McGuire J J, Haile W H
Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Arch Biochem Biophys. 1996 Nov 1;335(1):139-44. doi: 10.1006/abbi.1996.0491.
Suramin, a bis-hexasulfonated napthylurea, was studied as an inhibitor of human folylpolyglutamate synthetase (FPGS), a crucial enzyme in folate metabolism. Suramin is a more potent (IC50, 0.9 microM) inhibitor of FPGS partially purified from CCRF-CEM human leukemia cells than is bromosulfophthalein (IC50, 17 microM), the first reported nonsubstrate-analog inhibitor of FPGS (J. J. McGuire et al., Adv. Exptl. Med. Biol. 163, 199, 1983). FPGS inhibition by suramin is reversed by bovine serum albumin (which binds suramin). Suramin is a noncompetitive inhibitor with aminopterin (K(ii) = 0.9 microM; K(is) = 1.1 microM) and glutamic acid (K(ii) = 1.0 microM; K(is) = 5.2 microM) as the variable substrates; suramin inhibition tends toward being competitive with respect to the third FPGS substrate, ATP (K(ii) = 3.4 microM; K(is) = 0.35 microM), since the major effect is on its K(m). Suramin is a much less potent inhibitor of two other folate-dependent enzymes, dihydrofolate reductase (IC50, 38 microM; methotrexate (MTX), 0.6 nM) and thymidylate synthase (IC50, 87 microM; MTX, 48 microM). The effects of suramin on growth of CCRF-CEM cells and a MTX-resistant subline (R30dm) expressing low levels of FPGS activity were determined. R30dm is slightly collaterally sensitive to suramin consistent with FPGS inhibition contributing to the cytotoxic mechanism. These data, and those of Rideout et al. (Int. J. Cancer 61, 840, 1995), demonstrating that the reduced folate carrier system of CCRF-CEM is inhibited, suggest that inhibition of folate metabolism could be involved in the mechanism of action of suramin.
苏拉明是一种双六磺化萘脲，作为人叶酸聚谷氨酸合成酶（FPGS）的抑制剂进行了研究，FPGS是叶酸代谢中的一种关键酶。与首次报道的FPGS非底物类似物抑制剂溴磺酞（IC50，17 microM）相比，苏拉明是从CCRF-CEM人白血病细胞中部分纯化的FPGS的更有效抑制剂（IC50，0.9 microM）（J. J. 麦圭尔等人，《实验医学与生物学进展》163，199，1983）。苏拉明对FPGS的抑制作用可被牛血清白蛋白（与苏拉明结合）逆转。苏拉明是以氨蝶呤（K(ii)=0.9 microM；K(is)=1.1 microM）和谷氨酸（K(ii)=1.0 microM；K(is)=5.2 microM）作为可变底物的非竞争性抑制剂；就FPGS的第三种底物ATP而言，苏拉明的抑制作用趋于竞争性（K(ii)=3.4 microM；K(is)=0.35 microM），因为主要影响的是其K(m)。苏拉明对另外两种叶酸依赖性酶二氢叶酸还原酶（IC50，38 microM；甲氨蝶呤（MTX），0.6 nM）和胸苷酸合成酶（IC50，87 microM；MTX，48 microM）的抑制作用要弱得多。测定了苏拉明对CCRF-CEM细胞和表达低水平FPGS活性的MTX耐药亚系（R30dm）生长的影响。R30dm对苏拉明有轻微的旁系敏感性，这与FPGS抑制作用参与细胞毒性机制一致。这些数据，以及里德奥特等人（《国际癌症杂志》61，840，1995）的数据表明CCRF-CEM的还原叶酸载体系统受到抑制，提示叶酸代谢的抑制可能参与了苏拉明的作用机制。
