Rideout D C, Bustamante A, Patel R, Henderson G B
Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
Int J Cancer. 1995 Jun 9;61(6):840-7. doi: 10.1002/ijc.2910610616.
Suramin is an experimental anti-neoplastic agent which has shown promising activity against prostatic carcinoma and lymphoma in clinical trials. To elucidate its mechanism of action, suramin was examined for an effect on the transport of folate compounds by tumor cells. Influx of the anti-folate methotrexate via the reduced-folate carrier system of CCRF-CEM cells was found to be highly sensitive to inhibition by suramin but not to various other arylsulfonic acids. Inhibition by suramin was competitive, and the inhibition constant Ki was 1.3 microM, a value 3-fold lower than the Kt for half-maximal influx of methotrexate. Folate binding to the membrane-associated folate-binding protein of KB cells was not affected by suramin. Growth studies revealed that the response of human CCRF-CEM, KB, PC-3 and MCF-7 cells to methotrexate was antagonized from 6- to 17-fold by pharmacological levels (10-200 microM) of suramin. Conversely, growth inhibition was additive or synergistic when suramin was combined with metoprine, a lipophilic anti-folate which enters cells by diffusion. Synergism was observed between metoprine and suramin in CCRF-CEM cells, which take up folate exclusively through the reduced-folate carrier (inhibitable by suramin), whereas additivity was observed for KB cells, which rely largely on the folate-binding protein (unaffected by suramin) for folate import. Our results indicate that inhibition of cellular transport of folate compounds may explain part of the anti-neoplastic effects of suramin on tumor cells.
苏拉明是一种实验性抗肿瘤药物，在临床试验中已显示出对前列腺癌和淋巴瘤有良好的活性。为阐明其作用机制，研究了苏拉明对肿瘤细胞叶酸化合物转运的影响。发现抗叶酸甲氨蝶呤通过CCRF-CEM细胞的还原型叶酸载体系统流入对苏拉明抑制高度敏感，但对其他各种芳基磺酸不敏感。苏拉明的抑制作用是竞争性的，抑制常数Ki为1.3微摩尔，该值比甲氨蝶呤半最大流入量的Kt低3倍。苏拉明不影响叶酸与KB细胞膜相关叶酸结合蛋白的结合。生长研究表明，药理水平（10 - 200微摩尔）的苏拉明可使人类CCRF-CEM、KB、PC-3和MCF-7细胞对甲氨蝶呤的反应拮抗6至17倍。相反，当苏拉明与通过扩散进入细胞的亲脂性抗叶酸药物甲氨蝶呤联合使用时，生长抑制是相加或协同的。在仅通过还原型叶酸载体（可被苏拉明抑制）摄取叶酸的CCRF-CEM细胞中观察到甲氨蝶呤与苏拉明之间的协同作用，而对于主要依赖叶酸结合蛋白（不受苏拉明影响）进行叶酸摄取的KB细胞则观察到相加作用。我们的结果表明，抑制叶酸化合物的细胞转运可能解释了苏拉明对肿瘤细胞抗肿瘤作用的部分原因。
