Fluorouracil (Adrucil)
(Synonyms: 5-氟脲嘧啶; 5-FU) 目录号 : GC14466
A prodrug form of FdUMP
Cas No.:51-21-8
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.00%
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| Cell experiment [1]: | |
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Cell lines |
HCT116 parental cell line (ATCC CCL247) and HCT116 ContinB and ContinD resistant derivatives (all wild-type TP53 cell lines) |
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Preparation Method |
770 µM Fluorouracil (Adrucil) (5-FU) was added to the media 24 hours after seeding. Cells were harvested by trypsinization or scraping at 0, 8, and 24 hours after addition of 5-FU to the culture medium. Control wells received no Fluorouracil (Adrucil). |
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Reaction Conditions |
770µM for 0, 8, and 24 hours |
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Applications |
Cells were treated with Fluorouracil (Adrucil) (5-FU) for 24 hours and followed for up to 40 days in drug-free medium. After day 7, the cell counts for ContinD increased steadily, the cell counts for ContinB and parental cultures began to increase after about 15 and 20 days, respectively. |
| Animal experiment [2]: | |
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Animal models |
Male C57BL/6 mice, azoxymethane/dextran sodium sulfate (AOM/DSS) model of CRC |
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Preparation Method |
Fluorouracil (Adrucil) (5-FU) was dissolved in sterile PBS, pH7.4 and then sterile filtered through a 0.2µm syringe filter. Fluorouracil was administered in 3 cycles; cycle 1: 40mg/kg, cycle 2 and 3: 20mg/kg via intraperitoneal injection. Fluorouracil was prepared fresh at the beginning of each cycle. Sterile filtered PBS alone was used as the vehicle control. Each cycle consisted of 5 consecutive days of injections followed by 9days of recovery. The treatment period lasted for 5weeks and mice were sacrificed 24 hr after the final injection of the third cycle. |
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Dosage form |
Intraperitoneal injection, 40mg/kg and 20mg/kg |
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Applications |
Fluorouracil reduces tumor burden but decreases survival in AOM/DSS mice. |
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References: [1]: De Angelis P M, Svendsrud D H, Kravik K L, et al. Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery[J]. Molecular cancer, 2006, 5(1): 1-25. |
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Fluorouracil (Adrucil) (5-FU) is an analogue of uracil with a fluorine atom at the C-5 position in place of hydrogen [1]. Fluorouracil is widely used in the treatment of a range of cancers, including colorectal and breast cancers, and cancers of the aerodigestive tract [1].
The mechanism of cytotoxicity of Fluorouracil (Adrucil) has been ascribed to the misincorporation of fluoronucleotides into RNA and DNA and to the inhibition of the nucleotide synthetic enzyme thymidylate synthase (TS) [1]. Fluorouracil (Adrucil) at the concentration of 770µM treated HCT116 parental cell line and its 5-FU-resistant derivatives, Fluorouracil (Adrucil) led to a G1(/S) arrest at 8 and 24 hours [2]. The G1 arrest was most pronounced in ContinD cells at 24 hours, whereas the S phase arrest was most pronounced in parental HCT116 cells at 24 hours [3].
Fluorouracil (Adrucil) beneficial effected in intestinal tumorigenesis in the Apcmin/+ mice model where a 60-80% reduction in polyps [4]. Fluorouracil (Adrucil) reduces body weight, exacerbates symptom severity score, increases liver weight, and decreases epididymal fat mass, and decrease in survival [5].
References:
[1]. Longley D B, Harkin D P, Johnston P G. 5-fluorouracil: mechanisms of action and clinical strategies[J]. Nature reviews cancer, 2003, 3(5): 330-338.
[2]. Takeda H, Haisa M, Naomoto Y, Kawashima R, Satomoto K, Yamatuji T, Tanaka N: Effect of 5-fluorouracil on cell cycle regulatory proteins in human colon cancer cell line. Jpn J Cancer Res. 1999, 90: 677-684.
[3]. De Angelis P M, Svendsrud D H, Kravik K L, et al. Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery[J]. Molecular cancer, 2006, 5(1): 1-25.
[4]. J.M. Tucker, C. Davis, M.E. Kitchens, et al. Response to 5-fluorouracil chemotherapy is modified by dietary folic acid deficiency in Apc(Min/+) mice. Cancer Lett., 187 (2002), pp. 153-162
[5]. Sougiannis A T, VanderVeen B N, Enos R T, et al. Impact of 5 fluorouracil chemotherapy on gut inflammation, functional parameters, and gut microbiota[J]. Brain, behavior, and immunity, 2019, 80: 44-55.
