Myelosuppression is a major dose-limiting toxicity of many widely used cancer chemotherapeutic drugs. This toxicity limits the absolute amount of drug that can be given at one time, as well as the number of cycles that can be delivered. This project studies two different approaches to circumvention of chemotherapy-induced toxicity in which the effects of positive regulators (IL-7, G-CSF) of hematopoiesis are contrasted with the effects TGF-beta, a potent negative regulator of hematopoiesis. The ultimate goals of these studies are to determine whether cytokine-permitted dose escalation of chemotherapy yields better antitumor effects, to propose appropriate combinations of positive and/or negative regulators for amelioration of myelosuppression in clinical trials, and whether better approaches to the mobilization of pluripotent stem cells can be developed. We have already demonstrated that TGF-beta is a potent, but reversible, negative regulator of myelopoiesis in mice with progenitors for CFU-c, CFU- GEMM, and HPP-CFC all exhibiting some sensitivity. Treatment of proliferating progenitor and pluripotent stem cells with rhTGF-beta1, or rhTGF-beta2 in vivo partially protects these cells from toxicity by 5FU in vitro and under some conditions results in significantly improved hematopoietic responses in vivo. The mechanism for the hematopoietic and chemoprotective effects of TGF-beta is being studied at the cellular and molecular levels. We have also found that the repeated injection of IL-7 to mice mobilizes hematopoietic progenitor and pluripotent stem cells into the peripheral blood such that PBL from IL-7-treated mice are able to completely reconstitute irradiated recipient mice. Further, IL-7 synergizes with G-CSF for mobilization of these various cell types. There are qualitative differences between these two cytokines in terms of the cycling status of mobilized precursors (i.e. G-CSF mobilizes cell that are non-cycling, while IL-7 actively cycling). These results suggest that IL-7 may be useful for stem cell transfer into myeloablated cancer patients as well as generation of cells that could be targeted for a gene transfer.
