SURAMIN IN LYMPHOMA--CLINICAL AND MECHANISTIC STUDIES

苏拉明是一种多磺化的尿嘧啶类药物， 抗转移性激素难治性前列腺癌的活性， 低度恶性淋巴瘤 然而，在这些早期试验中观察到的毒性 是很重要的 虽然苏拉明与许多生物蛋白质结合， 有趣的是，其抗肿瘤作用机制仍然不清楚。 在 此外，很少有人了解的细胞药理学， 苏拉明：这些知识对于临床发展至关重要 有效的苏拉明类似物。 我们建议进行苏拉明的第二阶段试验， 化疗难治性低度恶性淋巴瘤 所有患者将进行 通过NCI固定间歇推注时间表用苏拉明治疗。 患者将进行肿瘤存款活检，恶性肿瘤 获得的淋巴细胞将在短期培养中生长以进行研究 下面给出。 对苏拉明的反应率，有足够的统计学 力量，将被决定。 我们假设，参数，如1） 细胞表面结合的动力学和平衡参数; 2）速率和 内化机制; 3）细胞内 分布; 4）外排率和机制; 5） 苏拉明的假定细胞内靶向机制将影响 答复率。 我们将获得荧光标记的苏拉明类似物， 并将监测肿瘤细胞内吞和胞吐的速率， 活检标本和淋巴细胞系使用流式细胞术。 我们将 确定荧光素-苏拉明是否进入酸性环境， 用离子载体莫能菌素和大环内酯处理细胞 抗生素巴弗洛霉素，它特异性地阻断H+- 液泡ATP酶 我们将计算动力学常数A，alpha，B β等。含苏拉明细胞的平均细胞内pH 将计算车厢。 苏拉明的近似浓度 将确定细胞质隔室的可用性，并且 通过渗透裂解增加该隔室中的浓度， 核内体 当从活检中获得这些数据时， 标本，以及观察到的临床反应。 作为努力的一部分 为了提高苏拉明的治疗效果，我们将获得 评估D.博士的苏拉明类似物，骑马 这些将被评估 在苏拉明具有活性的选定系统中， 这些系统 1)抑制活检衍生的恶性淋巴细胞的生长， 淋巴瘤细胞系; 2）肝素结合生长因子（bFGF， PDGF）与其细胞表面受体的结合; 3）LDL与转铁蛋白的结合 在其细胞表面受体中; 4）抑制PKC-β 1 磷酸化能力;和5）抑制磷酸化酶的活性。 糖胺聚糖分解代谢酶L-艾杜糖醛酸硫酸酯酶和β- 葡萄糖醛酸酶。 这些数据将有助于确定 苏拉明，并为进一步药物开发提供线索。

Suramin is a polysulfonated nephthylurea with significant clinical activity against metastatic hormone refractory cancer of the prostate and low grade lymphoma. However, the toxicity observed in these early trials was substantial. Although suramin binds to many proteins of biological interest, its anti-tumor mechanism of action remains obscure. In addition, very little is understood about the cellular pharmacology of suramin: Such knowledge is vital in order to develop more clinically effective suramin analogs. We propose a Phase II trial of suramin in chemotherapy refractory low grade lymphoma. All patients will undergo treatment with suramin by the NCI fixed intermittent bolus schedule. Patients will have a tumor deposit biopsied, and the malignant lymphocytes obtained will be grown in short term culture for the studies given below. The response rate to suramin, with sufficient statistical power, will be determined. We hypothesize that parameters such as 1) kinetic and equilibrium parameters of cell surface binding; 2) rates and mechanisms of internalization; 3) patterns of intracellular distribution; 4) rates and mechanisms of efflux; 5) accessibility of the putative intracellular target mechanisms to suramin will affect the response rates. We will obtain fluorescently-labeled suramin analogs, and will monitor the rates of endocytosis and exocytosis, both in tumor biopsy specimens and lymphoid cell lines using flow cytometry. We will determine if fluorescein-suramin enters an acidic environment by treatment of cell with the ionophore monensin, and with the macrolide antibiotic bafilomycin, which specifically blocks the function of the H+- vacuolar ATPase. We will calculate the kinetic constants A, alpha, B Beta, etc. The average intracellular pH of the suramin-containing compartment will be calculated. The approximate concentration of suramin available to the cytoplasmic compartment will be determined, and the concentration in this compartment increased by osmotic lysis of the endosome. We will correlate these data, when obtained from biopsy specimens, with the observed clinical responses. As part of the effort to improve the therapeutic efficacy of suramin, we will obtain and evaluate suramin analogs from Dr. D., Rideout. These will be evaluated in selected systems in which suramin has activity,. These systems are 1) Inhibition of growth of biopsy derived malignant lymphocytes and lymphoma cell lines; 2) Binding of heparin-binding growth factors (bFGF, PDGF) to their cell surface receptors; 3) Binding of LDL and transferrin in their cell surface receptors; 4) Inhibition of PKC-Beta1 phosphorylating ability; and 5) Inhibition of the activity of the glycosaminoglycan catabolizing enzymes L-iduronate sulfatase and Beta- glucuronidase. These data will help define the mechanism of action of suramin, as well as provide leads for further drug development.