Biochemical pharmacology of the lipophilic antifolate, trimetrexate.
Biochemical pharmacology of the lipophilic antifolate, trimetrexate.
复制标题
亲脂性抗叶酸剂曲美曲沙的生化药理学。
DOI：
10.1016/0065-2571(84)90014-1
复制
发表时间：
1984
期刊：
影响因子：
--
通讯作者：
E. Elslager
中科院分区：
文献类型：
--
作者：
R. Jackson;D. W. Fry;T. Boritzki;J. Besserer;W. Leopold;B. Sloan;E. Elslager
曲美曲塞是一种新型的亲脂性叶酸拮抗剂，在组织培养中可在纳摩尔浓度下引起生长抑制、核酸生物合成抑制和细胞毒性。甲氨蝶呤对大多数细胞株的细胞毒作用强于甲氨蝶呤。甲氨蝶呤在几种小鼠白血病和实体肿瘤系统中具有体内抗肿瘤活性，包括甲氨蝶呤无效的肿瘤。口服、静脉或腹膜给药后可观察到抗肿瘤活性。曲美曲塞在脱氧尿嘧啶核苷与DNA的结合中引起明显的早期抑制。在肿瘤细胞系中，由于药物转运缺陷而对甲氨蝶呤产生耐药性，曲美他酯保持活性。在许多这样的病例中，对甲氨蝶呤耐药的肿瘤显示出对曲美他酯的侧支敏感性。在药物转运受损的甲氨蝶呤耐药细胞中，当细胞生长在添加生理水平的四氢叶酸辅因子的无叶酸培养基中时，对曲美他索的敏感性更加明显。在人类肿瘤干细胞集落试验中，在体内可达到的浓度下，曲美曲塞对许多人类肿瘤具有活性，包括对甲氨蝶呤无效的样本。曲美曲塞可以穿过血脑屏障，在非常高的剂量下可能会引起神经毒性。在常规剂量下，对小鼠的主要毒性作用是胃肠道。这种毒性在治疗剂量下是可逆的。与早期的亲脂性抗叶酸不同，曲美曲塞具有快速的血浆清除能力(小鼠的T1/2为45分钟)。曲美曲塞是一种紧密结合的二氢叶酸还原酶竞争性抑制剂。抑制人类酶的KI斜率为4×10~(-11)M。曲美曲塞可剂量依赖性地减少细胞内的嘌呤核糖核酸库。在处理的细胞中，嘧啶核糖核酸库趋于增加。曲美曲塞对dTTP和dGTP的细胞池有明显的抑制作用，对dATP的抑制作用较轻。甲氨蝶呤的体外细胞毒性可被亚叶酸钙阻断。亚叶酸钙还保护小鼠免受曲美他酯的毒性。胸腺嘧啶核苷可以保护细胞免受低浓度曲美曲塞的致死作用，但不能保护细胞免受高浓度的影响。胸腺嘧啶核苷和次黄嘌呤的联合使用可以完全保护细胞免受低浓度和高浓度的甲氧蝶呤的影响。开发了一种新的、稳定的、高度水溶性的曲美曲克索制剂。由于曲美曲塞有趣的生化和药理特性，以及其实验性的抗肿瘤活性，临床试验正在计划中。
Trimetrexate is a novel lipophilic folate antagonist that causes growth inhibition, inhibition of nucleic acid biosynthesis, and cytotoxicity at nanomolar concentrations in tissue cultures. The potency of trimetrexate cytotoxicity against most cell lines is greater than that of methotrexate. Trimetrexate has antitumor activity in vivo in several murine leukemia and solid tumor systems, including tumors in which methotrexate is inactive. Antitumor activity was seen following oral, intravenous, or intraperitoneal administration. Trimetrexate causes a pronounced and early depression in incorporation of deoxyuridine into DNA. In tumor cell lines resistant to methotrexate because of a drug transport defect, trimetrexate retains activity. In many such cases the methotrexate-resistant tumors show collateral sensitivity to trimetrexate. In methotrexate-resistant cells with impaired drug transport, trimetrexate sensitivity was even more pronounced when cells were grown in folate-free medium supplemented with physiological levels of tetrahydrofolate cofactor. In the human tumor stem cell colony assay, trimetrexate, at concentrations achievable in vivo, gave activity against many human tumors, including samples that were unresponsive to methotrexate. Trimetrexate crosses the blood-brain barrier, and at very high doses may cause neurotoxicity. 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.
有效的“非经典”2,4-二氨基喹唑啉叶酸拮抗剂曲美曲沙在正常狗中的药理学和毒性。
影响因子：
11.2
作者：
Weir,EC;Cashmore,AR;Dreyer,RN;Graham,ML;Hsiao,N;Moroson,BA;Sawicki,WL;Bertino,JR
通讯作者：
Bertino,JR
2,4-二氨基-5-甲基-6-[(3,4,5-三甲氧基苯胺基)甲基]喹唑啉（一种有前途的新型“非经典”抗叶酸剂）的酶法测定。
影响因子：
3.8
作者：
Heusner,JJ;McCormack,JJ
通讯作者：
McCormack,JJ