Hematopoietic recovery after autologous bone marrow transplantation (AMT) can be significantly improved by the use of hematopoietic growth factors such as G-CSF that stimulate specific cell populations. The number of different growth factors available for clinical evaluation will soon exceed the number that can reasonably be tested. Many of these cytokines exhibit redundant functional activities and may or may not be able to increase overall therapeutic effect. Thus, there is a need for preclinical """"""""head- to-head"""""""" evaluation of related molecules with overlapping functions, prior to choosing candidates for Phase I clinical trials. One basis for prioritization is molecular structure: gene organization, sequence homologies, and similarities in tertiary structure suggest that certain cytokines have evolved from a common ancestral gene. Such a relationship has recently been discovered for four cytokines: G-CSF, IL-6, leukemia inhibitory factor (LIF), and oncostatin M (OSM). Each of the four was, in fact, first discovered in a different biological assay. Some functional similarities have been observed among these molecules, but direct comparisons are needed to determine whether therapeutic effects observed with G-CSF will be equalled, surpassed, or complimented by other members of this novel subfamily. Project 13 will evaluate growth regulatory functions of all four cytokines, both in vitro and in vivo, in identical experimental systems to determine if their clinical effects may be expected to be competitive, additive, or synergistic. The factors will be tested for inhibitory effects on tumor cell lines for stimulatory effects on embryonic cells and normal stem cells, and for regulatory effects on genes that control proliferation and differentiation. In vivo studies will compare the effects of the four family members on normal marrow function in mice and dogs. Such studies will be used to predict which of the molecules may be most effective in a canine hematopoietic recovery model, and these predictions will be tested in the second and third years of the project. This systematic study of biological activity, directly comparing these structurally-related cytokines, (one of which, G-CSF, has already been shown to have clinical utility) will allow correlation of functional effects with structural organization. the objective of the project is to evaluate the other three factors to develop, based on preclinical data, improved treatment regimens for AMT.
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