DT-5461
DT-5461 is an IL-1 and TNF-α antagonist. DT-5461 competitively binds lipid A-binding sites on macrophage receptors, blocks LPS (HY-D1056)-initiated signaling, inhibits LPS-induced cytokine release, prevents LPS-induced serum cytokine production in mice, and protects against LPS-induced lethal endotoxemia. DT-5461 can be used for the research of lethal endotoxemia, medullary tubular mammary carcinoma, poorly differentiated colon adenocarcinoma, squamous-cell lung carcinoma, and gelatinous gastric adenocarcinoma.
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- CAS No.: 123598-19-6
- Formule: C73H133N4O22P
- Masse moléculaire:1449.82
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
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Chemical Information
- Pureté et documentation
- Références
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Activité biologique
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IL-1 |
DT-5461 (0.1-10 μg/mL; 2 h pre-incubation) acts as an LPS antagonist in human peripheral blood monocytes, significantly inhibiting E. coli LPS-induced IL-1 and TNF-α secretion in a concentration-dependent manner, with maximal suppression observed at 10 μg/mL[1].
DT-5461 (10 μg/mL; 4 h) stimulates TNF production in IFN-γ-treated nude mouse peritoneal macrophages, and this production is augmented 2-4 times by co-culture with PC-6, QG56, or MX-1 human tumor cells, with MX-1 cells exerting the strongest augmentative effect[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
DT-5461 (i.v.; 4-6 doses) exhibits an LD50 greater than 68000 ng/kg via bolus intravenous injection and greater than 20000 ng/kg via drip intravenous infusion in naive male Sprague-Dawley rats, with no difference in lethality between administration routes at tested doses[2].
DT-5461 (i.v.; 4-6 doses) exhibits an LD50 greater than 400 ng/kg via bolus intravenous injection in 2/3 hepatectomized male Sprague-Dawley rats, with enhanced but lower-potency lethality compared to C506 and LPS[2].
DT-5461 (35 mg/kg; i.v.; single dose) induces persistent splenomegaly, transient increases in blood cell counts and serum IgG, and splenic B-cell and T-cell population changes in naive male Sprague-Dawley rats, with characteristic histopathological alterations[2].
DT-5461 (1.0-2.5 mg/kg; i.v.; drip infusion; single dose) does not induce DIC-related clinico-pathological changes in 0.4 M lactic acid-pretreated male Sprague-Dawley rats[2].
DT-5461 (0.64-10 mg/kg; i.v.; daily; 14 days) induces splenomegaly at 0.64 mg/kg or higher, decreased platelet counts and hepatocellular necrosis at 4 mg/kg or higher, and increased serum alanine aminotransferase at 10 mg/kg in male Sprague-Dawley rats[2].
DT-5461 (4-25 mg/kg; i.v.; daily; 14 days) causes no changes at 4 mg/kg, slight hepatocellular necrosis and reticuloendothelial system activation at 10 mg/kg, and increased serum alanine aminotransferase, extensive hepatocellular necrosis, and reticuloendothelial system activation at 25 mg/kg in male squirrel monkeys[2].
DT-5461 (200 μg/mouse; i.v.; three times at 5-day intervals) exhibits significant antitumor activity against Meth A fibrosarcoma in BALB/c mice, resulting in a T/C value of 29%[3].
DT-5461 (200 μg/mouse; i.v.; three times at 5-day intervals) exhibits significant antitumor activity against Meth A fibrosarcoma in BALB/c-nu/nu mice, resulting in a T/C value of 35%[3].
DT-5461 (200-800 μg/mouse; i.v.; 9 times at 3-day intervals) exhibits dose-dependent, statistically significant antitumor activity against PC-6 oat-cell lung carcinoma in BALB/c-nu/nu mice, with T/C values of 21% at 200 μg/mouse and 8% at 800 μg/mouse, and induces intratumoral TNF activity that correlates with antitumor efficacy[3].
