INTESTINAL TOXICITY OF 5-FLUOROURACIL AND LEUCOVORIN

5-氟尿嘧啶和亚叶酸的肠道毒性

• 批准号: 3185592
• 负责人: Jessie L.-S. Au
• 金额: $ 7.12万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-05-01 至 1991-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3185592
• 关键词: 5 fluorouridine; cell growth regulation; cytotoxicity; drug adverse effect; drug metabolism; floxuridine; fluorouracil; folate; gastrointestinal epithelium; intestine disorder; laboratory rat; leucovorin; neoplasm /cancer pharmacology; rectum neoplasms; thymidine; thymidylate synthase; uridine

This investigation is to examine the toxicity of 5-fluorouracil (FU) and leucovorin (LV) to intestinal epithelial cells. The antitumor activity of FU is due to the incorporation of its anabolite 5- fluorouridine triphosphate (FUTP) into fradulent RNA, and to its other anabolite 5-fluorodeoxyuridylate (FdUMP) which inhibits the synthesis of thymidylate and DNA by forming a ternary complex with the enzyme thymidylate synthase (TS) and the cofactor N-5, 10-methylenetetrahydrofolate (CH2-THF). In some tumor cells, folate analogues by increasing the intracellular CH2-THF concentration enhanced the TS inhibition and cytotoxicity of FU. Phase I-II trials of FU and LV showed that LV significantly improved the response rate of FU in gastric and colorectal cancers, but also potentiated its intestinal toxicity. Anticancer drugs cause intestinal toxicity by inhibiting the mitosis of the proliferating intestinal epithelial crypt cells. The crypt cell kill and recovery is determined by the concentration and duration of tissue exposure to the drug (AUC). The ongoing phase III trials use 10 vastly different regimens of FU and LV, which produce in the intestinal cells different drug AUC's and therefore likely different toxicity to patients. The objectives of this study are to examine the cellular metabolism, pharmacodynamics and mechanism of FU toxicity to the intestinal crypt cells, and the interaction between FU and folates. Preliminary studies, using our newly established cultured intestinal crypt (RIEC) cells derived from normal adult rats, showed that FU was incorporated into RNA, inhibited DNA synthesis and cell growth. The following studies will be done using the RIEC cells. 1. Define the relationship between the cytotoxicity and the AUC of FU alone and FU-folates, using the therapeutic/toxic AUC's from phase III FU-LV protocols. 2. Establish the mechanism of FU toxicity by examining its intracellular metabolism, DNA (inhibition of DNA synthesis) and RNA (incorporation into RNA) effcts, and the modulation of its activity by thymidine and uridine. 3. Compare the kinetics of TS inhibition with those of FdUMP and dUMP. 4. Assess the effects of folates. The proposed studies are expected to illustrate the pharmacology of FU and folates in the intestinal crypt cells, and the reversibility of drug toxicity by thymidine and/or uridine. The comparative cytotoxicity of different AUC's of FU-folates may indicate the relative intestinal toxicity of the different phase III FU-LV regimens.

本研究旨在检测5-氟尿嘧啶(FU)的毒性。 和亚叶酸钙(LV)对肠上皮细胞的作用。抗肿瘤药物 FU的活性是由于其合成代谢产物5-氟尿嘧啶的结合。 将三磷酸氟尿苷(FUTP)转化为FUTP，并将其转化为FUTP 其他合成代谢产物5-氟脱氧尿苷(FdUMP)，它抑制 三元络合物合成胸苷和DNA 在胸苷合成酶(TS)和辅因子N-5的作用下， 10-亚甲基四氢叶酸(CH2-THF)。在一些肿瘤细胞中， 增加细胞内CH2-THF的叶酸类似物 浓度可增强FU对TS的抑制作用和细胞毒作用。 FU和LV的I-II期试验显示LV显著 提高FU在胃、结直肠的有效率 但也增强了它的肠道毒性。抗癌 药物通过抑制细胞有丝分裂而引起肠道毒性 增殖的肠上皮隐窝细胞。隐窝细胞杀伤力 而回收率则取决于浓度和持续时间。 组织暴露于药物(AUC)。正在进行的第三阶段试验 使用10种截然不同的FU和LV方案，这两种方案在 肠道细胞不同的药物AUC，因此很可能 对患者有不同的毒性。这项研究的目的是 检查细胞代谢、药效学和 氟尿嘧啶对肠道隐窝细胞的毒性机制 氟尿嘧啶与叶酸的相互作用。初步研究，使用 我们新建立的培养的肠腺(RIEC)细胞 取自正常成年大鼠，表明FU被掺入 转化为RNA，抑制DNA合成和细胞生长。以下是 研究将使用RIEC细胞进行。1.定义 单药氟尿嘧啶的细胞毒性与AUC的关系 和氟叶酸，使用III期的治疗性/毒性AUC FU-LV协议。2.通过以下途径建立FU的毒性机制 检测其细胞内代谢，DNA(DNA抑制 合成)和RNA(结合到RNA中)的效果，以及 胸苷和尿苷对其活性的调节。3.比较 TS的抑制动力学与FdUMP和DUMP相同。4. 评估叶酸的影响。拟议的研究是可望完成的 说明氟尿嘧啶和叶酸在肠道的药理作用 隐窝细胞和胸腺嘧啶核苷对药物毒性的可逆性 和/或尿苷。不同AUC的细胞毒性比较 FU-叶酸的相对肠道毒性可能表明 不同的III期FU-LV方案。

项目成果

Effect of uridine coadministration on 5'-deoxy-5-fluorouridine disposition in rats.

尿苷联合给药对大鼠 5-脱氧-5-氟尿苷处置的影响。

• DOI: 10.1007/bf00254172
• 发表时间: 1988
• 期刊: Cancer chemotherapy and pharmacology
• 影响因子: 3
• 作者: Au,JL;Wientjes,MG;Bramer,SL
• 通讯作者: Bramer,SL

Effects of 5-fluorouracil, leucovorin, and glucarate in rat colon-tumor explants.

5-氟尿嘧啶、亚叶酸和葡萄糖二酸盐对大鼠结肠肿瘤外植体的影响。

• DOI: 10.1007/bf00686481
• 发表时间: 1992
• 期刊: Cancer chemotherapy and pharmacology
• 影响因子: 3
• 作者: Schmittgen,TD;Koolemans-Beynen,A;Webb,TE;Rosol,TJ;Au,JL
• 通讯作者: Au,JL

Extraction of intracellular nucleosides and nucleotides with acetonitrile.

• DOI: 10.1093/clinchem/35.1.48
• 发表时间: 1989
• 期刊: Clinical chemistry
• 影响因子: 9.3
• 作者: J. L. Au;M. Su;M. Wientjes