Potentiation of the anti-tumor effect of actinomycin D by tumor necrosis factor alpha in mice: correlation between in vitro and in vivo results.
The anti-tumor effects of actinomycin D (Act D) and recombinant human tumor necrosis factor (TNF)-alpha have been studied on 4 established murine tumor cell lines: MmB16 melanoma, Lewis lung (LL/2) carcinoma, L1 sarcoma and L1210 leukemia. During short-term incubation (24 hr) Act D produced dose-dependent cytostatic/cytotoxic effects against MmB16, LL/2 and L1 tumor cells but did not reduce the viability of these cells even at high concentration (10 micrograms/ml), below a threshold of 30-60%. However, L1210 leukemic cells were highly susceptible to Act D, and no viable cells were detected in cultures incubated with 1 microgram/ml of Act D. TNF-alpha alone, when used under the same culture conditions, had only a negligible effect on all cell lines tested. However, the combination of this cytokine with Act D produced synergistic cytotoxic effects against MmB16, LL/2 and L1 cells but not against L1210 leukemia cells. In an in vivo model of regional therapy in which tumor-bearing mice were treated with Act D and TNF-alpha, a correlation with in vitro results was observed. In mice bearing MmB16 melanoma, LL/2 carcinoma and L1 sarcoma, the most potent anti-tumor effects were observed in mice treated with Act D and TNF-alpha together. This treatment led to a delay of tumor growth and induced complete tumor regression in some cases. On the contrary, TNF-alpha did not enhance the effect of Act D in mice injected with L1210 leukemia cells. Our results show that TNF-alpha can potentiate the anti-tumor effects of Act D against tumors weakly susceptible to Act D and may be a useful adjuvant to chemotherapy in the local treatment of neoplasia.
Lasek
W
W
Department of Immunology, Institute of Biostructure Medical School, Warsaw, Poland.
Giermasz
A
A
Kuc
K
K
Wańkowicz
A
A
Feleszko
W
W
Gołab
J
J
Zagozdzon
R
R
Stokłosa
T
T
Jakóbisiak
M
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use / Q000633:toxicity*; D002460:Cell Line; D003609:Dactinomycin / Q000627:therapeutic use / Q000633:toxicity*; D004357:Drug Synergism; D007939:Leukemia L1210 / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D012513:Sarcoma, Experimental / