SURAMIN IN LYMPHOMA--CLINICAL AND MECHANISTIC STUDIES

苏拉明是一种聚磺化硫脲，具有重要的临床应用价值。 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 是相当可观的。尽管苏拉明与许多生物蛋白结合 但其抗肿瘤作用机制尚不清楚。在……里面 此外，人们对其细胞药理学知之甚少。 苏拉明：这些知识对于发展更多的临床知识是至关重要的 有效的苏拉明类似物。我们建议苏拉明进行二期临床试验。 化疗难治性低度恶性淋巴瘤。所有患者都将接受 苏拉明按NCI固定间歇给药方案进行治疗。 患者将接受肿瘤沉积物的活组织检查，而恶性的 获得的淋巴细胞将在短期培养中培养出来，用于研究。 如下所示。苏拉明的应答率，有足够的统计数据 权力，将被决定。我们假设如下参数：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)细胞内模式 分布；4)流出速率和机制；5)可获得性 苏拉明可能的细胞内靶向机制将影响 应答率。我们将获得荧光标记的苏拉明类似物， 并将监测肿瘤的内吞和胞吐的比率 用流式细胞术检测活检标本和淋巴样细胞系。我们会 通过以下方法确定荧光素-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类药物处理细胞 抗生素巴菲罗星，它能特异性地阻断H+- 液泡型ATPase。我们将计算动力学常数A，α，B 含苏拉明的细胞内平均pH 车厢将被计算。苏拉明的近似浓度 细胞质隔间的可利用性将被确定，并且 该隔室中的浓度因渗透裂解而增加 内生体。当从活检中获得这些数据时，我们将对这些数据进行关联 标本，并观察到临床反应。作为努力的一部分 为了提高苏拉明的疗效，我们将获得和 评估Rideout D.博士的苏拉明类似物。将对这些项目进行评估 在苏拉明具有活性的选定系统中。这些系统是 1)抑制活检来源的恶性淋巴细胞的生长和 淋巴瘤细胞系；2)结合肝素结合生长因子(bFGF， PDGF)与其细胞表面受体结合；3)低密度脂蛋白与转铁蛋白的结合 4)对PKC-β1的抑制作用 磷酸化能力；以及5)抑制酶的活性 糖胺聚糖分解酶L-艾杜糖酸硫酸酯酶和β- 葡萄糖醛酸酶。这些数据将有助于确定其作用机制。 苏拉明，以及为进一步的药物开发提供线索。

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.