SPID#: 27 High-dose, marrow lethal chemotherapy (+ radiation therapy) with stem cell support is an established, potentially curative treatment modality for patients with a variety of malignancies. The major toxicity of such aggressive treatment is pancytopenia with a resultant increase in susceptibility to infections, and necessitating platelet and red cell transfusions. Recombinant human G-CSF and GM-CSF have been shown to be clinically useful in shortening the period of neutropenia following chemotherapy, with or without stem cell rescue. The optimal means to enhance regeneration of thrombocytes as well as various immunocytes has yet to be defined, although rhIL-6, rhIL-11, and rhIL-3 and the GM- CSF/IL-3 fusion protein, PIXY 321, all have been demonstrated to have enhancing effects on thrombopoietic regeneration following marrow injury. The number of primitive immuno-hematopoietic regenerating cells in the cell preparation used for grafting after severe marrow damaging chemotherapy directly influences cytokine effectiveness during marrow regeneration. Therefore, reliable methods to enhance the content of regenerating cells in the cell preparation infused following marrow lethal chemo/irradiation therapy are essential. Ideal for this purpose should be the in vivo administration of a cytokine (or cytokines) that stimulates amplification of the cells with the highest proliferative and differentiative capacity (e.g. stem cells or their immediate progeny) prior to collection of the cells to be used for post-treatment hematopoietic rescue. Flk2/flt3 is a receptor tyrosine kinase identified on brain, placental, testicular and primitive murine hematopoietic cells . The murine flt3 ligand has been recently cloned and has been shown to stimulate proliferation of primitive hematopoietic cells. Flt-3 ligand also functions as an enhancing factor to other early acting cytokines such as Steel factor, IL-6 and IL-3. Therefore, flt-3 ligand, administered in vivo as a single agent or in combination, may be useful for enriching the marrow or blood content of early regenerating cells. The human homologue of murine flt3 ligand has recently been cloned (rh- flt3 ligand). In the proposed experiments, we administered rh-flt3 to rhesus macaques and assessed blood and marrow for changes in the content of primitive immuno-hematopoietic cells. This cytokine proved highly effective in amplifying marrow clonogenic myeloid cells and CD34+ cells, and mobilizing these cells to the peripheral circulation.
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