Selected cytokines have been evaluated for their ability to regulate the development of early hematopoietic progenitor cells and thereby protect mice from the acute toxicity of lethal doses of chemotherapy. Both rIL-1Alpha and rTGFBeta1 have been shown to have potent regulatory effects on leukocytes and bone marrow-stem cells. A single intra-arterial (ia) injection of TGFBeta into normal BALB/c mice, transiently inhibits the proliferation of bone marrow cells by 30-50%. The formation of CFU-C from bone marrow is inhibited by about 30% and the formation of multipotential CFU-GEMM is inhibited by 50-100%. Because the number of CFU-GEMM per culture is quite low in normal marrow, we have also studied the ability of rTGFBeta1 to inhibit the formation of colonies during the hyperproliferative phase of bone marrow repopulation that ensues about 7-9 days after the administration of 150 mg/kg 5FU. A single ia administration of rTGFBeta1 also inhibits CFU-C by 30% and CFU-GEMM by about 50% in this setting. Subsequently, further studies have demonstrated that the administration of multiple doses of TGFBeta1 via the ip or iv routes has profound effects on the proliferation of progenitor cells. IL-1 also has myeloproliferative and chemoprotective effects. The daily (5-7 days) administration of rIL-1Alpha (greater than 10,000 U/day) protects 70-100% of mice from acutely toxic doses of several chemotherapeutic drugs. Current studies are focused on 1) the cellular and molecular mechanisms for the hematological and chemoprotective effects of rTGFBeta1 and rIL-1Alpha and 2) further investigation into improved therapeutic efficacy of intensified chemotherapy.
