IN VITRO CORRELATIONS OF SURAMIN RESPONSE IN MELANOMA

黑色素瘤中苏拉明反应的体外相关性

• 批准号: 3423428
• 负责人: CHARLES W TAYLOR
• 金额: $ 7.11万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-01 至 1992-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3423428
• 关键词: biopsy; clinical trials; epidermal growth factor; flow cytometry; growth factor receptors; human subject; human therapy evaluation; human tissue; immunocytochemistry; melanoma; metastasis; neoplasm /cancer chemotherapy; neoplastic cell; plaque assay; receptor expression; suramin; tissue /cell culture

Suramin is a polyanionic napthylurea used since the 1920s as an anti-parasitic agent. Recently, suramin was found to have antiretroviral and antitumor activities. It has been tested clinically in patients with AIDS, and has shown some antitumor activity in adrenocortical cancer, renal cancer and prostate cancer. Suramin binds tumor growth factors (e.g., epidermal growth factor, platelet derived growth factor) in vitro and thus potentially has a novel antitumor mechanism. The growth and differentiation of malignant melanoma is influenced by a number of growth factors including epidermal growth factor (EGF). Patients with advanced melanoma have poor clinical outcomes. A generally effective treatment with survival benefit is not available. Suramin has been tested in vitro, against fresh melanoma biopsy specimens in the Human Tumor Colony Forming Assay (HTCA) at the University of Arizona. Approximately 57% of the tumor specimens were sensitive (survival less than 30% of control). The in vitro results with suramin are much better than other agents commonly used to treat melanoma (DTIC, Cisplatin, vinca alkaloids, alpha interferon). The major hypothesis of this investigation is that suramin has antitumor activity against malignant melanoma. The objectives related to this hypothesis are to study suramin in a phase II clinical trial in patients with metastatic melanoma and to further test the in vitro suramin sensitivity of fresh melanoma biopsy specimens from patients entered on the clinical trial using the HTCA and the in vitro sensitivity of early passage melanoma cell lines using the HTCA and MTT assays. The relationship between in vitro suramin sensitivity and the clinical antitumor activity of suramin will be examined. The second hypothesis of this investigation is that the antitumor activity of suramin is mediated via its ability to bind tumor growth factors, such as EGF, thus interrupting a pathway of autocrine growth stimulation. Tumors with EGF growth dependence are expected to express the cell surface receptor for EGF. The major objective related to the second hypothesis will be to determine the frequency of expression at the EGF receptor on clinical melanoma specimens and the early passage melanoma cell lines using an anti-EGF receptor monoclonal antibody in flow cytometric and immunohistochemical methods. EGF receptor expression will be correlated with antitumor activity.

苏拉明是一种聚阴离子萘脲，自 20 年代起用作 抗寄生虫剂。最近，苏拉明被发现具有抗逆转录病毒作用 和抗肿瘤活性。它已在患有以下疾病的患者中进行了临床测试 艾滋病，并在肾上腺皮质癌、肾癌中表现出一定的抗肿瘤活性 癌症和前列腺癌。苏拉明结合肿瘤生长因子（例如， 表皮生长因子、血小板衍生生长因子）在体外，因此 可能具有新颖的抗肿瘤机制。成长与分化 恶性黑色素瘤的发生受到多种生长因子的影响，包括 表皮生长因子（EGF）。晚期黑色素瘤患者病情较差 临床结果。具有生存益处的普遍有效的治疗方法是 无法使用。苏拉明已针对新鲜黑色素瘤进行了体外测试 人类肿瘤集落形成试验 (HTCA) 中的活检标本 亚利桑那大学。大约57%的肿瘤标本 敏感（存活率低于对照的 30%）。体外结果与 苏拉明比其他常用于治疗黑色素瘤的药物要好得多 （DTIC、顺铂、长春花生物碱、α 干扰素）。主要假设 这项研究的重点是苏拉明具有抗肿瘤活性 恶性黑色素瘤。与该假设相关的目标是研究 苏拉明在转移性黑色素瘤患者的 II 期临床试验中 并进一步测试新鲜黑色素瘤的体外苏拉明敏感性 使用 HTCA 参加临床试验的患者的活检标本 以及早期传代黑色素瘤细胞系的体外敏感性 HTCA 和 MTT 测定。体外苏拉明敏感性的关系 并检查苏拉明的临床抗肿瘤活性。第二个 这项研究的假设是苏拉明的抗肿瘤活性 是通过其结合肿瘤生长因子（例如 EGF）的能力介导的，因此 中断自分泌生长刺激的途径。具有 EGF 的肿瘤 预计生长依赖性表达细胞表面受体 表皮生长因子。与第二个假设相关的主要目标是 确定临床上 EGF 受体的表达频率 黑色素瘤标本和早期传代黑色素瘤细胞系 流式细胞仪中的抗 EGF 受体单克隆抗体和 免疫组织化学方法。 EGF受体表达将相关 具有抗肿瘤活性。