Trimetrexate (CI-898) is an antifolate agent that inhibits Toxoplasma gondii dihydrofolate reductase (DHFR) with the IC50 value of 1.35nM [1]. Trimetrexate has been widely used as an anti-cancer compound to inhibit the growth of many cancer cells[2]. Trimetrexate has been extensively used as a model compound to develop a range of derivatives and build a small molecule library to screen for inhibitors against S. mutans[3].
In vitro, Trimetrexate treatment for 96h inhibited the viability of U-2OS cells and Saos-2 cells with the IC50 values of 3.3±2.1µM and 6.5±2.1µM, respectively[4]. After a 24h exposure to Trimetrexate (1µM), the colony formation of H630 cells was decreased, and the apparent free DHFR binding capacity was reduced[5]. Trimetrexate treatment at 100µM for 14 days irreversibly inhibited the proliferation of murine haemopoietic progenitor cells[6].
In vivo, Trimetrexate treatment via intraperitoneal injection at a dose of 60mg/kg/day for 49 days reduced tumor progression and improved the survival of the murine 32Dp210 model of chronic myeloid leukemia[7]. Oral administration of Trimetrexate at a dose of 180mg/kg/day for 14 days extended the survival of T. gondii-infected mice[8].
References:
[1] Hopper A T, Brockman A, Wise A, et al. Discovery of selective Toxoplasma gondii dihydrofolate reductase inhibitors for the treatment of toxoplasmosis[J]. Journal of medicinal chemistry, 2019, 62(3): 1562-1576.
[2] Miyachi H, Takemura Y, Kobayashi H, et al. Cytotoxicity of Trimetrexate against Antifolate‐resistant Human T‐Cell Leukemia Cell Lines Developed in Oxidized or Reduced Folate[J]. Japanese journal of cancer research, 1997, 88(9): 900-906.
[3] Zhang Q, Nguyen T, McMichael M, et al. New small-molecule inhibitors of dihydrofolate reductase inhibit Streptococcus mutans[J]. International journal of antimicrobial agents, 2015, 46(2): 174-182.
[4] Serra M, Reverter-Branchat G, Maurici D, et al. Analysis of dihydrofolate reductase and reduced folate carrier gene status in relation to methotrexate resistance in osteosarcoma cells[J]. Annals of oncology, 2004, 15(1): 151-160.
[5] Grem J L, Voeller D M, Geoffroy F, et al. Determinants of trimetrexate lethality in human colon cancer cells[J]. British journal of cancer, 1994, 70(6): 1075-1084.
[6] Strømhaug A, Slørdal L, Warren D J. Differential effects of the antifolates methotrexate, aminopterin and trimetrexate on murine haemopoietic progenitor cells[J]. British journal of haematology, 1996, 92(3): 514-520.
[7] Sweeney C L, Frandsen J L, Verfaillie C M, et al. Trimetrexate inhibits progression of the murine 32Dp210 model of chronic myeloid leukemia in animals expressing drug-resistant dihydrofolate reductase[J]. Cancer research, 2003, 63(6): 1304-1310.
[8] Allegra C J, Kovacs J A, Drake J C, et al. Potent in vitro and in vivo antitoxoplasma activity of the lipid-soluble antifolate trimetrexate[J]. The Journal of clinical investigation, 1987, 79(2): 478-482.
Trimetrexate (CI-898)是一种抗叶酸剂，可抑制弓形虫二氢叶酸还原酶（DHFR），IC50值为1.35nM[1]。Trimetrexate作为抗癌剂广泛应用于抑制多种癌细胞生长[2]。Trimetrexate并作为先导化合物用于开发系列衍生物及构建靶向变形链球菌抑制剂的小分子库[3]。
在体外，Trimetrexate处理96小时可抑制U-2OS和Saos-2细胞活力，IC50值分别为3.3±2.1µM和6.5±2.1µM[4]。1µM的Trimetrexate处理H630细胞24小时能减少克隆形成并降低表观游离DHFR结合能力[5]。100µM的Trimetrexate处理小鼠造血祖细胞14天不可逆地抑制细胞增殖[6]。
在体内，慢性髓性白血病小鼠模型（32Dp210）每日腹腔注射Trimetrexate（60mg/kg/天；持续49天）可延缓肿瘤进展并提高生存率[7]。弓形虫感染小鼠每日口服180mg/kg剂量的Trimetrexate（持续14天）能延长生存期[8]。