MTIC
(Synonyms: 替莫唑胺代谢物- MTIC) 目录号 : GC44251A DNA alkylating agent
Cas No.:3413-72-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
MTIC is a DNA alkylating agent, an active metabolite of dacarbazine, and an active degradation product of temozolomide.[1],[2],[3] MTIC is cytotoxic to L-cells and decreases thymidine and uridine uptake by 55 and 65%, respectively, when used at a concentration of 1 mM.[2] It is also cytotoxic to TLX5 murine lymphoma cells in a concentration-dependent manner.[3] In vivo, MTIC induces formation of mammary adenofibromas in rats when administered at a cumulative dose of 890 mg per animal over 14 weeks.[4]
Reference:
[1]. Nagasawa, H.T., Shirota, F.N., and Mizuno, N.S. The mechanism of alkylation of DNA by 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MIC), a metabolite of DIC (NSC-45388). Non-involvement of diazomethane. Chem. Biol. Interact. 8(6), 403-413 (1974).
[2]. Beal, D.D., Skibba, J.L., Whitnable, K.K., et al. Effects of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide and its metabolites on Novikoff hepatoma cells. Cancer Res. 36(8), 2827-2831 (1976).
[3]. Tsang, L.L.H., Quarterman, C.P., Gescher, A., et al. Comparison of the cytotoxicity in vitro of temozolomide and dacarbazine, prodrugs of 3-methyl-(triazen-1-yl)imidazole-4-carboxamide. Cancer Chemother. Pharmacol. 27(5), 342-346 (1991).
[4]. Beal, D.D., Skibba, J.L., Croft, W.A., et al. Carcinogenicity of the antineoplastic agent, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, and its metabolites in rats. J. Natl. Cancer Inst. 54(4), 951-957 (1975).
| Cas No. | 3413-72-7 | SDF | |
| 别名 | 替莫唑胺代谢物- MTIC | ||
| 化学名 | 5-[2-(methylimino)hydrazinyl]-1H-imidazole-4-carboxamide | ||
| Canonical SMILES | NC(C1=C(/N=N/NC)NC=N1)=O | ||
| 分子式 | C5H8N6O | 分子量 | 168.2 |
| 溶解度 | DMSO : 25 mg/mL (148.67 mM; ultrasonic and warming and heat to 60°C) | 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 | 5.9453 mL | 29.7265 mL | 59.453 mL |
| 5 mM | 1.1891 mL | 5.9453 mL | 11.8906 mL |
| 10 mM | 0.5945 mL | 2.9727 mL | 5.9453 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。
Enhanced Copper-Temozolomide Interactions by Protein for Chemotherapy against Glioblastoma Multiforme
ACS Appl Mater Interfaces 2019 Nov 13;11(45):41935-41945.PMID:31644262DOI:10.1021/acsami.9b14849.
Current treatment of recurrent glioblastoma multiforme (GBM) demands dose-intense temozolomide (TMZ), a prodrug of 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), based on the spontaneous hydrolysis of TMZ at basic pH. However, how to control the activity of MTIC remains unknown, which poses a particular challenge to search a reliable MTIC receptor. We reported that copper, for the first time, is found to recognize and bind MTIC in the process of TMZ degradation, which means copper can play an important role in enhancing the bioavailability of MTIC derived from TMZ. Using apoferritin as a model copper-bound protein, we studied the copper-TMZ interaction in protein and observed efficient MTIC immobilization with high binding efficiency (up to 92.9% based on original TMZ) and capacity (up to 185 MTIC moieties per protein). The system was stable against both alkaline and acidic pH and could be activated by glutathione to liberate MTIC, which paves a way to deliver a DNA-alkylating agent for both TMZ-sensitive and TMZ-resistant GBM chemotherapy. Our study provides a new insight for understanding the potential relationship between the special GBM microenvironment (specific copper accumulation) and the therapeutic effect of TMZ.
Development of a pharmacokinetic limited sampling model for temozolomide and its active metabolite MTIC
Cancer Chemother Pharmacol 2005 May;55(5):433-8.PMID:15818507DOI:10.1007/s00280-004-0896-9.
Purpose: To develop a pharmacokinetic limited sampling model (LSM) for temozolomide and its metabolite MTIC in infants and children. Methods: LSMs consisting of either two or four samples were determined using a modification of the D-optimality algorithm. This accounted for prior distribution of temozolomide and MTIC pharmacokinetic parameters based on full pharmacokinetic sampling from 38 patients with 120 pharmacokinetic studies (dosage range 145-200 mg/m(2) per day orally). Accuracy and bias of each LSM were determined relative to the full sampling method. We also assessed the predictive performance of the LSMs using Monte-Carlo simulations. Results: The four strategies generated from the D-optimality algorithm were as follows: LSM 1=0.25, 1.25, and 3 h; LSM 2=0.25, 1.25, and 6 h; LSM 3=0.25, 0.5, 1.25, and 3 h; LSM 4=0.25, 0.5, 1.25, and 6 h. LSM 2 demonstrated the best combination of low bias [0.1% (-8.9%, 11%) and 11% (4.3%, 15%)] and high accuracy [-1.0% (-12%, 24%) and 14% (7.9%, 37%)] for temozolomide clearance and MTIC AUC, respectively. Furthermore, adding a fourth sample (e.g., LSM 4) did not substantially decrease the bias or increase the accuracy for temozolomide clearance or MTIC AUC. Results from Monte-Carlo simulations also revealed that LSM 2 had the best combination of lowest bias (0.1+/-6.1% and -0.8+/-6.5%), and the highest accuracy (4.5+/-4.1% and 5.0+/-4.3%) for temozolomide clearance and MTIC apparent clearance, respectively. Conclusions: Using data derived from our population analysis, the sampling times for a limited sample pharmacokinetic model for temozolomide and MTIC in children are prior to the temozolomide dose, and 15 min, 1.25 h and 6 h after the dose.
