ORIGINAL PAPER Yasuhiro Hirano ® Tatsuya Takayama Shinji Kageyama ® Tomomi Ushiyama Kazuo Suzuki ® Kimio Fujita Thymidine phosphorylase activity in renal cell carcinoma: relationship between histological parameters and chemosensitivity to ﬂuorouracil-related drugs Received: 21 August 2001 /Accepted: 1 February 2002 / Published online: 22 March 2002 Ó Springer-Verlag 2002 Abstract Thymidine phosphorylase (TdR-Pase) is an essential enzyme in the metabolism of ﬂuorouracil-re- lated drugs and is also a potent angiogenic factor. We measured the TdR-Pase activity in human renal cell carcinomas (RCCs) to assess the relationship between TdR-Pase activity and the degree of tumor malignancy. We also investigated the relationship between TdR-Pase activity and chemosensitivity to ﬂuorouracil-related drugs. A total of 61 RCC tissue specimens and 39 nor- mal kidney tissue specimens were obtained. TdR-Pase activity was measured by enzyme-linked immunosorbent assay. The in vitro histoculture drug response assay was also performed to examine tumor sensitivity to 5-ﬂu- orouracil (5-FU) and doxiﬂuridine (5¢-DFUR). The TdR-Pase activity of RCCs was 13-fold that of the normal tissues. Activity increased with histological grade, and was signiﬁcantly higher in high-stage tumors (T3 or higher). TdR-Pase activity exhibited a signiﬁcant positive correlation with sensitivity to 5-FU and 5¢- DFUR. High TdR-Pase activity in human RCC was conﬁrmed to predict high tumor grade and stage. RCCs with high TdR-Pase activity were also sensitive to FU- related drugs. Keywords Thymidine phosphorylase ® Renal cell carcinoma ® Chemosensitivity ® 5-ﬂuorouracil Introduction Thymidine phosphorylase (TdR-Pase) is known to be identical to platelet-derived endothelial cell growth factor (PDECGF), which has a potent angiogenic ac- tivity [6]. High levels of this enzymatic activity have been observed in various malignant tumors [4, 5, 15]. A cor- relation between the expression of this enzyme and the prognosis of human renal cell carcinoma (RCC) has also been observed [5, 14]. TdR-Pase is also one of the key enzymes involved in the metabolism of ﬂuorouracil-related drugs, since it is important in the initial process of 5-FU activation. Doxiﬂuridine (5¢-DFUR), a pro-drug of 5-FU, is con- verted to 5-FU by TdR-Pase. Thus, carcinoma cells with high TdR-Pase activity might be more sensitive to ﬂu- orouracil. If the sensitivity to FU-related drugs could be predicted by measuring TdR-Pase activity, this might be a good clinical parameter for choosing drugs for che- motherapy. However, there have only been a few reports published concerning the relationship between the TdR- Pase activity of RCC and sensitivity to FU-related drugs [2, 10]. In this study, we measured the TdR-Pase activity in clinical specimens obtained from human RCCs and conﬁrmed the correlation between TdR-Pase activity and the degree of tumor malignancy. We also inves- tigated the chemosensitivity of tumors to FU-related drugs using an in vitro histoculture drug response assay and compared the results with TdR-Pase activity. Materials and methods Cancer specimens Surgical specimens were obtained from 61 RCC patients at Hamamatsu University Hospital and related hospitals between August 1996 and January 2000. Informed consent to study TdR- Pase activity and chemosensitivity was obtained from all patients before surgery. All of the cancer tissue specimens were histo- logically conﬁrmed to be RCC. Histological grades and stages were classiﬁed according to the 1997 International Union Against Cancer TNM classiﬁcation and were as follows: grade (G) 1: n=16, G 2: n=40, and G 3: n=5; T1: n=16, T2: n=31, T3: n=13, and T4: n=1. Urol Res (2002) 30: 112–115 DOI 10.1007/s00240-002-0241-x Y. Hirano (&) ® T. Takayama ® S. Kageyama T. Ushiyama ® K. Suzuki ® K. Fujita Department of Urology, Hamamatsu University School of Medicine, 431-3192, 1-20-1 Handayama Hamamatsu City, Japan E-mail: hirano@hama-med.ac.jp Tel.: +81-53-4352306 Fax: +81-53-4352305