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


METHODS
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.
Saito
Koichiro
K
Department of Otorhinolaryngology-Head & Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Khan
Khurram
K
Yu
Shu-Zhen
SZ
Ronson
Steve
S
Rhee
Joung
J
Li
Gouyan
G
Van Echo
David
D
Suntharalingam
Mohan
M
O'Malley
Bert W
BW
Li
Daqing
D
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D000069287:Capecitabine; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000032:analysis*; D004797:Enzyme-Linked Immunosorbent Assay; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011237:Predictive Value of Tests; D012044:Regression Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D013939:Thymidine Phosphorylase / Q000032:analysis*; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D003841:Deoxycytidine; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D013939:Thymidine Phosphorylase; D005472:Fluorouracil