A major limiting toxic side-effect of many cancer chemotherapeutic regimens is a severe and occasionally fatal suppression of hematopoiesis. Specifically, this toxicity results in the development of neutropenia and/or thrombocytopenia. The degree and extent of damage to the hematopoietic system usually is the major limiting factor that determines the feasibility of delivering further tumor control doses of therapy. The development of specific agents that may either enhance the recovery of blood cell production or reduce the degree of hematopoietic suppression could have important clinical applications. It is the purpose of this proposal to conduct investigations to examine the myelopoietic and thrombopoietic activity of the monokine-interleukin-1 (IL-1). Studies will focus on the ability of IL-1 to influence regenerating hematopoiesis either before or following drug administration in a suitable animal and human model. The drugs to be used are vinblastine, cyclophosphamide, colchicine, cytosine arabinoside, actinomycin-D, 5-fluorouracil, methotrexate and bleomycin. The protocols will evaluate the direct in vivo and in vitro effects of this potentially useful chemical probe as well as to determine the most efficacious use of IL-I treatment to provide either for the prevention of hematopoietic suppression or possibly by enhancing hematopoietic recovery following drug administration. In vivo and in vitro studies will incorporate the ability of these agents to examine their effect on various peripheral blood indices (hematocrit, WBC, platelets and differential), while also examining the stem cell content in hematopoietic tissues (bone marrow and spleen) by the following in vivo (CFU-S, CFU-DG) and in vitro stem cell assays (CFU-Mix, CFU-E, BFU-E, CFU-GM, CFU-Meg, and stromal cells). In addition serum will be analyzed for their GM-CSA, Meg- CSA and BPA content. If accomplished, IL-1 by reversing or preventing the onset of neutropenia and/or thrombocytopenic episodes, may then decrease the chance of infection and bleeding, thus permitting longer and possibly more intensive chemotherapy. Preliminary results indicate that IL-1 indeed may provide a significant degree of protection to item cells against drug induced toxicity. Toward this long-term goal to develop a specific agent(s) that may either enhance the recovery of blood cell production or reduce hematopoietic damage as the result of chemotherapy, therefore, may have important clinical applications.
