Prognostic significance of orotate phosphoribosyltransferase activity in bladder carcinoma
Prognostic significance of orotate phosphoribosyltransferase activity in bladder carcinoma
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作者：
Mizutani, Y;Wada, H;Miki, T
背景。5-氟尿嘧啶（5-FU）是一种抗肿瘤药物，临床上用于治疗多种恶性肿瘤，包括膀胱癌。5-氟尿嘧啶是一种前药，而旋转磷酸核糖基转移酶（OPRT）是转化5-氟尿嘧啶的主要酶。U直接转化为一种活性抗肿瘤代谢物，5-氟-2'-脱氧尿苷5'-单磷酸。此外，OPRT是DNA和RNA从头合成过程中的关键酶。据作者所知，关于OPRT在各种恶性肿瘤（包括膀胱癌）中的意义知之甚少。作者分析了60例膀胱癌患者的OPRT活性水平，并评估了OPRT活性水平与膀胱癌分期和分级之间的关系。他们还研究了膀胱癌患者OPRT活性的预后意义，以及膀胱癌细胞中OPRT活性水平与细胞对5- fu敏感性的相关性。使用5-FU磷酸化法测定膀胱癌和正常膀胱非固定、新鲜冷冻标本中的OPRT活性水平。膀胱细胞对5-FU的敏感性采用微培养四氮唑进行评估。染料assay.RESULTS。膀胱癌标本中OPRT活性水平约为正常膀胱标本活性水平的7.5倍。肌肉浸润性膀胱癌的OPRT活性比浅表性膀胱癌的高2倍（分为Ta和T1）。此外，OPRT在T1膀胱癌中的活性是Ta膀胱癌活性的2倍。3级膀胱癌患者的OPRT活性水平分别是1级和2级膀胱癌患者的6倍和2倍。与OPRT活性高的膀胱癌患者相比，低OPRT活性的Ta和T1膀胱癌患者术后无瘤期更长。OPRT与胸腺苷酸合成酶/胸腺苷激酶的活性水平呈正相关，而胸腺苷酸合成酶/胸腺苷激酶是DNA合成过程中的关键酶。膀胱癌细胞中OPRT活性与其对5- fu的敏感性呈正相关。据作者所知，本研究首次证实了膀胱癌组织中OPRT活性水平高于正常膀胱组织，且OPRT活性水平与膀胱癌的分期和分级呈正相关。此外，浅表性膀胱癌患者的高OPRT活性水平预示着早期复发和对5-FU的高敏感性。这些结果提示，OPRT活性水平可作为膀胱癌患者5-FU疗效的预后参数和预测指标，OPRT可能是膀胱癌的分子治疗靶点。(C) 2003年美国癌症协会。
BACKGROUND. 5-Fluorouracil (5-FU), an antitumor agent, is used clinically against a variety of malignancies, including bladder carcinoma. 5-FU is a prodrug, and orotate phosphoribosyltransferase (OPRT) is the principal enzyme that converts 5-F.U directly into an active antitumor metabolite, 5-fluoro-2'-deoxyuridine 5'-monophosphate. In addition, OPRT is the key enzyme in the de novo DNA and RNA synthetic process. To the authors' knowledge, little is known regarding the significance of OPRT in various malignancies, including bladder carcinoma. The authors analyzed the activity levels of OPRT in 60 bladder carcinomas and evaluated the association between the level of OPRT activity and the stage and grade status of bladder carcinoma. They also examined the prognostic significance of OPRT activity in patients with bladder carcinoma and the correlation between OPRT activity levels in bladder carcinoma cells and the sensitivity of those cells to 5-FU.METHODS. OPRT activity levels in nonfixed, fresh-frozen specimens of bladder carcinoma and normal bladder were determined enzymatically using a 5-FU phosphorylation assay. The sensitivity of bladder cells to 5-FU was assessed using a microculture tetrazolium. dye assay.RESULTS. The activity levels of OPRT were approximately 7.5-fold higher in bladder carcinoma specimens compared with the activity levels in normal bladder specimens. OPRT activity in muscle-invasive bladder carcinoma was 2-fold higher compared with the activity in superficial bladder carcinoma (classified as Ta and T1). In addition, the activity of OPRT in T1 bladder carcinoma was 2-fold higher compared with the activity in Ta bladder carcinoma. The level of OPRT activity in Grade 3 bladder carcinoma was 6-fold and 2-fold higher compared with the activity in Grade 1 and Grade 2 bladder carcinoma, respectively. Patients who had Ta and T1 bladder carcinoma with low OPRT activity had a longer postoperative tumor free period compared with patients who had bladder carcinoma with high OPRT activity in the 3-year follow-up. There was a positive association between the activity levels of OPRT and thymidylate synthase/thymidine kinase, which are the key enzymes in the de novo/salvage DNA synthetic process. OPRT activity in bladder carcinoma cells was correlated positively with their sensitivity to 5-FU.CONCLUSIONS. to the authors' knowledge, the current study is the first to demonstrate that OPRT activity levels in bladder carcinoma were higher compared with its activity in the normal bladder tissues and that OPRT activity levels were correlated positively with the stage and grade of bladder carcinoma. In addition, high OPRT activity levels in patients with superficial bladder carcinoma predicted early recurrence and high sensitivity to 5-FU. These results suggest that the level of OPRT activity may be used both as a prognostic parameter and as a predictive indicator for 5-FU efficacy in patients with bladder carcinoma and that OPRT may be a molecular therapeutic target in bladder carcinoma. (C) 2003 American Cancer Society.