EFFECTS OF FIBROBLAST-MEDIATED INTERLEUKIN-3 AND INTERLEUKIN-6 GENE-THERAPY ON HEMATOPOIESIS IN MICE TREATED WITH 5-FLUOROURACIL

Fibroblast-mediated cytokine gene therapy has proven to be a promising strategy for restoring hematopoiesis following repeated chemotherapy. Interleukin 3 (IL-3) and interleukin 6 (IL-6) can synergistically pro mote the recovery of hematopoiesis following chemotherapy. In this inv estigation, combined use of fibroblast-mediated IL-3 and IL-6 gene the rapy was tested for hematopoietic effects on mice with or without 5-fl uorouracil administration. The results demonstrated that combined ther apy with IL-3 gene-modified NIH3T3 cell (NIH3T3-IL-3) and IL-6 gene-mo dified fibroblast NIH3T3 cell (NIH3T3-IL-6) implantation achieves obvi ous stimulation of hematopoiesis in normal mice and accelerates recove ry of hematopoiesis. In normal mice the quantities of platelets, neutr ophils, and total white blood cells in peripheral blood increased sign ificantly after the combined implantation of NIH3T3-IL-3 and NIH3T3-IL -6 cells. The numbers of colony-forming unit (CFU) granulocyte/macroph age (CFU-GM) and CFU megakaryocyte (CFU-MK) formed by stem cells in bo ne marrow was significantly higher after the combined implantation of NIH3T3-IL-3 and NIH3T3-IL-6 cells than after the implantation of NIH3T 3-IL-3 alone, NIH3T3-IL-6 alone, or neomycin gene-modified NIH3T3 cell s. In hematopoiesis-depressed mice induced by preinjection with 5-fluo rouracil at the dose of 150 mg/kg before cell implantation, the platel ets, neutrophils, and white blood cells showed accelerated recovery, a nd the numbers of CFU-GM and CFU-MK formed by bone marrow cells were a lso markedly higher after the combined implantation of NIH3T3-IL-3 and NIH3T3-IL-6 cells than in control groups. Our data show that combined use of fibroblast-mediated IL-3 and IL-6 gene therapy may be of clini cal relevance for the recovery of hematopoietic depression for patient s after chemotherapy.