In vivo inhibition of the development of myeloid leukemia by injection of macrophage‐and granulocyte‐inducing protein

Abstract It is shown that injection of macrophage‐ and granulocyte‐inducing protein (MGI) can inhibit the development of myeloid leukemia in vivo and stimulate normal myelopoiesis. The MGI injected contained MGI‐1 activity that induces colony formation with normal myeloblasts, and MGI‐2 activity that induces differentiation of normal and MGI + D + leukemic myeloblasts to mature macrophages or granulocytes. The MGI preparations injected did not contain interferon and it was shown that the results obtained were not due to minute amounts of contaminating lipopolysaccharide (LPS). Intraperitoneal injection of MGI stimulated myelopoisesis in normal adult mice. Markedly higher levels of serum MGI activity could be obtained by injecting MGI than by injecting LPS, a compound that stimulates the in vivo production of MGI. Injection of MGI into mice that had been inoculated intravenously with MGI + D + or MGI + D − myeloid leukemic cells showed that, 3 weeks after the beginning of treatment, there was a 3‐ to 5‐fold decrease in the number of leukemic colony‐forming cells and an increase in mature granulocytes in the bone marrow, together with a 2‐ to 5‐fold decrease in the percentage of morphologically identified myeloid blast cells in the bone marrow and peripheral blood. The remaining leukemic colony‐forming cells in the MGI‐treated mice inoculated with MGI + D + cells were not resistant to the induction of differentiation by MGI‐2. Injection of LPS to mice inoculated with LPS‐resistant MGI + D − leukemic cells also inhibited the development of leukemia, but this inhibition was less effective than with MGI and was presumably indirect. Injection of MGI reduced the tumor volume in mice subcutaneously inoculated with leukemic cells at least 50‐fold. The median survival time of MGI‐treated mice inoculated intravenously with MGI + D + cells or subcutaneously with MGI + D − cells was increased by about 40%, and 50% of the MGI‐treated mice inoculated subcutaneously with MGI + D + cells did not develop tumors. MGI also increased the anti‐tumor effect of cyclophosphamide. The leukemia‐inhibiting activity in the injected MGI preparations was associated with the peak of MGI activity separated on a hydroxylapatite column and was destroyed by treatment at the temperature which destroys MGI‐2 activity. This indicates that the inhibition of leukemia development was mediated by MGI‐2. It is suggested that improved schedules of MGI treatment, with or without compounds used in the cytotoxic types of therapy, should be able to give an even better inhibition of leukemia development and that these results should also be applicable to the therapy of human myeloid leukemia.