的亲脂性的生化药理学antifolate trimetrexate。

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杰克逊RC炸DW, Boritzki TJ,贝瑟是的,利奥波德WR,斯隆BJ, Elslager EF

的亲脂性的生化药理学antifolate trimetrexate。

阿德酶Regul。1984; 22:187 - 206。0065 - 2571 . doi: 10.1016 / (84) 90014 - 1。

PubMed ID

6236675 (在PubMed

]

文摘

Trimetrexate是一种新型的亲脂性的叶酸拮抗剂导致生长抑制,抑制核酸的生物合成,细胞毒性在组织培养的摩尔浓度。的效力trimetrexate对大多数细胞系细胞毒性大于甲氨蝶呤。Trimetrexate已经在几个小鼠体内抗肿瘤活性白血病和实体瘤系统,包括肿瘤的甲氨蝶呤是不活跃的。抗肿瘤活性被认为后口服、静脉注射或腹腔内管理。Trimetrexate导致合并明显的抑郁和早期脱氧尿苷的DNA。在肿瘤细胞株抗甲氨蝶呤药物运输的缺陷,因为trimetrexate保留活动。在许多这样的情况下,methotrexate-resistant trimetrexate敏感性肿瘤显示抵押品。methotrexate-resistant细胞受损药物运输、trimetrexate敏感性更为明显,细胞生长在folate-free中补充tetrahydrofolate代数余子式的生理水平。在人类肿瘤干细胞集落试验,trimetrexate,在体内的浓度可以实现的,给活动对许多人类肿瘤,包括对甲氨蝶呤的样本。Trimetrexate穿过血脑屏障,在高剂量可能引起神经毒性。 At conventional doses the primary toxic effects in mice are gastrointestinal. This toxicity is reversible at therapeutic doses. Unlike earlier lipophilic antifolates, trimetrexate has rapid plasma clearance (t1/2 in mice of 45 minutes). Trimetrexate is a tight-binding competitive inhibitor of dihydrofolate reductase. The Ki,slope for inhibition of the human enzyme was 4 X 10(-11) M. A dose-dependent decrease in cellular purine ribonucleotide pools is given by trimetrexate. Pyrimidine ribonucleotide pools tend to increase in treated cells. Trimetrexate caused a marked depression of cellular pools of dTTP and dGTP, and a lesser depression in dATP. Cytotoxicity of trimetrexate in vitro was prevented by leucovorin. Leucovorin also protected mice from trimetrexate toxicity. Thymidine protected cells from lethal effects of low concentrations of trimetrexate, but not from high concentrations. The combination of thymidine and hypoxanthine completely protected cells from low and high concentrations of trimetrexate. A new, stable and highly water-soluble formulation of trimetrexate has been developed. Because of the interesting biochemical and pharmacological properties of trimetrexate, and its experimental antitumor activity, clinical trials are planned.

DrugBank数据引用了这篇文章

药物转运蛋白

药物	转运体	类	生物	药理作用	行动
Trimetrexate	叶酸转运体1	蛋白质	人类	未知的	底物	细节