The underlying consequences of normal tissue toxicity continue to limit even the most effective therapeutic agents in the management of cancer. One recently proposed solution to this problem is the use of biological molecules (and/or cytokines) that stimulate hematopoietic stem cell subpopulations (HSC-SP's) that serve as respective target cells. Recognizing that toxicity involves both cell kill as well as a (temporal) recovery component, several of these cytokines (e.g. IL-1, IL-3, M-CSF) have the potential to influence hematopoietic toxicity via two mechanisms: (a) by a redistribution of the HSC-SP's into a more resistant configuration, and (b) by accelerating the recovery rate through the stimulation of those HSC-SP's involved in repopulation. Since their first recognition as potential """"""""biological"""""""" protectors, however, sufficient evidence has been provided to suggest that the cytokine(s) influence in vivo may be far more complex than originally suspected. We will, therefore, establish a comprehensive data base for the biological response to four hematopoietic cytokines (IL-1, IL-3, M-CSF,K GM-CSF) administered in vivo with emphasis on the following considerations: (a) acute vs prolonged (either abbreviated or protracted) treatment; (b) primary and secondary target cells for individual cytokines; (c) multiple cytokine treatment (concomitant vs concatenated interactions); and (d) sequencing for HSC-SP's, progenitor cells and secondary targets in the microenvironment. Using this information, we will define optimal cytokine schedules for integrating into treatment protocols to prevent (or reduce) the respective toxicities associated with the development of acute (5-FU), delayed (CTx) or residual (AdR) lesions in the marrow. Both """"""""priming"""""""" (pre-drug) and """"""""rescue"""""""" (post-drug) approaches for protection will be investigated. After having established a paradigm for hematopoietic protection, we will determine whether this paradigm is effective for (a) gastrointestinal toxicity, (b) both the marrow and GI under tumor-induced altered physiologies,k and (c) enhancing the therapeutic ratio for the representative drugs studied. Collectively, these studies will provide a more rational approach to chemoprotection based on biological response to the cytokines (either alone or combined) which could then be incorporated into clinical studies of dose intensification.
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