Enhanced antitumor effects of bone marrow transplantation in combination with fibroblast-mediated IL-2 and IL-3 gene therapy

Background. Bone marrow transplantation (BMT) and gene therapy are potent a pproaches to the recovery of bone marrow depression and induction of antitu mor immunity after chemotherapy for the treatment of malignancies. In the p resent study, enhanced antitumor effect of BMT in combination with fibrobla st-mediated interleukin (IL)-2 and IL-3 gene therapy was observed in tumor- bearing mice after chemotherapy. Methods. BALB/c mice were inoculated s.c. with J558L plasmacytoma cells and injected i.p. with cyclophosphamide 300 mg/kg 3 days later. 24 hours after chemotherapy syngeneic bone marrow cells in combination with NIH3T3 fibrob last cells engineered to produce IL-2 (NIH3T3-IL-2) and/or NIH3T3 cells eng ineered to produce IL-3 (NIH3T3-IL-2 3) were implanted into the tumor-beari ng mice. Results. BMT in combination with implantation of either NIH3T3-IL-2 or NIH3 T3-IL3 cells exerted significant inhibition on the growth of J558L tumors a nd prolonged the survival period of the tumor-bearing mice as compared with the treatments with Hanks solution, BMT alone, or BMT plus implantation of NIH3T3 cells transduced with Neo gene. Synergistic antitumor effect was ob served in mice after combined BRIT and cytokine gene therapy. The cytotoxic ities of natural killer cells, cytotoxic T lymphocytes, and macrophages in mice increased markedly after the combined treatment. Recovery of CFU-GM, C FU-MK and CFU-E formation in mice after combined therapy was accelerated ob viously in mice after combined therapy. Conclusions. BMT in combination with fibroblast-mediated IL-2 and IL-3 gene therapy elicited augmented antitumor effects synergistically in tumor-bear ing mice after chemotherapy mainly through induction of antitumor immune re sponse and accelerated recovery of hematopoiesis.