SPID#: 29 High-dose chemotherapy and marrow lethal chemotherapy with marrow or peripheral blood stem cell support are established, potentially curative treatment modalities for patients with a variety of malignancies. The major toxicity of such aggressive treatment is marrow damage with low blood counts, 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. The optimal means to enhance multilineage marrow and immunocyte regeneration has yet to be defined. In addition, little is known about the potential for cytokines to protect stem cells from the cumulative damaging effects of prolonged chemotherapy courses. IL-3 has been demonstrated to have enhancing effects on multiple lineages following marrow injury, but side effects related to histamine release associated with higher dosages of the cytokine have been a problem. Recently, mutated versions of natural human cytokines were synthesized in efforts to reduce unwanted side-effects, and improve hematopoietic stimulation. One such synthetic cytokine is a recombinant, mutant human IL-3 (Synthokine) which has been selected for clinical development based on its decreased potency in stimulating basophil function and histamine release, and increased potency in stimulating colony formation by cultured hematopoietic cells. In addition, Synthokine has recently been shown to accelerate marrow regeneration following sublethal radiation in a non-human primate model. Our studies were designed to use Synthokine in 2 types of experiments employing our recently developed non-human primate model of sublethal marrow injury employing hepsulfam. In one type of experiment, animals were treated with Synthokine by subcutaneous injection over 10 days prior to receiving hepsulfam chemotherapy. We quantified the extent of multilineage hematopoietic expansion that occurs in marrow and blood during Synthokine administration, and determined whether hyperexpansion prior to chemotherapy lessened hepsulfam-induced marrow damage. In a second type of experiment, we administered Synthokine to animals following hepsulfam induced marrow damage. Post-chemotherapy marrow and blood count regeneration in the Synthokine treated animals were compared to results obtained in previous control experiments using no post- chemotherapy cytokine. The results of these studies indicated that the Synthokine markedly expands progenitor cells and CD34+ cells in the marrow and that this expansion did not afford protection from the pancytopenia resulting from subsequent hepsulfam administration. Furthermore, Synthokine administered after hepsulfam induced marrow injury does not result in accelerated marrow recovery. Synthokine's clinical value may be in expanding primitive hematopoietic cells prior to collection for transfusion.
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