Ropidoxuridine (IPdR)
(Synonyms: 1-(2-脱氧-beta-呋喃核糖基)-5-碘-2-嘧啶酮,IPdR) 目录号 : GC34191
Ropidoxuridine (IPdR) (IPdR) 是一种新型的口服卤代胸苷类似物，是一种用于人类肿瘤的潜在放射增敏剂。
Cas No.:93265-81-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Ropidoxuridine (IPdR) is a novel orally available, halogenated thymidine analog and is a potential radiosensitizer for use in human tumors.
Ropidoxuridine is an orally bioavailable pro-drug of IUdR (5-iodo-2'-deoxyuridine). Ropidoxuridine demonstrates strong synergy effects with Alisertib at clinically relevant concentrations[1].
In an orthotopic tumor model, Ropidoxuridine (750 mg/kg/day) and Alisertib (30 mg/kg/day) demonstrate strong synergy effects[1].
[1]. Rampurwala MM, et al. Ropidoxuridine (IPdR) potentiates alisertib (MLN8237) activity in triple-negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-16.
| Cas No. | 93265-81-7 | SDF | |
| 别名 | 1-(2-脱氧-beta-呋喃核糖基)-5-碘-2-嘧啶酮,IPdR | ||
| Canonical SMILES | O=C1N=CC(I)=CN1[C@H]2C[C@H](O)[C@@H](CO)O2 | ||
| 分子式 | C9H11IN2O4 | 分子量 | 338.1 |
| 溶解度 | Soluble in DMSO | 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 | 2.9577 mL | 14.7885 mL | 29.577 mL |
| 5 mM | 0.5915 mL | 2.9577 mL | 5.9154 mL |
| 10 mM | 0.2958 mL | 1.4789 mL | 2.9577 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。
IPdR: a novel oral radiosensitizer
Expert Opin Investig Drugs 2007 Sep;16(9):1415-24.PMID:17714027DOI:10.1517/13543784.16.9.1415.
IPdR (5-iodo-2-pyrimidinone-2'-deoxyribose) is a novel orally available, halogenated thymidine (TdR) analog and is a potential radiosensitizer for use in human tumors, such as rectal, pancreas, sarcoma and glioma tumors. IPdR is a prodrug that is efficiently converted to IUdR (5-iodo-2'-deoxyuridine), an intravenous radiosensitizer by a hepatic aldehyde oxidase, resulting in high IPdR and IUdR plasma levels in mice for > or = 1 h after oral IPdR. Athymic mice tolerated oral IPdR to doses up to 1500 mg/kg/day t.i.d. for 6 - 14 days without significant systemic toxicities. A number of in vivo preclinical studies have demonstrated that IPdR is a superior radiosensitizer compared with IUdR given as a continuous infusion in terms of safety and efficacy with a significantly lower toxicity profile, including gastrointestinal and hematologic side effects. A preclinical study has shown that IPdR is effective in inducing human colon cancer xenograft radiosensitization in drug-resistant DNA mismatch repair-proficient and -deficient tumor models, as well as in human globlastoma xenograft. In anticipation of performing a clinical Phase I trial in humans, investigators also studied the drug pharmacokinetics and host toxicities in two non-rodent, animal species during a 14-day treatment course. Dose-limiting systemic toxicities (diarrhea, emesis, weight loss and decreased motor activity) were observed in ferrets receiving IPdR at 1500 mg/kg/day on a 14-day schedule that were not found previously in athymic mice. Recently, a once-daily IPdR dosing up to 2000/mg/kg for 28 days in Fischer-344 rats showed reversible mild-to-moderate systemic toxicities without any severe or life-threatening toxicities. However, in all preclinical toxicity studies so far, no significant hematologic, biochemical or histopathologic changes have been found. Hepatic aldehyde oxidase activity was reduced in a dose-dependent fashion in the ferret liver, suggesting partial enzyme inactivation by this IPdwR schedule, but that is not found in Fischer-344 rats. The plasma pharmacokinetic profile in Rhesus monkeys showing biexponential clearance are similar to previously published data in athymic mice. In this paper, the authors review the development, mechanism of action, preclinical data and rationale for clinical studies.