氟尿嘧啶 (Adrucil) (5-FU) 是尿嘧啶的类似物，在 C-5 位置用氟原子代替氢 [1]。氟尿嘧啶广泛用于治疗多种癌症，包括结直肠癌、乳腺癌和呼吸消化道癌症[1]。
氟尿嘧啶的细胞毒性作用机制（ Adrucil) 归因于氟核苷酸错误掺入 RNA 和 DNA 以及核苷酸合成酶胸苷酸合酶 (TS) [1] 的抑制。浓度为 770&88888181 的氟尿嘧啶 (Adrucil)；M 处理 HCT116 亲本细胞系及其 5-FU 抗性衍生物，氟尿嘧啶 (Adrucil) 在 8 小时和 24 小时导致 G1(/S) 停滞 [2]< /sup>。在 24 小时时，ContinD 细胞中的 G1 期停滞最明显，而在 24 小时时亲代 HCT116 细胞中的 S 期停滞最明显[3]。
氟尿嘧啶 (Adrucil)在 Apcmin/+ 小鼠模型中对肠道肿瘤发生产生有益影响，其中息肉减少 60-80% [4]。氟尿嘧啶 (Adrucil) 可减轻体重，加重症状严重程度评分，增加肝脏重量，减少附睾脂肪量，并降低生存率[5]。
| Cas No. | 51-21-8 | SDF | |
| 别名 | 5-氟脲嘧啶; 5-FU | ||
| 化学名 | 5-fluoro-1H-pyrimidine-2,4-dione | ||
| Canonical SMILES | C1=C(C(=O)NC(=O)N1)F | ||
| 分子式 | C4H3FN2O2 | 分子量 | 130.1 |
| 溶解度 | ≥ 6.5 mg/mL in DMSO, ≥ 10.04 mg/mL in Water with ultrasonic and warming | 储存条件 | 4°C, protect from light |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 7.6864 mL | 38.432 mL | 76.864 mL |
| 5 mM | 1.5373 mL | 7.6864 mL | 15.3728 mL |
| 10 mM | 0.7686 mL | 3.8432 mL | 7.6864 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Clinical pharmacology of 5-fluorouracil
Clin Pharmacokinet1989 Apr;16(4):215-37.PMID: 2656050DOI: 10.2165/00003088-198916040-00002
5-Fluorouracil, first introduced as a rationally synthesized anticancer agent 30 years ago, continues to be widely used in the management of several common malignancies including cancer of the colon, breast and skin. This drug, an analogue of the naturally occurring pyrimidine uracil, is metabolised via the same metabolic pathways as uracil. Although several potential sites of antitumour activity have been identified, the precise mechanism of action and the extent to which each of these sites contributes to tumour or host cell toxicity remains unclear. Several assay methods are available to quantify 5-fluorouracil in serum, plasma and other biological fluids. Unfortunately, there is no evidence that plasma drug concentrations can predict antitumour effect or host cell toxicity. The recent development of clinically useful pharmacodynamic assays provides an attractive alternative to plasma drug concentrations, since these assays allow the detection of active metabolites of 5-fluorouracil in biopsied tumour or normal tissue. 5-Fluorouracil is poorly absorbed after oral administration, with erratic bioavailability. The parenteral preparation is the major dosage form, used intravenously (bolus or continuous infusion). Recently, studies have demonstrated the pharmacokinetic rationale and clinical feasibility of hepatic arterial infusion and intraperitoneal administration of 5-fluorouracil. In addition, 5-fluorouracil continues to be used in topical preparations for the treatment of malignant skin cancers. Following parenteral administration of 5-fluorouracil, there is rapid distribution of the drug and rapid elimination with an apparent terminal half-life of approximately 8 to 20 minutes. The rapid elimination is primarily due to swift catabolism of the liver. As with all drugs, caution should be used in administering 5-fluorouracil in various pathophysiological states. In general, however, there are no set recommendations for dose adjustment in the presence of renal or hepatic dysfunction. Drug interactions continue to be described with other antineoplastic drugs, as well as with other classes of agents.
