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 a potent positive regulator (IL-1) of hematopoiesis are contrasted with the effects TGF-beta1, a potent negative regulator of hematopoiesis for various cancer chemotherapeutic drugs. In addition, the ability of cytokines to mobilize pluripotent stem cells into the peripheral blood is also under study. The ultimate goals of these studies are to determine optimum approaches for chemoprotection in preclinical tumor models, to determine whether cytokine-permitted dose escalation of chemotherapy yields better antitumor effects, and then to propose appropriate combinations of positive and/or negative regulators for amelioration of myelosuppression in clinical trials. We have already demonstrated that pretreatment with IL-1 permits the dose escalation of a variety of chemotherapeutic drugs, and that TGF-beta is a potent, but reversible, negative regulator of myelopoiesis in mice with progenitor for CFU-c, CFU- GEMM, and HPP-CFC all exhibiting some sensitivity. Treatment of proliferating progenitor cells with rhTGF-beta1, or rhTGF-beta2 in vivo partially protects these progenitors toxicity of 5FU in vitro and under some conditions results in improved hematopoietic responses in vivo. Interestingly, rhTGFbeta is most effective in vivo in protecting mice from acutely toxic doses of doxorubicin hydrochloride. The mechanism for the hematopoietic and chemoprotective effects of TGF-beta are being studied at the cellular and molecular levels. We have also found that the repeat 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. These results suggest that IL-7 may be useful for stem cell transfer int myeloablated cancer patients.
