Elacytarabine (CP 4055)
(Synonyms: CP 4055) 目录号 : GC34182
Elacytarabine (CP 4055) (CP 4055) 是核苷类似物阿糖胞苷的脂质偶联衍生物。 Elacytarabine (CP 4055) (CP 4055) 是一种在实体瘤中具有细胞毒性的抗肿瘤药物。
Cas No.:188181-42-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Elacytarabine (CP 4055) is a lipid-conjugated derivative of the nucleoside analog cytarabine. Elacytarabine (CP 4055) is an antineoplastic drug with cytotoxicity in solid tumors.
[1]. DiNardo CD, et al. Elacytarabine (CP-4055) in the treatment of acute myeloid leukemia. Future Oncol. 2013 Aug;9(8):1073-82.
| Cas No. | 188181-42-2 | SDF | |
| 别名 | CP 4055 | ||
| Canonical SMILES | CCCCCCCC/C=C/CCCCCCCC(OC[C@H]([C@@H](O)[C@@H]1O)O[C@H]1N2C(N=C(N)C=C2)=O)=O | ||
| 分子式 | C27H45N3O6 | 分子量 | 507.66 |
| 溶解度 | DMSO : 125 mg/mL (246.23 mM) | 储存条件 | Store at -20°C |
| 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 | 1.9698 mL | 9.8491 mL | 19.6982 mL |
| 5 mM | 0.394 mL | 1.9698 mL | 3.9396 mL |
| 10 mM | 0.197 mL | 0.9849 mL | 1.9698 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % 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。
Elacytarabine (CP-4055) in the treatment of acute myeloid leukemia
Future Oncol 2013 Aug;9(8):1073-82.PMID:23902239DOI:10.2217/fon.13.130.
Elacytarabine (formerly CP-4055) is a lipid-conjugated derivative of the nucleoside analog cytarabine. Elacytarabine was rationally designed to circumvent cytarabine resistance related to decreased cellular uptake, due to the ability of the lipophilic drug moiety to enter the cell without the requirement of specialized nuclear transport proteins, including the hENT1. In preclinical and clinical studies, Elacytarabine has demonstrated both safety and efficacy in acute myeloid leukemia (AML), with noteworthy activity among the cytarabine-refractory AML population. Elacytarabine was granted orphan drug designation status from the European Commission in 2007 and from the US FDA in 2008, with a fast-track approval designation from the FDA in 2010. Results of a recent randomized Phase III clinical trial, however, failed to show superiority of Elacytarabine over the investigator's choice of therapy for relapsed or refractory AML.
Induction of resistance to the lipophilic cytarabine prodrug Elacytarabine (CP-4055) in CEM leukemic cells
Nucleosides Nucleotides Nucleic Acids 2010 Jun;29(4-6):394-9.PMID:20544525DOI:10.1080/15257771003741166.
The deoxynucleoside analogs cytarabine (Ara-C) and gemcitabine (dFdC) are widely used in the treatment of cancer. Due to their hydrophilic nature they need the equilibrative (hENT) and concentrative (hCNT) nucleoside transporters to enter the cell. To bypass drug resistance due to decreased uptake, lipophilic 5'elaidic acid esters were synthesized, Elacytarabine (CP-4055, from ara-C) and CP-4126 (from gemcitabine), which are currently in clinical development for solid and hematological tumors. We investigated whether resistance can be induced in vitro, and treated the CEM leukemic cell line with weekly increasing Elacytarabine concentrations, up to 0.28 microM (10 times IC(50)). The IC(50) of the resistant CEM/CP-4055 was 35 microM, about 1,000 times that of the wildtype CEM, and comparable to that of CEM/dCK- (deoxycytidine kinase deficient) (22 microM). CEM/CP-4055 was also cross-resistant to Ara-C, gemcitabine and CP-4126 (28 and 33 microM, respectively). A low level of mRNA dCK was observed, and similar to CEM/dCK-, CEM/CP-4055 did not accumulate Ara-CTP after exposure to Ara-C or Elacytarabine, which is consistent with a deficiency in dCK. In conclusion, Elacytarabine induced resistance similar to Ara-C. This resistance was caused by downregulation of dCK.
Cell cycle effects of fatty acid derivatives of cytarabine, CP-4055, and of gemcitabine, CP-4126, as basis for the interaction with oxaliplatin and docetaxel
Int J Oncol 2010 Jan;36(1):285-94.PMID:19956857doi
To bypass resistance due to limited entry into the cell derivatives of cytarabine (CP-4055, Elacytarabine) and gemcitabine (CP-4126) containing a fatty acid chain at the 5' position of the nucleoside were developed. CP-4055 showed an increased retention of the active metabolite, the triphosphate. This characteristic was supposed to favor combinations, such as with the tubulin antagonist docetaxel, the platinum oxaliplatin and the antifolate pemetrexed. The role of the cell cycle effects of CP-4055 and CP-4126 on the efficacy of the combination with docetaxel or pemetrexed was determined. The combination of CP-4055 with oxaliplatin and docetaxel was also evaluated in a mouse xenograft model. CP-4055 induced a G2/M and S phase accumulation and CP-4126 an S phase accumulation. Both analogs induced a dose-dependent cell kill (apoptosis and necrosis). None of the docetaxel combinations induced a synergistic effect. The combination of docetaxel with CP-4055 or CP-4126 induced a G2/M accumulation in the A549 (lung cancer) cell line, but a G0/G1 accumulation in the WiDR (colon cancer) cell line. Preincubation with docetaxel induced an increased cell kill in both cell lines. The combination with oxaliplatin showed a synergistic effect in both cell lines. Combinations with pemetrexed were antagonistic in both cell lines. In the A549 cell line pemetrexed with CP-4055 led to an increase of the G0/G1 phase and the S phase. In WiDR the combination of pemetrexed with CP-4055 increased the G0/G1 phase and increased the cell kill. Pemetrexed with CP-4126 induced an increase in the G0/G1 phase and the S phase in the A549 cell line. In the xenograft study, on a colon cancer and a lung metastasis model, the combination of CP-4055 with docetaxel showed the best results. Treatment with CP-4055 followed by docetaxel after 4 h resulted in a reduction in metastasis in a lung metastasis model, and a favorable toxicity profile was observed. In conclusion, the combinations with oxaliplatin showed a synergistic effect in the combination studies. Although the combinations with docetaxel did not show an enhanced effect in the in vitro studies, this combination revealed an increased effect in the xenograft model.
