Petty Russell D, Cassidy J
Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, UK.
Curr Cancer Drug Targets. 2004 Mar;4(2):191-204. doi: 10.2174/1568009043481533.
The fluoropyrimidines were first synthesised nearly 50 years ago as rationally designed anti-cancer agents. Their target was pyrimidine and hence DNA synthesis. 5-Fluorouracil has been the most extensively used in a wide variety of malignancies. In more recent years a fuller understanding of the pharmacokinetics of these agents has lead to their utilisation as more effective and versatile anti-cancer drugs than might have been initially envisaged. This in part has occurred due to recognition of the schedule dependency of efficacy of 5-FU and modulation of its activity by leucovorin. However the development of novel fluropyrimidines such as capcetabine, UFT, and eniluracil which can be administered orally, has offered equal if not superior efficacy with improved tolerability and patient acceptance. It is now recognised that enzyme polymorphism's and heterogeneity of expression of key molecules are important determinants of the pharmacokinetic handling and pharmacodynamic effects of these drugs in individual patients. Further characterisation of such inter-individual and inter-tumoral variability, for example in enzymes such as DPD and thymidine phosphorylase is ongoing. This work offers the promise of improvements in efficacy and tolerability by the process of individualisation of chemotherapy (for both patient and tumour). In contrast to the advances made in the understanding of the pharmacokinetics, less progress has been made in Fluropyrimidine pharmacodynamics. The inhibition of thymidylate synthetase by dFUMP and thereby dTMP and DNA synthesis is thought to be the critical mechanism. The incorporation of FUTP and dFUTP into RNA and DNA are also postulated to be of importance. While these events have been well defined, exactly how they lead to cell death is less clearly understood. Similarly, the mechanism of selective cancer cell cytotoxicity is not well understood. Pharmacokinetics and cell cycle kinetics provide a partial explanation. There is some evidence to suggest that the most important factor in determining cytotoxicity is the cellular response to fluoropyrimidine induced biochemical abnormalities rather than the lesions themselves. In this hypothesis the difference in response between normal and cancer cells is of critical importance. Further improvements in efficacy and tolerability could be made by elucidation of the molecular mechanisms behind this process. This knowledge in combination with the advances already made (and ongoing) in pharmacokinetics may allow the full potential of fluoropyrimidines as anti-cancer agents to be realised in the future.
氟嘧啶近50年前首次合成，是经过合理设计的抗癌药物。它们的作用靶点是嘧啶，从而影响DNA合成。5-氟尿嘧啶在多种恶性肿瘤中应用最为广泛。近年来，对这些药物药代动力学的更深入了解使其成为比最初设想更有效、更具通用性的抗癌药物。这部分是由于认识到5-氟尿嘧啶疗效的给药方案依赖性以及亚叶酸对其活性的调节。然而，新型氟嘧啶如卡培他滨、优福定和依诺尿嘧啶的开发，这些药物可以口服，其疗效即使不优于也等同于传统药物，且耐受性和患者接受度有所提高。现在人们认识到，酶多态性和关键分子表达的异质性是这些药物在个体患者中药代动力学处理和药效学效应的重要决定因素。对这种个体间和肿瘤间变异性的进一步表征，例如对二氢嘧啶脱氢酶和胸苷磷酸化酶等酶的研究正在进行。这项工作有望通过化疗个体化（针对患者和肿瘤）来提高疗效和耐受性。与在药代动力学理解方面取得的进展相比，氟嘧啶药效学方面的进展较少。dFUMP对胸苷酸合成酶的抑制以及由此导致的dTMP和DNA合成被认为是关键机制。FUTP和dFUTP掺入RNA和DNA也被假定具有重要意义。虽然这些事件已经得到明确界定，但它们究竟如何导致细胞死亡尚不清楚。同样，选择性癌细胞细胞毒性的机制也未得到很好的理解。药代动力学和细胞周期动力学提供了部分解释。有证据表明，决定细胞毒性的最重要因素是细胞对氟嘧啶诱导的生化异常的反应，而不是损伤本身。在这个假设中，正常细胞和癌细胞之间反应的差异至关重要。通过阐明这一过程背后的分子机制，可以进一步提高疗效和耐受性。这些知识与药代动力学方面已经取得（以及正在取得）的进展相结合，可能会在未来实现氟嘧啶作为抗癌药物的全部潜力。
