5 -氟尿嘧啶:药理范式的使用细胞毒性。
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托马斯•DM Zalcberg JR .
5 -氟尿嘧啶:药理范式的使用细胞毒性。
Exp杂志杂志》1998;11月25 (11):887 - 95。
- PubMed ID
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9807659 (在PubMed]
- 文摘
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1。艰苦的药物开发的进展也说明了5 -氟尿嘧啶(5 fu), 40年前最初设计的氟化模拟天然基尿嘧啶。创新药代动力学和药效学策略显著的临床改善癌症患者在过去的十年。2。5 -氟尿嘧啶行为的三个主要机制。总之,中间代谢物fluorodeoxyuridine一磷酸抑制嘧啶生物合成的关键酶,即thymidylate合成酶(TS)。此外,5 fu是代谢日博deoxy-ribonucleotides,充当假并入RNA和DNA的基地。3所示。Biomodulation 5 fu一直试图与甲氨蝶呤(MTX)、叶酸、干扰素、顺铂和放射治疗。甲氨蝶呤增强5 -氟尿嘧啶的行为通过抑制二氢叶酸还原酶和减少所需的叶酸池嘧啶生物合成,抑制TS通过MTX-polyglutamate和直接抑制嘌呤生物合成。 Interferons increase steady state concentrations of 5FU. 5-Fluorouracil enhances the cytotoxicity of cisplatin and radiotherapy by inhibiting DNA repair. Folinic acid enhances TS inhibition by increasing the intracellular pool of folates that stabilize the 5FU-TS complex. 4. 5-Fluorouracil has a short plasma half-life. Thymidylate synthase inhibition is limited to the S-phase of the cell cycle and only a small fraction of most cancer cells are in S-phase at any one time. Increased response rates seen with infusional protocols may reflect the effective recruitment of additional mechanisms of cytotoxicity, not dependent on cell cycle, including effects on RNA synthesis. 5. Patients with localized metastatic disease may benefit from locoregional treatments. These include hepatic intra-arterial therapy with related compounds, such as floxuridine, which reach high concentrations at sites of tumour, while systemic toxicities are minimized by efficient hepatic clearance. 6. Recent developments include orally bioavailable formulations, such as ftorafur, capecitabine and the combination of 5FU with the dihydropyrimidine phosphate dehydrogenase inhibitor ethynyluracil. Recognition of diurnal variation in the activity of such key enzymes as DPD has led to the administration of 5FU at regulated, variable infusion rates (chronomodulation). These promising pharmacological approaches may further improve clinical outcomes in common cancers.