Jindal H K, Anderson C W, Davis R G, Vishwanatha J K
Department of Biochemistry, University of Nebraska Medical Center, Omaha 68198-4525.
Cancer Res. 1990 Dec 15;50(24):7754-7.
Suramin, a polysulfonated naphthylurea widely used in the treatment of trypanosomiasis and onchocerciasis, is currently being investigated as an antitumor agent for the treatment of advanced cancer. Suramin exerts a wide variety of biological effects. We have shown that suramin inhibits cell proliferation and DNA synthesis in cultured HeLa cells. The replication in vitro of SV40 DNA is completely abolished by 40 microM suramin. The inhibition of DNA replication is due to inhibition of DNA polymerases alpha and delta, the replicative enzymes in eukaryotic cells. DNA polymerase alpha is sensitive to lower concentrations of suramin [concentration to achieve 50% inhibition (IC50) of 8 microM] than is DNA polymerase delta (IC50 36 microM), whereas DNA polymerase beta is relatively insensitive to the drug (IC50 of 90 microM). Suramin inhibits other replicative DNA polymerases such as Escherichia coli polymerase I (Klenow fragment) and Thermus aquaticus polymerase. Suramin is noncompetitive with both substrate deoxyribonucleotides and template-primers with respect to DNA polymerase inhibition. Much lower concentrations (8-30 microM) of the drug are required for 50% inhibition of DNA polymerases than for 50% inhibition of other enzymes such as protein kinase C and reverse transcriptase. These results show an important biological effect of this drug and indicate the need for more studies before its clinical use as an antitumor agent.
苏拉明是一种广泛用于治疗锥虫病和盘尾丝虫病的多磺酸萘脲，目前正作为一种治疗晚期癌症的抗肿瘤药物进行研究。苏拉明具有多种生物学效应。我们已经表明，苏拉明可抑制培养的HeLa细胞的细胞增殖和DNA合成。40微摩尔的苏拉明可完全消除SV40 DNA在体外的复制。DNA复制的抑制是由于抑制了DNA聚合酶α和δ，这两种酶是真核细胞中的复制酶。DNA聚合酶α比DNA聚合酶δ对较低浓度的苏拉明更敏感[达到50%抑制（IC50）的浓度为8微摩尔]，而DNA聚合酶β对该药物相对不敏感（IC50为90微摩尔）。苏拉明可抑制其他复制性DNA聚合酶，如大肠杆菌聚合酶I（克列诺片段）和嗜热栖热菌聚合酶。就DNA聚合酶抑制而言，苏拉明与底物脱氧核糖核苷酸和模板引物均无竞争性。与50%抑制其他酶（如蛋白激酶C和逆转录酶）相比，50%抑制DNA聚合酶所需的药物浓度要低得多（8 - 30微摩尔）。这些结果显示了这种药物的重要生物学效应，并表明在其作为抗肿瘤药物临床应用之前需要进行更多研究。