Phase I and Pharmacology Study of Ropidoxuridine (IPdR) as Prodrug for Iododeoxyuridine-Mediated Tumor Radiosensitization in Advanced GI Cancer Undergoing Radiation
Clin Cancer Res 2019 Oct 15;25(20):6035-6043.PMID:31337643DOI:10.1158/1078-0432.CCR-19-0862.
Purpose: Iododeoxyuridine (IUdR) is a potent radiosensitizer; however, its clinical utility is limited by dose-limiting systemic toxicities and the need for prolonged continuous infusion. 5-Iodo-2-pyrimidinone-2'-deoxyribose (IPdR) is an oral prodrug of IUdR that, compared with IUdR, is easier to administer and less toxic, with a more favorable therapeutic index in preclinical studies. Here, we report the clinical and pharmacologic results of a first-in-human phase I dose escalation study of IPdR + concurrent radiation therapy (RT) in patients with advanced metastatic gastrointestinal (GI) cancers. Patients and methods: Adult patients with metastatic GI cancers referred for palliative RT to the chest, abdomen, or pelvis were eligible for study. Patients received IPdR orally once every day × 28 days beginning 7 days before the initiation of RT (37.5 Gy in 2.5 Gy × 15 fractions). A 2-part dose escalation scheme was used, pharmacokinetic studies were performed at multiple time points, and all patients were assessed for toxicity and response to Day 56. Results: Nineteen patients were entered on study. Dose-limiting toxicity was encountered at 1,800 mg every day, and the recommended phase II dose is 1,200 mg every day. Pharmacokinetic analyses demonstrated achievable and sustainable levels of plasma IUdR ≥1 μmol/L (levels previously shown to mediate radiosensitization). Two complete, 3 partial, and 9 stable responses were achieved in target lesions. Conclusions: Administration of IPdR orally every day × 28 days with RT is feasible and tolerable at doses that produce plasma IUdR levels ≥1 μmol/L. These results support the investigation of IPdR + RT in phase II studies.
5-iodo-2-pyrimidinone-2'-deoxyribose-mediated cytotoxicity and radiosensitization in U87 human glioblastoma xenografts
Int J Radiat Oncol Biol Phys 2007 Nov 15;69(4):1254-61.PMID:17967315DOI:10.1016/j.ijrobp.2007.08.004.
Purpose: 5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) is a novel orally administered (p.o.) prodrug of 5-iododeoxyuridine. Because p.o. IPdR is being considered for clinical testing as a radiosensitizer in patients with high-grade gliomas, we performed this in vivo study of IPdR-mediated cytotoxicity and radiosensitization in a human glioblastoma xenograft model, U87. Methods and materials: Groups of 8 or 9 athymic male nude mice (6-8 weeks old) were implanted with s.c. U87 xenograft tumors (4 x 10(6) cells) and then randomized to 10 treatment groups receiving increasing doses of p.o. IPdR (0, 100, 250, 500, and 1000 mg/kg/d) administered once daily (q.d.) x 14 days with or without radiotherapy (RT) (0 or 2 Gy/d x 4 days) on days 11-14 of IPdR treatment. Systemic toxicity was determined by body weight measurements during and after IPdR treatment. Tumor response was assessed by changes in tumor volumes. Results: IPdR alone at doses of > or =500 mg/kg/d resulted in moderate inhibition of tumor growth. The combination of IPdR plus RT resulted in a significant IPdR dose-dependent tumor growth delay, with the maximum radiosensitization using > or =500 mg/kg/d. IPdR doses of 500 and 1000 mg/kg/d resulted in transient 5-15% body weight loss during treatment. Conclusions: In U87 human glioblastoma s.c. xenografts, p.o. IPdR given q.d. x 14 days and RT given 2 Gy/d x 4 days (days 11-14 of IPdR treatment) results in a significant tumor growth delay in an IPdR dose-dependent pattern. The use of p.o. IPdR plus RT holds promise for Phase I/II testing in patients with high-grade gliomas.
First-in-human phase 0 trial of oral 5-iodo-2-pyrimidinone-2'-deoxyribose in patients with advanced malignancies
Clin Cancer Res 2013 Apr 1;19(7):1852-7.PMID:23403637DOI:10.1158/1078-0432.CCR-12-3118.
