| 生物活性 |
DT-5461 is an IL-1 and TNF-α antagonist, with low endotoxicity and potent antitumor activity dissociated from toxic potential. DT-5461 competitively binds lipid A-binding sites on macrophage receptors, blocks LPS-initiated signaling, inhibits LPS-induced cytokine release, prevents LPS-induced serum cytokine production in mice, and protects against LPS-induced lethal endotoxemia. DT-5461 induces minimal cytokine production, inhibits tumor metastasis, prolongs tumor-bearing mouse survival, induces splenomegaly, avoids DIC induction, causes hepatocellular necrosis with repeated intravenous administration, induces endogenous TNF and interferon a/b, reduces tumor microcirculatory blood flow, augments tumor cell-induced TNF production, activates host immune systems, and exhibits activity against human tumor xenografts. DT-5461 has weaker activity against tumors linked to elevated host blood immunosuppressive factors, with rat lethality unaffected by injection speed but enhanced in partially hepatectomized or D-galactosamine-treated rats. DT-5461 can be used for the research of lethal endotoxemia, gram-negative bacterial septicemia, meth a fibrosarcoma, oat-cell lung carcinoma, medullary tubular mammary carcinoma, poorly differentiated colon adenocarcinoma, squamous-cell lung carcinoma, poorly differentiated gastric adenocarcinoma, and gelatinous gastric adenocarcinoma[1][2][3].
|
体内研究
(In Vivo) |
DT-5461 (每只小鼠 1-100 μg；腹腔注射；单次给药) 可剂量依赖性地预防脂多糖 (LPS) 诱导的 D-半乳糖胺致敏 C57BL/6 小鼠致死性内毒素血症，在每只小鼠 100 μg 的剂量下可实现 100%的存活率，并能抑制 LPS 介导的血清 IL-1 和 TNF-α 的产生[1]。
DT-5461 (静脉注射；4-6 次给药) 在未处理的雄性 Sprague-Dawley 大鼠中，单次静脉推注的 LD50 大于 68000 ng/kg，静脉滴注的 LD50 大于 20000 ng/kg，在测试剂量下不同给药途径的致死率无差异[2]。
DT-5461 (静脉注射；4-6 次给药) 在 2/3 肝切除的雄性 Sprague-Dawley 大鼠中经静脉推注给药的 LD50 大于 400 ng/kg，与 C506 和 LPS 相比，其致死性增强但效力更低[2]。
DT-5461 (35 mg/kg；静脉注射；单次给药) 可在未处理的雄性 Sprague-Dawley 大鼠中诱发持续性脾肿大、血细胞计数和血清 IgG 的一过性升高，以及脾脏 B 细胞和 T 细胞群体的变化，并伴有特征性组织病理学改变[2]。
DT-5461 (1.0-2.5 mg/kg；静脉滴注；单次给药) 不会在经 0.4 M lactic acid 预处理的雄性 Sprague-Dawley 大鼠中诱发弥散性血管内凝血 (DIC) 相关的临床病理改变[2]。
DT-5461 (0.64-10 mg/kg；静脉注射；每日 1 次；连续 14 天) 可在雄性 Sprague-Dawley 大鼠中引发：剂量≥0.64 mg/kg 时出现脾肿大，剂量≥4 mg/kg 时出现血小板计数降低和肝细胞坏死，剂量为 10 mg/kg 时出现血清丙氨酸氨基转移酶升高[2]。
DT-5461 (4-25 mg/kg；静脉注射；每日一次；连续 14 天) 对雄性松鼠猴的作用表现为：4 mg/kg 剂量下无变化，10 mg/kg 剂量下出现轻微肝细胞坏死和网状内皮系统激活，25 mg/kg 剂量下则出现血清丙氨酸氨基转移酶升高、广泛肝细胞坏死及网状内皮系统激活[2]。
DT-5461 (每只小鼠 200 μg；静脉注射；每 5 天 1 次，共 3 次) 对 BALB/c 小鼠体内的 Meth A 纤维肉瘤表现出显著的抗肿瘤活性，T/C 值达 29%[3]。
DT-5461 (每只小鼠 200 μg；静脉注射；每 5 天 1 次，共 3 次) 在 BALB/c-nu/nu 小鼠中对 Meth A 纤维肉瘤表现出显著的抗肿瘤活性，T/C 值达 35%[3]。
DT-5461 (每只小鼠 200-800 μg；静脉注射；每 3 天 1 次，共 9 次) 在 BALB/c-nu/nu 小鼠中对 PC-6 燕麦细胞肺癌表现出剂量依赖性、具有统计学意义的抗肿瘤活性，200 μg/小鼠剂量下的 T/C 值为 21%，800 μg/小鼠剂量下为 8%，并能诱导与抗肿瘤疗效相关的瘤内 TNF 活性[3]。
DT-5461 (每只小鼠 200-800 μg；静脉注射；每 3 天 1 次，共 9 次) 在 BALB/c-nu/nu 小鼠中对 MX-1 髓样管状乳腺癌表现出剂量依赖性、具有统计学意义的抗肿瘤活性，200 μg/小鼠剂量下的 T/C 值为 30%，800 μg/小鼠剂量下为 14%，并能诱导与抗肿瘤疗效相关的高水平瘤内 TNF 活性[3]。
DT-5461 (每只小鼠 200-800 μg；静脉注射；每 3 天 1 次，共 9 次) 在 BALB/c-nu/nu 小鼠中对低分化结肠腺癌 Co-4 表现出具有统计学意义的抗肿瘤活性，200 μg/小鼠剂量下的 T/C 值为 27%，800 μg/小鼠剂量下的 T/C 值为 29%，并能诱导与抗肿瘤疗效相关的高水平瘤内 TNF 活性[3]。
DT-5461 (每只小鼠 200-800 μg；静脉注射；每 3 天 1 次，共 9 次) 在 BALB/c-nu/nu 小鼠中对 QG56 肺鳞状细胞癌表现出剂量依赖性的、具有统计学意义的抗肿瘤活性，200 μg/小鼠剂量下的 T/C 值为 54%，800 μg/小鼠剂量下为 27%，并能诱导与抗肿瘤疗效相关的瘤内 TNF 活性[3]。
DT-5461 (每只小鼠 200-800 μg；静脉注射；每 3 天 1 次，共 9 次) 对 BALB/c-nu/nu 小鼠体内的 SC-6 低分化胃腺癌表现出剂量依赖性抗肿瘤活性，在 800 μg/mouse 剂量下 T/C 值达 32%，具有统计学显著性，同时可诱导与抗肿瘤疗效相关的瘤内 TNF 活性[3]。
