Jackson R C, Fry D W, Boritzki T J, Besserer J A, Leopold W R, Sloan B J, Elslager E F
Adv Enzyme Regul. 1984;22:187-206. doi: 10.1016/0065-2571(84)90014-1.
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.
三甲曲沙是一种新型亲脂性叶酸拮抗剂，在组织培养中，它在纳摩尔浓度下即可引起生长抑制、核酸生物合成抑制及细胞毒性。三甲曲沙对大多数细胞系的细胞毒性效力大于甲氨蝶呤。在多种小鼠白血病和实体瘤系统中，三甲曲沙在体内具有抗肿瘤活性，包括甲氨蝶呤无活性的肿瘤。口服、静脉注射或腹腔注射后均可见抗肿瘤活性。三甲曲沙可导致脱氧尿苷掺入DNA的过程出现明显且早期的抑制。在因药物转运缺陷而对甲氨蝶呤耐药的肿瘤细胞系中，三甲曲沙仍保持活性。在许多此类情况下，对甲氨蝶呤耐药的肿瘤对三甲曲沙表现出间接敏感性。在药物转运受损的甲氨蝶呤耐药细胞中，当细胞在补充有生理水平四氢叶酸辅因子的无叶酸培养基中生长时，三甲曲沙的敏感性更为明显。在人肿瘤干细胞集落试验中，三甲曲沙在体内可达到的浓度下，对许多人类肿瘤具有活性，包括对甲氨蝶呤无反应的样本。三甲曲沙可穿过血脑屏障，在非常高的剂量下可能会引起神经毒性。在常规剂量下，小鼠的主要毒性作用是胃肠道反应。这种毒性在治疗剂量下是可逆的。与早期的亲脂性抗叶酸药物不同，三甲曲沙的血浆清除速度很快（小鼠的半衰期为45分钟）。三甲曲沙是二氢叶酸还原酶的紧密结合竞争性抑制剂。对人酶抑制的Ki斜率为4×10⁻¹¹M。三甲曲沙可使细胞嘌呤核糖核苷酸池呈剂量依赖性减少。在经处理的细胞中，嘧啶核糖核苷酸池往往会增加。三甲曲沙可导致细胞内dTTP和dGTP池明显减少，而dATP池减少程度较小。亚叶酸可预防三甲曲沙在体外的细胞毒性。亚叶酸还可保护小鼠免受三甲曲沙的毒性作用。胸腺嘧啶可保护细胞免受低浓度三甲曲沙的致死作用，但不能保护免受高浓度的作用。胸腺嘧啶和次黄嘌呤的组合可完全保护细胞免受低浓度和高浓度三甲曲沙的作用。已开发出一种新的、稳定且高度水溶性的三甲曲沙制剂。由于三甲曲沙具有有趣的生化和药理特性及其实验性抗肿瘤活性，因此计划开展临床试验。