DT-5461 (200-800 μg/mouse; i.v.; 9 times at 3-day intervals) exhibits dose-dependent, statistically significant antitumor activity against MX-1 medullary tubular mammary carcinoma in BALB/c-nu/nu mice, with T/C values of 30% at 200 μg/mouse and 14% at 800 μg/mouse, and induces high intratumoral TNF activity that correlates with antitumor efficacy[3].
DT-5461 (200-800 μg/mouse; i.v.; 9 times at 3-day intervals) exhibits statistically significant antitumor activity against Co-4 poorly differentiated colon adenocarcinoma in BALB/c-nu/nu mice, with T/C values of 27% at 200 μg/mouse and 29% at 800 μg/mouse, and induces high intratumoral TNF activity that correlates with antitumor efficacy[3].
DT-5461 (200-800 μg/mouse; i.v.; 9 times at 3-day intervals) exhibits dose-dependent, statistically significant antitumor activity against QG56 squamous-cell lung carcinoma in BALB/c-nu/nu mice, with T/C values of 54% at 200 μg/mouse and 27% at 800 μg/mouse, and induces intratumoral TNF activity that correlates with antitumor efficacy[3].
DT-5461 (200-800 μg/mouse; i.v.; 9 times at 3-day intervals) exhibits dose-dependent antitumor activity against SC-6 poorly differentiated gastric adenocarcinoma in BALB/c-nu/nu mice, with a statistically significant T/C value of 32% at 800 μg/mouse, and induces intratumoral TNF activity that correlates with antitumor efficacy[3].
DT-5461 (200-800 μg/mouse; i.v.; 9 times at 3-day intervals) exhibits weak antitumor activity against St-15 gelatinous gastric adenocarcinoma in BALB/c-nu/nu mice, with T/C values of 72% at 200 μg/mouse and 57% at 800 μg/mouse, and induces low intratumoral TNF activity[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C57BL/6 (female, 7-10 weeks old, specific-pathogen-free, sensitized with E. coli 0127:B8 LPS and D-galactosamine for lethal endotoxemia model)[1]
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Dosage:1 μg per mouse; 10 μg per mouse; 100 μg per mouse
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Administration:i.p.; single dose
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Result:Inhibited LPS-mediated increases in endogenous serum IL-1 and TNF-α in a dose-dependent manner.
Reduced serum IL-1 and TNF-α levels significantly relative to LPS-only controls at 1 μg per mouse.
Achieved greater reductions in serum IL-1 and TNF-α levels at 10 μg per mouse.
Suppressed serum IL-1 and TNF-α levels most strongly at 100 μg per mouse (P < 0.001 vs.
LPS-only group).
Resulted in 37.5% (3/8) survival rate through day 6 at 1 μg per mouse.
Resulted in 75% (6/8) survival rate through day 6 at 10 μg per mouse.
Resulted in 100% (8/8) survival rate through day 6 at 100 μg per mouse.
Had a 50% protection dose of 2.1 μg per mouse and a 100% protection dose of 25 μg per mouse.
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Animal Model:Sprague-Dawley (male, 8-9 weeks old, 220-260 g)[2]
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Dosage:35 mg/kg
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Administration:i.v.; single bolus injection
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Result:Induced splenomegaly from day 1, with no full recovery to control levels by day 28.
Caused a marked increase in white blood cell, lymphocyte, and neutrophil counts on days 3-6, returning to baseline by day 28.
Induced serum IgG levels to peak between days 2-6, mirroring white blood cell fluctuations.
Caused splenic nucleated cells to increase from day 3.
Induced B-cells to significantly increase from day 3, and T-cells to increase from day 14.
Caused enlargement of B-cell area lymphatic follicles with large phagocytic cell infiltration and decreased T-cell area lymphocytes from 6 h to day 3.
Triggered lympho-reticular cell proliferation in the red pulp zone from days 1-28.
Induced megakaryopoiesis on days 2-6, and enhanced erythropoiesis on days 4-6.
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Animal Model:Sprague-Dawley (male, 8-9 weeks old, 220-260 g, lactic acid-pretreated)[2]
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Dosage:1.0 mg/kg; 2.5 mg/kg
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Administration:i.v.; drip infusion; single dose
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Result:Caused no changes in platelet counts, activated partial thromboplastin time, fibrin-fibrinogen degradation products, serum alanine aminotransferase, or urea nitrogen at both 1.0 mg/kg and 2.5 mg/kg.
