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 micrograms/kg/day) or hM-CSF (20 micrograms/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 [3H]thymidine in L1210 cells was inhibited. The inhibition was abolished by the addition of NG-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.
Douzono
M
M
Biochemical Research Laboratory, Morinaga Milk Industry Co., Ltd., Kanagawa.
Suzu
S
S
Yamada
M
M
Yanai
N
N
Kawashima
T
T
Hatake
K
K
Motoyoshi
K
K
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000627:therapeutic use; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008099:Liver / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D017737:Macrophages, Peritoneal / Q000502:physiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D019001:Nitric Oxide Synthase; D013154:Spleen / Q000473:pathology; D015996:Survival Rate; D019323:omega-N-Methylarginine
D019323:omega-N-Methylarginine; D004317:Doxorubicin; D016173:Macrophage Colony-Stimulating Factor; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases