ANTITUMOR ACTIVITY OF RECOMBINANT INTERLEUKIN I

该项目的总体目标是定义 重组人IL-1对RIF-1和Panc02小鼠的抗肿瘤活性 肿瘤模型，并探索实体肿瘤治疗的新方法 联合IL-1和化疗。克隆细胞的存活和再生 延迟终点将用于确定剂量和时间依赖的IL-1 介导的肿瘤细胞毒作用。由于IL-1对RIF-1细胞没有细胞毒性，因此在 连续培养，体内细胞毒作用可能由肿瘤宿主介导 细胞。这一假设将在研究中得到验证，以确定 IL-1介导的肿瘤细胞中的肿瘤巨噬细胞及其产物(如肿瘤坏死因子) 活体内杀戮。 IL-1介导的血管和增殖反应可影响血管内皮细胞 实体瘤其他治疗方法的有效性。时间和 将进行剂量反应研究，以确定IL-1对 肿瘤的血流量、血管通畅度、pH和水分分布 用同位素稀释法测定正常组织。肾上腺的调节作用 IL-1介导的血管反应中的激素和前列腺素，以及 肿瘤血流量和肿瘤pH值降低在IL-1介导中的重要性 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的抗肿瘤活性进行测定。来自这些的信息 实验将被用于设计治疗策略，其中 化疗(CP、ADR、脂质体包裹ADR)用于开发 IL-1介导的抗肿瘤活性。这些策略将在 RIF-1和Panc02肿瘤，利用克隆细胞存活和再生长延迟 终端。 这些研究的结果将为 使用IL-1作为单一药物并与化疗和 外科手术，以改善对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.