Visible Light and Glutathione Dually Responsive Delivery of a Polymer-Conjugated Temozolomide Intermediate for Glioblastoma Chemotherapy
ACS Appl Mater Interfaces 2021 Dec 1;13(47):55851-55861.PMID:34788006DOI:10.1021/acsami.1c16962.
Temozolomide (TMZ) is a prodrug of 5-(3-methyltriazene-1-yl)imidazole-4-carboxamide (MTIC, short-lived) and used as a first-line therapy drug for glioblastoma multiforme (GBM). However, little progress has been made in regulating the kinetics of TMZ to MTIC degradation to improve the therapeutic effect, particularly in the case of TMZ-resistant GBM. In this work, we introduced a strategy to cage MTIC by N-acylation of the triazene moiety to boost the MTIC stability, designed a diblock copolymer-based MTIC prodrug installed with a disulfide linkage, and achieved self-assembled polymer micelles without the concern of MTIC leakage under physiological conditions. Polymer micelles could be induced to disassemble by stimuli factors such as glutathione (GSH) and visible light irradiation through thiol/sulfide exchange and homolytic sulfide scission mechanisms, which contributed to MTIC release in GSH-dependent and GSH-independent pathways. The in vitro results demonstrated that microenvironment-responsive polymeric micelles benefited the suppression of both TMZ-sensitive and TMZ-resistant GBM cells. The chemistry of polymer-MTIC prodrug provided a new option for TMZ-based glioma treatment.
Cytotoxicity of 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC) on Mer+, Mer+Rem- and Mer- cell lines: differential potentiation by 3-acetamidobenzamide
Br J Cancer 1988 Jan;57(1):54-8.PMID:2831926DOI:10.1038/bjc.1988.8.
Mechanisms of resistance to the active metabolite 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC) of the drug 5-(3,3-dimethyl-1-triázeno)imidazole-4-carboxamide (DTIC) were studied in three human cell lines with differing amounts of the repair enzyme O6-alkylguanine-DNA alkyltransferase (O6AT). The lines were HT29 (Mer+Rem+), A549 (Mer+Rem-) and VA13 (Mer-). The ability to repair O6 methyl-guanine was directly related to resistance to MTIC (HT29 ID50 650 mumol l-1, A549 ID50 210 mumol l-1, VA13 ID50 15 mumol l-1. MTIC produced DNA single strand breaks over the range of one log of cell kill, but depletion of cellular NAD levels could not be detected until there was greater than 95% cell kill. Inhibitors of the repair enzyme adenosine diphosphoribosyl transferase (ADPRT) potentiated killing by 2-fold in the Mer+ cell lines but not the Mer- line. The enhancement was directly proportional to an increase in DNA strand breaks but not a change in their half-life. Therefore resistance to the clinically used methylating agent MTIC can be partly overcome by inhibiting ADPRT but a role for ADPRT as a suicide mechanism in response to alkylating agent damage is unlikely.
An LC/MS/MS method for the quantitation of MTIC (5-(3-N-methyltriazen-1-yl)-imidazole-4-carboxamide), a bioconversion product of temozolomide, in rat and dog plasma
J Pharm Biomed Anal 1999 Apr;19(5):659-68.PMID:10698531DOI:10.1016/s0731-7085(98)00198-8.
A sensitive and selective HPLC/electrospray ionization tandem mass spectrometric (LC/ESI/MS/MS) method for the quantitative determination of MTIC (5-(3-N-methyltriazen-1-yl)-imidazole-4-carboxamide), a pharmacologically active hydrolysis product of temozolomide, was developed and validated over a linear range from 10 to 400 ng ml(-1) in dog plasma and from 10 to 500 ng ml(-1) in rat plasma. This HPLC method utilized small plasma volumes (70 microl), rapid sample processing, and isocratic elusion conditions to achieve sensitive and selective MS/MS detection. Samples were processed and analyzed one at a time every 4.5 min in order to compensate for the inherent instability of MTIC. Both MTIC and the internal standard DTIC [5-(3,3'-N,N'-dimethyltriazen-1-yl)-imidazole-4-carboxamide] were quantitated in the positive ion, selected reaction monitoring (SRM) mode. The lower limit of quantitation (LLOQ) was 10 ng ml(-1) in the plasma from both species. Inter-assay accuracy and precision of all calibration standards and quality control (QC) samples were within +/- 11 and 12%, respectively, with the exception of the LLOQ in rat plasma (17%). The validated method was used to determine the time dependent plasma concentration of MTIC in rats and dogs following a single oral dose of temozolomide. The standard curve and the quality control data indicate that the method performed acceptably throughout the sample analysis period.