SYSTEMIC HEMATOLOGICAL EFFECTS OF GRANULOCYTE-COLONY-STIMULATING FACTOR PRODUCED BY IRRADIATED GENE-TRANSFECTED FIBROBLASTS

Although long-term expression of therapeutic molecules is necessary fo r the treatment of permanent deficiencies, short-term expression of th erapeutic molecules inducing local or systemic effects is preferable i n clinical situations where temporary substitution is the goal. One su ch clinical setting is the administration of hematopoietic growth fact ors in cancer chemotherapy-induced myelosuppression. Several plasmid v ectors containing the human granulocyte colony-stimulating factor (G-C SF) gene under transcriptional control of different regulatory element s were constructed. In vitro production of G-CSF by nonvirally transfe cted murine fibroblast clones initially increased after lethal irradia tion and was detectable for at least 12 days. We also demonstrate that a single injection of irradiated G-CSF-secreting fibroblasts leads to accelerated hematopoietic recovery and mobilization of committed peri pheral blood progenitor cells equivalent to that achieved by twice dai ly s.c. administration of high doses of recombinant human G-CSF. Using dicistronic vectors, high levels of G-CSF secretion were also obtaine d in human fibroblasts.