Showed no hepatocellular necrosis or glomerular fibrin thrombus formation at both doses, unlike C506 and LPS.
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Animal Model:Sprague-Dawley (male, 8-9 weeks old, 220-260 g)[2]
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Dosage:0.64 mg/kg; 1.6 mg/kg; 4 mg/kg; 10 mg/kg
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Administration:i.v.; bolus injection; daily; 14 days
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Result:Induced splenomegaly at all doses (0.64 mg/kg or more).
Caused decreased platelet counts and single hepatocellular necrosis at 4 mg/kg or more.
Induced increased serum alanine aminotransferase activity at 10 mg/kg.
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Animal Model:Squirrel monkey (male, over 4 years old, 0.7-1 kg)[2]
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Dosage:4 mg/kg; 10 mg/kg; 25 mg/kg
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Administration:i.v.; bolus injection; daily; 14 days
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Result:Caused no changes at 4 mg/kg.
Induced slight hepatocellular necrosis and moderate activation of the hepatic and splenic reticuloendothelial system at 10 mg/kg.
Caused increased serum alanine aminotransferase activity, extensive hepatocellular necrosis, and extensive activation of the hepatic and splenic reticuloendothelial system at 25 mg/kg.
Showed no effects on organ weights at any dose.
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Animal Model:BALB/c (male, 6-week-old, intradermal inoculation of Meth A fibrosarcoma cells)[3]
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Dosage:200 μg/mouse
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Administration:i.v.; three times at 5-day intervals
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Result:Produced a statistically significant tumor growth inhibitory effect with a T/C value of 29% relative to control mice.
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Animal Model:BALB/c-nu/nu (nude, male, 6-week-old, intradermal inoculation of Meth A fibrosarcoma cells)[3]
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Dosage:200 μg/mouse
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Administration:i.v.; three times at 5-day intervals
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Result:Produced a statistically significant tumor growth inhibitory effect with a T/C value of 35% relative to control mice.
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Animal Model:BALB/c-nu/nu (nude, male, 6-week-old, subcutaneous transplantation of PC-6 tumor pieces)[3]
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Dosage:200 μg/mouse; 800 μg/mouse
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Administration:i.v.; 9 times at 3-day intervals
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Result:Produced a mean tumor weight of 0.65 g, a statistically significant T/C value of 21% relative to control mice at 200 μg/mouse.
Produced a mean tumor weight of 0.24 g, a statistically significant T/C value of 8% relative to control mice at 800 μg/mouse.
Induced intratumoral TNF activity with a single i.v.
dose of 200 μg/mouse.
Induced higher intratumoral TNF activity and serum TNF activity with a single i.v.
dose of 800 μg/mouse.
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Animal Model:BALB/c-nu/nu (nude, male, 6-week-old, subcutaneous transplantation of MX-1 tumor pieces)[3]
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Dosage:200 μg/mouse; 800 μg/mouse
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Administration:i.v.; 9 times at 3-day intervals
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Result:Produced a mean tumor weight of 1.98 g, a statistically significant T/C value of 30% relative to control mice at 200 μg/mouse.
Produced a mean tumor weight of 0.90 g, a statistically significant T/C value of 14% relative to control mice at 800 μg/mouse.
Induced intratumoral TNF activity with a single i.v.
dose of 200 μg/mouse.
Induced higher intratumoral TNF activity and serum TNF activity with a single i.v.
dose of 800 μg/mouse.
Augmented DT-5461-stimulated macrophage TNF production 4-fold in vitro by MX-1 tumor cells.
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Animal Model:BALB/c-nu/nu (nude, male, 6-week-old, subcutaneous transplantation of Co-4 tumor pieces)[3]
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Dosage:200 μg/mouse; 800 μg/mouse
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Administration:i.v.; 9 times at 3-day intervals
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Result:Produced a mean tumor weight of 0.49 g, a statistically significant T/C value of 27% relative to control mice at 200 μg/mouse.
