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. RIL- 1alpha, rTGFbeta1, and rIL-7 have been shown to have potent regulatory effects on leukocytes and bone marrow stem cells. The administration of rTGFbeta1 via the ip or iv routes inhibits the proliferation of CFU-c, CFU-GEMM, and HPP-CFC progenitor cells, and partially protects against the acute toxicity induced by high doses of doxorubicin. rIL-1alpha also has myeloproliferative and chemoprotective effects, whereby the daily (5-7 days) administration of greater than 10,000 U/day protects 50-100% of mice from acutely toxic doses of cyclophosphamide, 5FU, carboplatin, VP-16, and BCNU. In addition, the combination of rIL- 1alpha with several chemotherapeutic drugs results in increased antitumor effects in vivo or in vitro. Specifically, rIL-1alpha synergizes with VP-16 for direct lysis of the human A375/C6, SKMEL-3, and OVCAR-3 tumors, as well as the Renca mouse tumor in vitro. Further the combination of rIL-1alpha and VP-16 exhibits enhanced antitumor effects against A375/C6 and Renca in vivo. Potent hematopoietic effects have also been observed following the administration of rIL-7 to mice, whereby CFU-C and CFU-GEMM progenitors are suppressed in the bone marrow, but augmented in the spleen and liver. Interestingly, administration of rIL-7 to mice accelerates the recovery of T cell subsets following a bone marrow transplant and after treatment with high dose chemotherapy. Current studies are focused on 1) the cellular and molecular mechanisms for the hematological effects of rTGFbeta1, rIL- 1alpha, rIL-7, and 2) further investigation into improved therapeutic efficacy of intensified chemotherapy.
