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The predictive and therapeutic value of thymidine phosphorylase and dihydropyrimidine dehydrogenase in capecitabine (Xeloda)-based chemotherapy for head and neck cancer

Authors

  • Koichiro Saito MD,

    1. Department of Otorhinolaryngology–Head & Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, U.S.A.
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  • Khurram Khan MD,

    1. Department of Otorhinolaryngology–Head & Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, U.S.A.
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  • Shu-Zhen Yu MD,

    1. Department of Otolaryngology–Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A.
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  • Steve Ronson MD,

    1. Department of Otolaryngology–Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A.
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  • Joung Rhee PhD,

    1. Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A.
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  • Gouyan Li MD,

    1. Department of Otolaryngology–Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A.
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  • David Van Echo MD,

    1. Medicine Division of Oncology, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A.
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  • Mohan Suntharalingam MD,

    1. Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A.
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  • Bert W. O'Malley Jr. MD,

    1. Department of Otorhinolaryngology–Head & Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, U.S.A.
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  • Daqing Li MD

    Corresponding author
    1. Department of Otorhinolaryngology–Head & Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, U.S.A.
    • Department of Otorhinolaryngology–Head & Neck Surgery, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Clinical Research Building Room 145, Philadelphia, PA 19104
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  • Part of this study was presented at the 109th annual meeting of the Triological Society, Chicago, IL, May 19–22, 2006.

Abstract

Objectives:

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).

Experimental Design:

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.

Results:

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.

Conclusions:

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

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