Lometrexol (DDATHF) disodium 是一种抗嘌呤类抗叶酸 (antifolate) 药，可抑制甘氨酰胺核糖核苷酸甲酰基转移酶 (GARFT) 的活性，但不会引起可检测水平的 DNA 链断裂。Lometrexol disodium 可以进一步抑制嘌呤从头合成，导致异常的细胞增殖，凋亡 (apoptosis) 和细胞周期停滞。Lometrexol disodium 具有抗癌活性。Lometrexol disodium 还是一种有效的人丝氨酸羟甲基转移酶 1/2 (hSHMT1/2) 抑制剂。
| 生物活性 | Lometrexol (DDATHF) disodium, an antipurineantifolate, can inhibit the activity ofglycinamide ribonucleotide formyltransferase (GARFT)but do not induce detectable levels of DNA strand breaks. Lometrexol disodium can further inhibit de novo purine synthesis, causing abnormal cell proliferation andapoptosis, even cell cycle arrest. Lometrexol disodium has anticancer activity. Lometrexol disodium also is a potent human Serine hydroxymethyltransferase1/2 (hSHMT1/2) inhibitor[1][2][3]. |
体外研究
(In Vitro) | Lometrexol (DDATHF) disodium binds tightly to GART, resulting in a rapid and prolonged depletion of intracellular purine ribonucleotides[3].
Lometrexol (1-30 μM; 2-10 hours) disodium induces rapid and complete growth inhibition in L1210 cells[3].
Lometrexol (1 μM; 2-24 hours) disodium induces cell cycle arrest in murine leukemia L1210 cells[3].
Cell Viability Assay[3] | Cell Line: | Mouse leukemia L1210 cells | | Concentration: | 1, 30 μM | | Incubation Time: | 2, 4, 6, 8, 10 hours | | Result: | Induced rapid and complete growth inhibition. |
Cell Cycle Analysis[3] | Cell Line: | L1210 cells | | Concentration: | 1 μM | | Incubation Time: | 2, 4, 8, 12, 24 hours | | Result: | Caused a rapid loss of the G2/M phase population of cells and an early S phase accumulation of cells by 8 hours. By 24 h, the S phase population appeared to be slowly shifting to higher DNA content, and hence, from mid-to-late S phase. |
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体内研究
(In Vivo) | Lometrexol (DDATHF; i.p.; 15-60 mg/kg; on gestation day 7.5) disodium induces neural tube defects (NTDs) by disturbing purine metabolism and increases the rate of embryonic resorption and growth retardation in a dose-dependent manner[1].
Lometrexol (i.p.; 40 mg/kg; on gestation day 7.5) disodium decreases glycinamide ribonucleotide formyl transferase (GARFT) activity and Changes of ATP, GTP, dATP and dGTP levels[1].
Lometrexol (i.p.; 40 mg/kg; on gestation day 7.5) disodium induces abnormal proliferation and apoptosis exist in neural tube defects (NTDs)[1].
| Animal Model: | C57BL/6 mice (7-8 week, 18-20 g)[1] | | Dosage: | 15, 30, 35, 40, 45 and 60 mg/kg | | Administration: | Intraperitoneal injection; on gestation day 7.5 | | Result: | Increased the rate of embryonic resorption and growth retardation in a dose-dependent manner. |
| Animal Model: | C57BL/6 mice (7-8 week, 18-20 g)[1] | | Dosage: | 40 mg/kg | | Administration: | Intraperitoneal injection; on gestation day 7.5, for 0, 6, 24, 48 and 96 hours | | Result: | Inhibited glycinamide ribonucleotide formyl transferase (GARFT) activity and GARFT activity was maximally inhibited after at 6 hours.
Decreased the levels of ATP, GTP, dATP, and dGTP of NTDs embryonic brain tissue significantly at 6 hours.
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| Animal Model: | C57BL/6 mice (7-8 week, 18-20 g)[1] | | Dosage: | 40 mg/kg | | Administration: | Intraperitoneal injection; on gestation day 7.5, for 4 days | | Result: | Decreased the expression of proliferation-related genes (Pcna, Foxg1 and Ptch1) and increased the expression of apoptosis-related genes (Bax, Casp8 and Casp9) in NTD groups. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | | Powder | -20°C | 3 years | | In solvent | -80°C | 6 months | | -20°C | 1 month |
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