Augmentation of Cancer Chemotherapy by Preinjection of Human Macrophage Colony‐stimulating Factor in L1210 Leukemic Cell‐inoculated Mice

Abstract

Human macrophage colony‐stimulating factor (hM‐CSF) is a potent stimulator of the effector functions of monocytes/macrophages. We investigated the antitumor effects of this factor in CDF1 male mice inoculated with L1210 cells, a mouse B‐cell leukemia line. Mice preinoculated with various numbers of L1210 cells on day 0 were given intravenous injections of vehicle (human serum albumin; HSA) (100μg/kg/day) or hM‐CSF (20μg/kg/day) for 3 days from day 1. In mice preinoculated with 102 L1210 cells but not with 103 or more L1210 cells, a marked increment in survival rate was observed with hM‐CSF treatment. We next examined the effect of hM‐CSF treatment combined with chemotherapy on the survival of mice that had been preinoculated with 105 L1210 cells. In our system, the administration of 4.9 mg/kg adriamycin (ADM) alone slightly prolonged survival of the tumorbearing mice, but all of the mice died within 20 days. When hM‐CSF was injected for 3 days before this ADM treatment, the invasion and proliferation of tumor cells in the liver and spleen were markedly inhibited and 50% of the mice were still alive at day 50. We detected inhibitory activity toward L1210 growth in serum of mice administered with hM‐CSF, and the degree of the inhibitory activity was correlated with the level of nitrite (NO2) in the serum. When L1210 cells were co‐cultured with peritoneal macrophages from mice intraperitoneally injected with hM‐CSF, the uptake of [3H]thymidine in L1210 cells was inhibited. The inhibition was abolished by the addition of NG‐monomethyI‐L‐arginine, an inhibitor of NO2− synthesis, suggesting that the reactive nitrogen oxide intermediate is involved in hM‐CSF‐induced inhibition of L1210 growth.