Saito Koichiro, Khan Khurram, Yu Shu-Zhen, Ronson Steve, Rhee Joung, Li Gouyan, Van Echo David, Suntharalingam Mohan, O'Malley Bert W, Li Daqing
Department of Otorhinolaryngology-Head & Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Laryngoscope. 2009 Jan;119(1):82-8. doi: 10.1002/lary.20003.
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.
评估两种分子生物标志物——胸苷磷酸化酶（TP）和二氢嘧啶脱氢酶（DPD），在预测和改善口服氟嘧啶卡培他滨（5'-DFUR或希罗达）治疗人类头颈部鳞状细胞癌（HNSCC）的化疗效果方面是否具有临床实用性。
采用定量逆转录聚合酶链反应来测定不同HNSCC细胞系中TP和DPD的表达水平。计算TP与DPD的比值，并与用5'-DFUR处理后细胞系之间的相对化学敏感性进行比较。在人HNSCC小鼠模型中，使用免疫组织化学检测体内TP和DPD的表达，进一步评估TP转基因表达对改变TP与DPD比值从而优化卡培他滨治疗效果的作用。
在所测试的多个HNSCC细胞系中，未检测到对5'-DFUR的敏感性与TP或DPD的相对表达水平之间存在相关性。然而，观察到HNSCC细胞的TP与DPD比值与耐药性之间存在显著相关性（r = -0.914，p = 0.0281）。此外，我们证明，在原本内源性TP与DPD比值较低的HNSCC肿瘤中，TP的转基因表达显著增强了卡培他滨的杀肿瘤作用。这种抗肿瘤作用在治疗后30天仍可观察到。
本研究结果表明，通过检测肿瘤的TP与DPD比值，可以识别出最能从基于卡培他滨的化疗中获益的HNSCC患者。此外，我们证明了TP基因治疗在操纵TP与DPD比值以优化卡培他滨的杀肿瘤作用方面的潜在作用。
