ANTITUMOR ACTIVITY OF RECOMBINANT INTERLEUKIN I

该项目的总体目标是确定参与 重组人IL-1对RIF-1和Panc 02小鼠的抗肿瘤活性 肿瘤模型，并研究新的方法来治疗实体瘤， 联合IL-1和化疗。克隆原性细胞存活和再生长 延迟终点将用于确定剂量和时间依赖性IL-1 介导的肿瘤细胞毒性。由于IL-1对RIF-1细胞没有细胞毒性，因此， 连续培养，体内细胞毒性可能由肿瘤宿主介导 细胞这一假设将在研究中进行检验，以确定 IL-1介导的肿瘤细胞中的肿瘤巨噬细胞及其产物（例如TNF） 在体内杀死。 IL-1介导的血管和增殖反应可影响细胞增殖， 其他治疗方式在实体瘤中的有效性。时间和 将进行剂量反应研究以确定IL-1对 血流、血管通畅性、肿瘤pH和肿瘤中的水分布， 正常组织同位素稀释法。肾上腺的调节作用 激素和洋地黄素，在IL-1介导的血管反应， 肿瘤血流量和肿瘤pH值降低在IL-1介导的 细胞毒性，将进行研究。由于IL-1可能与其他 方式，免疫抑制治疗的效果（化疗，手术） 对IL-1抗肿瘤活性的影响。这些信息 实验将用于设计治疗策略， 应用化疗药物（Cp、Adr、脂质体包裹Adr）， IL-1介导的抗肿瘤活性。这些战略将在 RIF-1和Panc 02肿瘤，使用克隆源性细胞存活和再生长延迟 端点。 这些研究的结果将提供概念框架， IL-1作为单一药剂和与化疗组合的用途， 手术，以改善人类恶性肿瘤的管理。

The overall goal of this project is to define mechanisms involved in the antitumor activity of human recombinant IL-1 in RIF-1 and Panc02 murine tumor models, and to investigate new approaches to solid tumor therapy by combining IL-1 and chemotherapy. Clonogenic cell survival and regrowth delay endpoints will be used to determine dose and time dependent IL-1 mediated tumor cytotoxicity. Since IL-1 is not cytotoxic to RIF-1 cells, in continuous culture, in vivo cytotoxicity is likely mediated by tumor host cells. This hypothesis will be tested in studies to define the role of tumor macrophages and their products (e.g. TNF) in IL-1 mediated tumor cell kill in vivo. IL-1 mediated vascular and proliferative responses could influence the effectiveness of other therapeutic modalities in solid tumors. Time and dose response studies will be conducted to determine the effects of IL-1 on blood flow, vascular patency tumor pH and water distribution in tumor and normal tissues by isotope dilution methods. The regulatory role of adrenal hormones and prostaglandins, in IL-1 mediated vascular responses, and the importance of reduced tumor blood flow and tumor pH, in IL-1 mediated cytotoxicity, will be studied. Since IL-1 might be used with other modalities, the effect of immunosuppressive therapy (chemotherapy, surgery) on IL-1 antitumor activity will be determined. The information from these experiments will be used to design therapeutic strategies in which chemotherapy (Cp, Adr, liposome encapsulated Adr) is applied to exploit IL-1 mediated antitumor activities. These strategies will be tested in RIF-1 and Panc02 tumors, using clonogenic cell survival and regrowth delay endpoints. The results from these studies will provide the conceptual framework for the use of IL-1, as a single agent and in combination with chemotherapy and surgery, to improve the management of human malignancies.