Effects of 5-FU
Adv Exp Med Biol2010;678:157-64.PMID: 20738018DOI: 10.1007/978-1-4419-6306-2_20
5-fluorouracil (5-FU) is a chemotherapeutical agent used to treat cancers including breast and colorectal. Working as an antimetabolite to prevent cell proliferation, it primarily inhibits the enzyme thymidylate synthase blocking the thymidine formation required for DNA synthesis. Although having a relatively short half-life (< 30 mins) it readily enters the brain by passive diffusion. Clinically, it is used both as a single agent or in combination with other chemotherapies and has been associated with the long-term side effects of cognitive impairment, known as "chemo brain" or "chemo fog" These accounts have come primarily from patients undergoing treatment for breast cancer who report symptoms including confusion and memory impairment, which can last for months to years. Psychometric studies of patients have suffered from confounding variables, which has led to the use of rodent models to assess the cognitive effects of this drug. Researchers have used behavioral and physiological tests including the Morris water maze, novel object location/recognition tests, shock motivated T-maze, sensory gating and conditioning, to investigate the effect of this drug on cognition. The variety of cognitive tests and the difference in dosing and administration of 5-FU has led to varied results, possibly due to the different brain regions associated with each test and the subtlety of the drug's effect, but overall these studies indicates that 5-FU has a negative effect on memory, executive function and sensory gating. 5-FU has also been demonstrated to have biochemical and structural changes on specific regions of the brain. Evidence shows it can induce apoptosis and depress cell proliferation in the neurogenic regions of the adult brain including the sub granular zone (SGZ) within the hippocampus and in oligodendrocyte precursor populations within white matter tracts. Furthermore, investigations indicate levels ofdoublecortin, a marker for newly formed neurons and brain derived neurotrophic factor, a cell survival modulator, are also reduced by 5-FU in the SGZ. Thus, 5-FU appears to have a lasting negative impact on cognition and to affect cellular and biochemical markers in various brain regions. Further work is needed to understand the exact mechanisms involved and to devise strategies for the prevention or recovery from these symptoms.
5-Fluorouracil-associated cardiotoxicity
Cancer1988 Jan 1;61(1):36-45.PMID: 3275485DOI: 10.1002/1097-0142(19880101)61:1<36::aid-cncr2820610108>3.0.co;2-6
Cardiotoxicity manifested as myocardial ischemia is not generally recognized as a side effect of 5-fluorouracil. However, there have been at least 35 cases reported since 1975. In only one of these cases was a somewhat detailed evaluation done to rule out underlying coronary disease. The case reported here of 5-FU cardiotoxicity included an extensive cardiac evaluation to rule out underlying coronary disease and to assess spasm. The literature on 5-FU cardiotoxicity is also reviewed, and its possible mechanisms are analyzed.
Fluorouracil: biochemistry and pharmacology
J Clin Oncol1988 Oct;6(10):1653-64.PMID: 3049954DOI: 10.1200/JCO.1988.6.10.1653
Fluorouracil (5FU) is still considered the most active antineoplastic agent in the treatment of advanced colorectal cancer. The drug needs to be converted to the nucleotide level in order to exert its effect. It can be incorporated into RNA leading to interference with the maturation of nuclear RNA. However, its conversion to 5-fluoro-2'deoxy-5' monophosphate (FdUMP) leading to inhibition of thymidylate synthase (TS) and subsequently of DNA synthesis, is considered to be its main mechanism of action. In the presence of a folate cofactor a covalent ternary complex is formed, the stability of which is the main determinant of the action of 5FU. Resistance against 5FU can be mainly attributed to aberrations in its metabolism or to alterations of TS, eg, gene amplification, altered kinetics in respect to nucleotides or folates. Biochemical modulation of 5FU metabolism can be applied to overcome resistance against 5FU. A variety of normal purines, pyrimidines, and other antimetabolites have been studied in this respect, but only some of them have been clinically successful. Delayed administration of uridine has recently been shown to "rescue" mice and patients from toxicity, while pretreatment with leucovorin is the most promising combination to enhance the therapeutic efficacy. 5FU is frequently administered in an intravenous (IV) injection, and shows a rapid distribution and a triphasic elimination. The nonlinearity of 5FU pharmacokinetics is related to saturation of its degradation. Continuous infusion of 5FU led to different kinetics. Regional administration, such as hepatic artery infusion, offers a way to achieve higher drug concentrations in liver metastases and is accompanied by lower systemic concentration. The current status of the biochemical and pharmacokinetic data is reviewed.
Fluorouracil-induced Hyperammonemia in a Patient with Colorectal Cancer
Anticancer Res2015 Dec;35(12):6761-3.PMID: 26637893DOI: 10.1097/00001622-199212000-00014
Fluorouracil (5-FU; Adrucil?) is a pyrimidine analog antineoplastic chemotherapy agent which works by interfering with DNA and RNA synthesis. It has an uncommon toxicity called hyperammonemic encephalopathy. This neurotoxicity is associated with a high-dose administration of 5-FU (2,600 mg/m(2)/week), with an incidence rate of 5.7%, and is not normally seen with the current dose of 1,200 mg/m(2) infused over 46 h. The mechanism behind this neurotoxicity is not known but is possibly due to accumulation of fluorocitrate, a byproduct of 5-FU metabolism. This by-product inhibits the Krebs cycle, which causes impairment of the adenosine triphosphate-dependent urea cycle. By impairing this cycle, ammonia is not converted to urea, which in turn this leads to an accumulation of ammonia. The accumulated ammonia in the brain is metabolized to glutamine, which has been suggested to cause an increase in intracranial pressure and cerebral edema. This case report discusses how a 40-year-old male with colorectal cancer experienced 5FU-induced hyperammonemia and was treated for it and how reducing the dose by 50% led to resolution of this symptom from reoccurring.