DT-5461 (每只小鼠 200-800 μg；静脉注射；每 3 天 1 次，共 9 次) 对 BALB/c-nu/nu 小鼠体内的 St-15 胶状胃腺癌表现出微弱的抗肿瘤活性，200 μg/mouse 剂量下的 T/C 值为 72%，800 μg/mouse 剂量下的 T/C 值为 57%，且可诱导低水平的瘤内 TNF 活性[3]。
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
| 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] |
| Dosage: |
1 μg per mouse; 10 μg per mouse; 100 μg per mouse |
| Administration: |
i.p.; single dose |
| 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. |
| Animal Model: |
Sprague-Dawley (male, 8-9 weeks old, 220-260 g)[2] |
| Dosage: |
35 mg/kg |
| Administration: |
i.v.; single bolus injection |
| 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. |
| Animal Model: |
Sprague-Dawley (male, 8-9 weeks old, 220-260 g, lactic acid-pretreated)[2] |
| Dosage: |
1.0 mg/kg; 2.5 mg/kg |
| Administration: |
i.v.; drip infusion; single dose |
| 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. |
| Animal Model: |
Sprague-Dawley (male, 8-9 weeks old, 220-260 g)[2] |
| Dosage: |
0.64 mg/kg; 1.6 mg/kg; 4 mg/kg; 10 mg/kg |
| Administration: |
i.v.; bolus injection; daily; 14 days |
| 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. |
| Animal Model: |
Squirrel monkey (male, over 4 years old, 0.7-1 kg)[2] |
| Dosage: |
4 mg/kg; 10 mg/kg; 25 mg/kg |
| Administration: |
i.v.; bolus injection; daily; 14 days |
| 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. |
| Animal Model: |
BALB/c (male, 6-week-old, intradermal inoculation of Meth A fibrosarcoma cells)[3] |
| Dosage: |
200 μg/mouse |
| Administration: |
i.v.; three times at 5-day intervals |
| Result: |
Produced a statistically significant tumor growth inhibitory effect with a T/C value of 29% relative to control mice. |
| Animal Model: |
BALB/c-nu/nu (nude, male, 6-week-old, intradermal inoculation of Meth A fibrosarcoma cells)[3] |
| Dosage: |
200 μg/mouse |
| Administration: |
i.v.; three times at 5-day intervals |
| Result: |
Produced a statistically significant tumor growth inhibitory effect with a T/C value of 35% relative to control mice. |
| Animal Model: |
BALB/c-nu/nu (nude, male, 6-week-old, subcutaneous transplantation of PC-6 tumor pieces)[3] |
| Dosage: |
200 μg/mouse; 800 μg/mouse |
| Administration: |
i.v.; 9 times at 3-day intervals |
| 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. |
| Animal Model: |
BALB/c-nu/nu (nude, male, 6-week-old, subcutaneous transplantation of MX-1 tumor pieces)[3] |
| Dosage: |
200 μg/mouse; 800 μg/mouse |
| Administration: |
i.v.; 9 times at 3-day intervals |
| 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. |
| Animal Model: |
BALB/c-nu/nu (nude, male, 6-week-old, subcutaneous transplantation of Co-4 tumor pieces)[3] |
| Dosage: |
200 μg/mouse; 800 μg/mouse |
| Administration: |
i.v.; 9 times at 3-day intervals |
| 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] |
| Dosage: |
200 μg/mouse; 800 μg/mouse |
| Administration: |
i.v.; 9 times at 3-day intervals |
| 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. |
| Animal Model: |
BALB/c-nu/nu (nude, male, 6-week-old, subcutaneous transplantation of SC-6 tumor pieces)[3] |
| Dosage: |
200 μg/mouse; 800 μg/mouse |
| Administration: |
i.v.; 9 times at 3-day intervals |
| 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] |
| Dosage: |
200 μg/mouse; 800 μg/mouse |
| Administration: |
i.v.; 9 times at 3-day intervals |
| 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. |
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