Interleukin-1 (IL-1), a multifunctional cytokine, activates the immune system, potentiates hematopoiesis, and induces the synthesis of other cytokines and regulatory molecules (with effects on T cells, macrophages and endothelial cells). The ability of IL-1 to stimulate hematopoiesis and interact with other cytokines suggested that IL-1 might be able to increase the therapeutic index of cytotoxic drugs by reducing their dose limiting myelosuppression. Under support of this grant, we have demonstrated that IL-1alpha stimulates myeloid/monocyte progenitors with enhanced myeloid recovery by IL-1alpha in animals treated with cyclophosphamide and produces an acute hemorrhagic necrosis, restricted tumor blood flow and clonogenic cell kill in murine tumor model system. These significant acute anti-tumor activities are not the result of a direct anti-tumor effect, appear to be T cell independent and are not mediated through the biologically similar cytokine, tumor necrosis factor (TNF). In addition to IL-1alpha's acute effects, IL-1alpha has been shown to enhance cDDP mediated anti-tumor activity in vivo. Therefore, we propose to define and characterize the mechanisms of these two distinct anti-tumor activities, and whether they can be exploited for therapeutic use.
The aims of this study include: 1) To determine whether IL-1alpha/cDDP enhanced anti-tumor activity is the result of IL-1alpha induced changes in cDDP mediated DNA damage, tumor cell cycle status, or growth factor effects on tumor cells; 2) To determine whether IL-1alpha potentiates cDDP mediated anti-tumor activity through T cells, NK cells or induction of other cytokines (TNF/IL-6); 3) To determine whether IL-1alpha's anti-tumor activities are the result of direct effects on tumor endothelial cells; and 4) To establish whether IL-1 is the primary mediator of hemorrhagic necrosis by evaluating whether TNF and interferon (IFN) induced hemorrhage necrosis are mediated through IL-1. These studies will provide the groundwork for the use of IL-1 or related cytokines either alone or in combination with cytotoxic drugs for the therapy of human malignancies.
Showing the most recent 10 out of 21 publications
