Further studies on the interaction of nonpolyglutamatable aminopterin analogs with dihydrofolate reductase and the reduced folate carrier as determinants of in vitro antitumor activity.
Further studies on the interaction of nonpolyglutamatable aminopterin analogs with dihydrofolate reductase and the reduced folate carrier as determinants of in vitro antitumor activity.
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进一步研究非聚谷氨酸氨基蝶呤类似物与二氢叶酸还原酶和还原叶酸载体的相互作用作为体外抗肿瘤活性的决定因素。
DOI：
10.1016/s0006-2952(03)00102-3
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发表时间：
2003
影响因子：
5.8
通讯作者：
Rosowsky,Andre
中科院分区：
文献类型：
--
作者：
Wright,JoelE;Yurasek,GregoryK;Chen,Ying-Nan;Rosowsky,Andre
有效的非多聚谷氨酸二氢叶酸还原酶抑制剂Nα-评价在侧链、对氨基苯甲酰基部分或9，10-桥中具有修饰的（4-氨基-4-脱氧蝶酰基）-Nδ-半邻苯二甲酰基-1-鸟氨酸（PT 523）抑制人重组二氢叶酸还原酶（DHFR）、利用还原叶酸载体（RFC）进行内流、并抑制培养物中CCRF-CEM人白血病细胞的生长。在NADPH存在下DHFR还原二氢叶酸动力学的分光光度测定中，这些化合物的Ki值范围为0.2至1.3pM，因此与母体药物PT 523的效力没有很大差异。通过比较，氨基蝶呤（AMT）、甲氨蝶呤（MTX）和10-乙基-10-脱氮氨基蝶呤（EDX）的Ki值分别为3.7、4.8和11 pM。在竞争性抑制[3 H]MTX流入CCRF-CEM细胞的试验中，Ki值范围为0.21 - 7.3μM，而PT 523、AMT和EDX的Ki值为0.71、5.4和1.1μM。还重新分析了MTX的Kt，发现其为4.7μM，比我们之前报告的7.1μM值更符合文献。这些化合物作为CCRF-CEM细胞的生长抑制剂在药物暴露72小时后的ic 50值范围为0.53至55 nM，并且定性地与其他结果一致。
Thirteen structural analogs of the potent nonpolyglutamatable dihydrofolate reductase inhibitor Nα-(4-amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-l-ornithine (PT523) with modifications in the side chain, the para-aminobenzoyl moiety, or the 9,10-bridge were evaluated for the ability to inhibit human recombinant dihydrofolate reductase (DHFR), to utilize the reduced folate carrier (RFC) for influx, and to inhibit the growth of CCRF-CEM human leukemia cells in culture. In spectrophotometric assays of the kinetics of the reduction of dihydrofolate by DHFR in the presence of NADPH, these compounds had Kivalues ranging from 0.2 to 1.3pM, and thus were not greatly different in potency from the parent drug PT523. By comparison, the Kivalues of aminopterin (AMT), methotrexate (MTX), and 10-ethyl-10-deazaaminopterin (EDX) were 3.7, 4.8, and 11pM. In assays of competitive inhibition of [3H ]MTX influx into CCRF-CEM cells, the Kivalues ranged from 0.21 to 7.3μM, as compared with 0.71, 5.4, and 1.1μM for PT523, AMT, and EDX. The Ktfor MTX was also re-analyzed and found to be 4.7μM, in better agreement with the literature than our previously reported value of 7.1μM. The ic50values of these compounds as inhibitors of the growth of CCRF-CEM cells after 72hr of drug exposure ranged from 0.53 to 55nM, and were qualitatively consistent with the other results.