Tirapazamine (Synonyms: 3-Amino-1,2,4-benzotriazine 1,4-Dioxide, SR 259075, SR 4233, WIN 59075) |
| Catalog No.GC11150 |
Medicamento anticancerígeno
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 27314-97-2
Sample solution is provided at 25 µL, 10mM.
Tirapazamine is an anti-tumor agent showing cytotoxicity effect on A549, HT-29, SW620 and MDA-MB-468 cell in hypoxia condition with IC50 values of 6.8, 9.45, 1.2 and 1.304μM respectively[1][2]. Tirapazamine is converted by intercellular reductase to reactive radical species that can cause single- or double- strand DNA damage, and this reaction can be reversed under aerobic conditions. Tirapazamine is preferentially activated in solid tumors, which are characterized by a hypoxic environment[3]. Recognized as a commonly used bioreductive anticancer drug, Tirapazamine is extensively applied in the treatment of various cancer types, including hepatocellular carcinoma, colorectal carcinoma, and small cell lung cancer. Additionally, Tirapazamine is reported bactericidal and more active under anaerobic conditions, which reveals its potential as a antibacterial agents[4].
In vitro, Tirapazamine induces a dose-dependent increase in cell apoptosis under hypoxic conditions in murine C26 and MC38 colorectal carcinoma cells after a 24-hour treatment with concentrations ranging from 0 to 40μM, through the activation of caspase-3 cleavage[5]. Tirapazamine has been shown to inhibit the accumulation of HIF-1α in HeLa cells when exposed to a concentration of 20μM for 4 hours, an effect attributed to the reduction in HIF-1α protein synthesis via the phosphorylation of eIF2α[6]. Tirapazamine’s cytotoxic effect on LXFL 529 human lung carcinoma cells, within a concentration range of 0 to 100μM and a treatment duration of 1 hour, is mediated through topoisomerase II. This mediation occurs by stabilizing DNA-topoisomerase II complexes, resulting in the formation of DNA double-strand breaks (DSBs)[7].
In vivo, Tirapazamine was used to treat E.coli infected BALB/c mice by intraperitoneally adiministration at dosage of 25mg/kg, twice daily for 7 days, resulting in significant antibacterial activity and a prolonged survival period for the animal model[4]. Intraperitoneally administration of Tirapazamine (30mg/kg every 2 days) inhibited the tumor growth in HepG2 xenograft mouse model. Tirapazamine administration was observed to decrease the expression level of HIF-1α protein and increase p-eIF2α-positive staining in tumor tissues[6]. Tirapazamine (5,10mg/kg) was intraperitoneally injected into Wistar rats once a week for six weeks in combination with Doxorubicin (1.8mg/kg). Tirapazamine shows protective effect on rat myocardium by reduce oxidative stress and RyR2 protein level disturbed by Doxorubicin[8].
References:
[1] Cheng WY,Yuan YT, Ni Qiu N,et al.Identification of novel 4-anilinoquinazoline derivatives as potent EGFR inhibitors both under normoxia and hypoxia.Bioorganic & Medicinal Chemistry. 2014 Dec15,22(24):6796-6805
[2] Sansom N.G.,Kirk S.N.,Guise P.C.,et al.Prototyping kinase inhibitor-cytotoxin anticancer mutual prodrugs activated by tumour hypoxia: A chemical proof of concept study.Bioorg Med Chem Lett. 2019 May 15;29(10):1215-1219.
[3] Gandara R.D, Lara N.P.Jr,Goldberg Z,et al.Tirapazamine: prototype for a novel class of therapeutic agents targeting tumor hypoxia.Semin Oncol.2002 Feb;29(1 Suppl 4):102-9.
[4] Wu ZH,Wang Y,Li L,et al.New insights into the antimicrobial action and protective therapeutic effect of tirapazamine towards Escherichia coli-infected mice.Int J Antimicrob Agents. 2023 Sep;62(3):106923.
[5] Govaert K.M.,Nijkamp M.W.,Emmink B.L.,et al.Effects of tirapazamine on experimental colorectal liver metastases after radiofrequency ablation.Br J Surg.2012 Apr;99(4):567-75.
[6] Zhang J, Cao J, Weng QJ, et al.Suppression of hypoxia-inducible factor 1α (HIF-1α) by tirapazamine is dependent on eIF2α phosphorylation rather than the mTORC1/4E-BP1 pathway.PLoS One. 2010 Nov 9;5(11):e13910.
[7] Peters, K.B, Brown J.M.,Tirapazamine: a hypoxia-activated topoisomerase II poison.Cancer Res.2002 Sep 15;62(18):5248-53.
[8] Sliwinska J, et al. Tirapazamine-doxorubicin interaction referring to heart oxidative stress and Ca2+ balance protein levels. Oxid Med Cell Longev. 2012;2012:890826.
| Cell experiment [1]: | |
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Cell lines |
LXFL 529 human lung carcinoma cells |
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Preparation Method |
LXFL cells were grown in notched glass dishes, which were loaded into prewarmed aluminum jigs. For hypoxia treatment, jigs were evacuated and refilled five times with 95% air 5% CO2. The jigs were evacuated five times to 0.1 atmosphere with N2 5% CO2 reintroduction and constant shaking to achieve hypoxia (less than 200ppm O2). For aerobic treatment, jigs were evacuated and refilled five times with 95% air 5% CO2. The cells were then exposed to 0-100µM Tirapazamine for 1h at 37℃. |
|
Reaction Conditions |
50, 75, 100µM; 1h |
|
Applications |
The cytotoxic effect of Tirapazamine in hypoxic cells is mediated through topoisomerase II by stabilizing DNA-topoisomerase II complexes, which leads to the formation of DNA double-strand breaks (DSBs). Tirapazamine does not have the same effect on cells under aerobic environment. |
| Animal experiment [2]: | |
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Animal models |
Female BALB/c mice (5 weeks old) |
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Preparation Method |
Female BALB/c mice were randomly divided into three groups: control (C), E. coli infection (E), and E. coli infection+Tirapazamine treatment (ET). E. coli challenge tests were performed with a dose of 5.0×106 CFU/mouse via intraperitoneal injection. Three days after infection, Tirapazamine was administered to mice in the drug treatment group at 25mg/kg via intraperitoneal injection twice daily for 7 days, and the solvent without Tirapazamine was administered to the E. coli-infected group. The disease activity index (DAI) was calculated to evaluate colitis from days 0–14. |
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Dosage form |
25mg/kg; i.p.; twice daily for 7 days |
|
Applications |
Tirapazamine treatment cleared bacteria from the liver, spleen, and colon in treated mice 9 days after infection. Tirapazamine increased animal survival following E. coli-induced damage. |
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References: |
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| Cas No. | 27314-97-2 | SDF | |
| Sinónimos | 3-Amino-1,2,4-benzotriazine 1,4-Dioxide, SR 259075, SR 4233, WIN 59075 | ||
| Chemical Name | 4-hydroxy-1-oxido-1,2,4-benzotriazin-1-ium-3-imine | ||
| Canonical SMILES | C1=CC=C2C(=C1)N(C(=N)N=[N+]2[O-])O | ||
| Formula | C7H6N4O2 | M.Wt | 178.15 |
| Solubility | ≥ 8.9mg/mL in DMSO | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 5.6132 mL | 28.0662 mL | 56.1325 mL |
| 5 mM | 1.1226 mL | 5.6132 mL | 11.2265 mL |
| 10 mM | 0.5613 mL | 2.8066 mL | 5.6132 mL |
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