabine (Xeloda)-based chemotherapy for head and neck cancer. The Laryngoscope, 119: 82–88. doi: 10.1002/lary.20003
- Issue published online: 31 DEC 2008
- Article first published online: 31 DEC 2008
- Manuscript Accepted: 15 JUL 2008
- thymidine phosphorylase;
- dihydropyrimidine dehydrogenase;
To evaluate whether two molecular biomarkers, thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD), could be clinically useful in predicting and improving the chemotherapeutic outcome of the oral fluoropyrimidine capecitabine (5′-DFUR or Xeloda®), in the treatment of human head and neck squamous cell carcinoma (HNSCC).
Quantitative reverse-transcriptase polymerase chain reaction was used to determine the TP and DPD expression levels in different HNSCC cell lines. The TP to DPD ratio was calculated and compared to the relative chemosensitivity between cell lines after treatment with 5′-DFUR. The effect of TP transgene expression to alter the TP to DPD ratio and hence optimize the therapeutic outcome of capecitabine treatment was further evaluated in a murine model of human HNSCC using immunohistochemistry to detect TP and DPD expression in vivo.
No correlation was detected between sensitivity to 5′-DFUR and the relative expression levels of TP or DPD in the multiple HNSCC cell lines tested. However, significant correlation was observed between the TP to DPD ratio versus drug resistance of the HNSCC cells (r = −0.914, p = 0.0281). In addition, we demonstrate that transgene expression of TP significantly enhanced the tumoricidal effect of capecitabine in HNSCC tumors with otherwise low endogenous TP to DPD ratios. This antitumor effect was observed up to 30 days after treatment.
The results of this study suggest that HNSCC patients who would most benefit from capecitabine-based chemotherapy could be identified by examining the TP to DPD ratio of their tumors. Furthermore, we demonstrate the potential role of TP gene therapy in TP to DPD ratio manipulation to optimize the tumoricidal effect of capecitabine. Laryngoscope, 119:82–88, 2009