Purpose: Iododeoxyuridine (IdUrd), a halogenated nucleoside analog, produced clinical responses when administered as a radiosensitizer via continuous intravenous (c.i.v.) infusion over the course of radiotherapy. We conducted a phase 0 trial of 5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR), an oral prodrug of IdUrd, in patients with advanced malignancies to assess whether the oral route was a feasible alternative to c.i.v. infusion before embarking on large-scale clinical trials. Plasma concentrations of IPdR, IdUrd, and other metabolites were measured after a single oral dose of IPdR. Experimental design: Eligible patients had advanced refractory malignancies. A single oral dose of IPdR was administered per patient and patients were followed for 14 days for safety assessments; dose escalations were planned (150, 300, 600, 1,200, and 2,400 mg) with one patient per dose level and 6 patients at the highest dose level. Blood sampling was conducted over a 24-hour period for pharmacokinetic analysis. Results: There were no drug-related adverse events. Plasma concentrations of IdUrd generally increased as the dose of IPdR escalated from 150 to 2,400 mg. All patients at the 2,400 mg dose achieved peak IdUrd levels of (mean ± SD) 4.0 μmol/L ± 1.02 μmol/L at 1.67 ± 1.21 hours after IPdR administration. Conclusions: Adequate plasma levels of IdUrd were obtained to justify proceeding with a phase I trial of IPdR in combination with radiation. This trial shows the ability of a small, phase 0 study to provide critical information for decision-making regarding future development of a drug.
Schedule-dependent drug effects of oral 5-iodo-2-pyrimidinone-2'-deoxyribose as an in vivo radiosensitizer in U251 human glioblastoma xenografts
Clin Cancer Res 2005 Oct 15;11(20):7499-507.PMID:16243824DOI:10.1158/1078-0432.CCR-05-1138.
Purpose: 5-Iodo-2-pyrimidinone-2'-deoxyribose (IPdR) is an oral prodrug of 5-iodo-2'-deoxyuridine (IUdR), an in vitro/in vivo radiosensitizer. IPdR can be rapidly converted to IUdR by a hepatic aldehyde oxidase. Previously, we found that the enzymatic conversion of IPdR to IUdR could be transiently reduced using a once daily (q.d.) treatment schedule and this may affect IPdR-mediated tumor radiosensitization. The purpose of this study is to measure the effect of different drug dosing schedules on tumor radiosensitization and therapeutic index in human glioblastoma xenografts. Experimental design: Three different IPdR treatment schedules (thrice a day, t.i.d.; every other day, q.o.d.; every 3rd day, q.3.d.), compared with a q.d. schedule, were analyzed using athymic nude mice with human glioblastoma (U251) s.c. xenografts. Plasma pharmacokinetics, IUdR-DNA incorporation in tumor and normal proliferating tissues, tumor growth delay following irradiation, and body weight loss were used as end points. Results: The t.i.d. schedule with the same total daily doses as the q.d. schedule (250, 500, or 1,000 mg/kg/d) improved the efficiency of IPdR conversion to IUdR. As a result, the percentage of IUdR-DNA incorporation was higher using the t.i.d. schedule in the tumor xenografts as well as in normal small intestine and bone marrow. Using a fixed dose (500 mg/kg) per administration, the q.o.d. and q.3.d. schedules also showed greater IPdR conversion than the q.d. schedule, related to a greater recovery of hepatic aldehyde oxidase activity prior to the next drug dosing. In the tumor regrowth assay, all IPdR treatment schedules showed significant increases of regrowth delays compared with the control without IPdR (q.o.d., 29.4 days; q.d., 29.7 days; t.i.d., 34.7 days; radiotherapy alone, 15.7 days). The t.i.d. schedule also showed a significantly enhanced tumor growth delay compared with the q.d. schedule. Additionally, the q.o.d. schedule resulted in a significant reduction in systemic toxicity. Conclusions: The t.i.d. and q.o.d. dosing schedules improved the efficiency of enzymatic activation of IPdR to IUdR during treatment and changed the extent of tumor radiosensitization and/or systemic toxicity compared with a q.d. dosing schedule. These dosing schedules will be considered for future clinical trials of IPdR-mediated human tumor radiosensitization.