A phase I-II study of Elacytarabine (CP-4055) in the treatment of patients with ovarian cancer resistant or refractory to platinum therapy
Cancer Chemother Pharmacol 2011 Nov;68(5):1347-53.PMID:21909644DOI:10.1007/s00280-011-1735-4.
Purpose: Treatment of patients with recurrent ovarian cancer remains a challenge, and there is a need for new and more effective agents. A phase I-II study was designed to determine the recommended dose (RD) and the anti-tumour effect of a prolonged administration of Elacytarabine, the elaidic ester of cytarabine, in patients with refractory/resistant recurrent ovarian cancer. Experimental design: The primary objective of the dose escalation phase I part was to determine the RD for Elacytarabine when given twice for five consecutive days in a 4-week schedule, D1-5 and D8(+2)-12(+2) q4w. Three to six patients were to be enrolled at each dose level. The start dose was Elacytarabine 75 mg/m(2)/day. The phase II part was designed as a two-step study based on response. Results: A total of 28 patients entered the study, 17 patients in the phase I part and 11(#) patients in phase II. Three dose levels were tested: 75 mg/m(2)/day in 3 patients, 100 mg/m(2)/day in 7 + 11(#) patients, and 125 mg/m(2)/day in 7 patients. Three (17.6%) patients in phase I experienced a dose limiting toxicity (DLT), all at the 125 mg/m(2)/day dose level, establishing the lower dose of 100 mg/m(2)/day as the RD. The DLTs were neutropenia grade 4 according to the Common Terminology Criteria for Adverse Events (CTCAE) and thrombocytopenia grade 4 (2 patients), and vomiting grade 2 with hospitalisation and hypokalaemia grade 3 (1 patient). The best response was a clinically meaningful stabilization observed in 3 patients. In two of them, the disease stabilization exceeded the previous platinum-free interval (PFI). Conclusions: The RD for Elacytarabine was 100 mg/m(2)/day, D1-5 and D8-12 q4w. The safety profile was comparable to the safety profiles reported in previous clinical studies with Elacytarabine in solid tumours. Despite some longer-lasting disease stabilisations, two of them exceeding the previous progression-free interval, further investigations of Elacytarabine in the ovarian cancer indication are not warranted.
Metabolism and accumulation of the lipophilic deoxynucleoside analogs Elacytarabine and CP-4126
Invest New Drugs 2012 Oct;30(5):1908-16.PMID:22002019DOI:10.1007/s10637-011-9756-8.
Cytarabine (ara-C) and gemcitabine (dFdC) are commonly used anticancer drugs, which depend on the equilibrative (ENT) and concentrative-nucleoside-transporters to enter the cell. To bypass transport-related drug resistance, lipophilic derivatives Elacytarabine (CP-4055), ara-C-5'elaidic-acid-ester, and CP-4126, (CO 1.01) gemcitabine-5'elaidic-acid-ester, were investigated for the entry into the cell, distribution, metabolism and retention. The leukemic CEM-cell-line and its deoxycytidine-kinase deficient variant (CEM/dCK-) were exposed for 30 and 60 min to the radiolabeled drugs; followed by culture in drug-free medium in order to determine drug retention in the cell. The cellular fractions were analyzed with thin-layer-chromatography and HPLC. Elacytarabine and CP-4126 were converted to the parent compounds both inside and outside the cell (35-45%). The ENT-inhibitor dipyridamole did not affect their uptake or retention. Inside the cell Elacytarabine and CP-4126 predominantly localized in the membrane and cytosolic fraction, leading to a long retention after removal of the medium. In contrast, in cells exposed to the parent drugs ara-C and dFdC, intracellular drug concentration increased during exposure but decreased to undetectable levels after drug removal. In the dCK- cell line, no metabolism was observed. The concentrations of ara-CTP and dFdCTP reached a peak at the end of the incubation with the drugs, and decreased after drug removal; peak levels of dFdCTP were 35 times higher than ara-CTP and was retained better. In contrast, after exposure to Elacytarabine or CP-4126, ara-CTP and dFdCTP levels continued to increase not only during exposure but also during 120 min after removal of the Elacytarabine and CP-4126. Levels of ara-CTP and dFdCTP were higher than after exposure to the parent drugs. In conclusion, the lipophilic derivatives Elacytarabine and CP-4126 showed a nucleoside-transporter independent uptake, with long retention of the active nucleotides. These lipophilic nucleoside analogues are new chemical entities suitable for novel clinical applications.