Produced a mean tumor weight of 0.51 g, a statistically significant T/C value of 29% relative to control mice at 800 μg/mouse.
Induced intratumoral TNF activity with a single i.v.
dose of 200 μg/mouse.
Induced higher intratumoral TNF activity and serum TNF activity with a single i.v.
dose of 800 μg/mouse.
-
Animal Model:BALB/c-nu/nu (nude, male, 6-week-old, subcutaneous transplantation of QG56 tumor pieces)[3]
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Dosage:200 μg/mouse; 800 μg/mouse
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Administration:i.v.; 9 times at 3-day intervals
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Result:Produced a mean tumor weight of 1.97 g, a statistically significant T/C value of 54% relative to control mice at 200 μg/mouse.
Produced a mean tumor weight of 0.98 g, a statistically significant T/C value of 27% relative to control mice at 800 μg/mouse.
Induced intratumoral TNF activity with a single i.v.
dose of 200 μg/mouse.
Induced higher intratumoral TNF activity and serum TNF activity with a single i.v.
dose of 800 μg/mouse.
Augmented DT-5461-stimulated macrophage TNF production 2-fold in vitro by QG56 tumor cells.
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Animal Model:BALB/c-nu/nu (nude, male, 6-week-old, subcutaneous transplantation of SC-6 tumor pieces)[3]
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Dosage:200 μg/mouse; 800 μg/mouse
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Administration:i.v.; 9 times at 3-day intervals
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Result:Produced a mean tumor weight of 1.37 g, a T/C value of 44% relative to control mice at 200 μg/mouse.
Produced a mean tumor weight of 1.01 g, a statistically significant T/C value of 32% relative to control mice at 800 μg/mouse.
Induced intratumoral TNF activity with a single i.v.
dose of 200 μg/mouse.
Induced higher intratumoral TNF activity and serum TNF activity with a single i.v.
dose of 800 μg/mouse.
-
Animal Model:BALB/c-nu/nu (nude, male, 6-week-old, subcutaneous transplantation of St-15 tumor pieces)[3]
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Dosage:200 μg/mouse; 800 μg/mouse
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Administration:i.v.; 9 times at 3-day intervals
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Result:Produced a mean tumor weight of 1.00 g, a T/C value of 72% relative to control mice at 200 μg/mouse.
Produced a mean tumor weight of 0.79 g, a T/C value of 57% relative to control mice at 800 μg/mouse.
Induced low intratumoral TNF activity with a single i.v.
dose of 200 μg/mouse.
Induced higher intratumoral TNF activity and serum TNF activity with a single i.v.
dose of 800 μg/mouse.
Chemical Information
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CAS No. 123598-19-6
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Masse moléculaire 1449.82
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Formule C73H133N4O22P
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SMILES
CCCCCCCCCCCCCC(N[C@@H]1[C@H]([C@@H]([C@H](O[C@H]1OC[C@H]2O[C@@H]([C@@H]([C@H]([C@@H]2O)OC(CNC(CCCCCCCCCCC)=O)=O)NC(CCCCCCCCCCCCC)=O)OC(CC(O)=O)CC(O)=O)CO)OP(O)(O)=O)OC(CNC(CCCCCCCCCCC)=O)=O)=O
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
[1]. Sato K, et al. A novel synthetic lipid A analog with low endotoxicity, DT-5461, prevents lethal endotoxemia. Infect Immun. 1995;63(8):2859-2866. [Content Brief]
[2]. Sagara-Ishijima N, et al. Toxic characteristics of the synthetic lipid A derivative DT-5461 in rats and monkeys. Toxicol Sci. 1999;49(2):324-331. [Content Brief]
[3]. Kumazawa E, et al. Antitumor effect of DT-5461, a lipid A derivative, against human tumor xenografts is mediated by intratumoral production of tumor necrosis factor and affected by host immunosuppressive factors in nude mice. Cancer Invest. 1997;15(6):522-530. [Content Brief]
Calculators
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