La Rocca R V, Danesi R, Cooper M R, Jamis-Dow C A, Ewing M W, Linehan W M, Myers C E
Medicine Branch, National Cancer Institute, Bethesda, Maryland 20892.
J Urol. 1991 Feb;145(2):393-8. doi: 10.1016/s0022-5347(17)38351-9.
Suramin, a polyanionic compound with known antiparasitic activity, has been shown to be adrenocorticolytic in primates and to have clinical efficacy in the treatment of patients with metastatic prostate cancer refractory to conventional hormonal manipulation. To better characterize the activity of suramin on prostate cancer biology, we studied the effect of the drug on plasma adrenal androgens of patients and on the human prostate adenocarcinoma cell lines PC-3, DU 145 and LNCaP-FGC. Five cancer patients treated with suramin had an approximate 40% decline in circulating androstenedione, dehydroepiandrosterone and dehydroepiandrosterone sulfate levels. The drug inhibited the colony formation in two of the three cell lines at concentrations clinically achievable in humans without excessive drug-related toxicity. The presence of suramin 300 micrograms./ml. partially inhibited the growth stimulatory effect of testosterone and basic fibroblast growth factor, but not that of epidermal growth factor. The cellular concentration of suramin following exposure to a single dose increases linearly over time in each of the cell lines with LNCaP-FGC accumulating the highest levels of the drug; cellular levels of suramin, not androgen or growth factor sensitivity, correlated with the sensitivity to the drug. The concentrations of prostatic acid phosphatase and prostatic specific antigen released by LNCaP-FGC cells in cell culture medium declined in the presence of increasing levels of suramin in a manner which exceeded the decrease in cell number. We conclude that suramin, aside from decreasing circulating androgens through its adrenocorticolytic effect, is also capable exerting a direct inhibitory effect on cell proliferation of prostate cancer cells, and interfere at a cellular level with the growth stimulatory effects of exogenous testosterone and basic fibroblast growth factor.
苏拉明是一种具有已知抗寄生虫活性的多阴离子化合物，已被证明在灵长类动物中具有肾上腺皮质溶解作用，并在治疗对传统激素治疗无效的转移性前列腺癌患者方面具有临床疗效。为了更好地表征苏拉明对前列腺癌生物学的活性，我们研究了该药物对患者血浆肾上腺雄激素以及人前列腺腺癌细胞系PC-3、DU 145和LNCaP-FGC的影响。接受苏拉明治疗的5名癌症患者，其循环中的雄烯二酮、脱氢表雄酮和硫酸脱氢表雄酮水平大约下降了40%。该药物在人体可达到的临床浓度下，且无过度药物相关毒性的情况下，抑制了三种细胞系中两种的集落形成。300微克/毫升的苏拉明部分抑制了睾酮和碱性成纤维细胞生长因子的生长刺激作用，但对表皮生长因子的作用无抑制效果。在每个细胞系中，单次给药后，苏拉明的细胞浓度随时间呈线性增加，其中LNCaP-FGC积累的药物水平最高；苏拉明的细胞水平与药物敏感性相关，而非雄激素或生长因子敏感性。在细胞培养基中，随着苏拉明水平的增加，LNCaP-FGC细胞释放的前列腺酸性磷酸酶和前列腺特异性抗原的浓度下降，其下降方式超过了细胞数量的减少。我们得出结论，苏拉明除了通过其肾上腺皮质溶解作用降低循环雄激素外，还能够对前列腺癌细胞的细胞增殖产生直接抑制作用，并在细胞水平上干扰外源性睾酮和碱性成纤维细胞生长因子的生长刺激作用。
