AUGMENTATION OF CANCER-CHEMOTHERAPY BY PREINJECTION OF HUMAN MACROPHAGE-COLONY-STIMULATING FACTOR IN L1210 LEUKEMIC CELL-INOCULATED MICE

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) (100 mu g/kg/day) or hM-CSF (20 mu g/kg/day) for 3 days from day 1. In mice preinoculated with 10(2) L1210 cells but not with 10(3) 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 10(5) L1210 cells. In our system, the administration of 4.9 mg/kg adriamycin (ADM) alone slightly prolonged survival of the tumor-bearing 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 [H-3]thymidine in L1210 cells was inhibited. The inhibition was abolished by the addition of N-G-monomethyl-L-arginine, an inhibitor of NO2- synthesis, suggesting that the reactive nitrogen oxide intermediate is involved in hM-CSF-induced inhibition of L1210 growth.