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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA048077-06
Application #
3192034
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1989-09-01
Project End
1994-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
6
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Eye and Ear Institute of Pittsburgh
Department
Type
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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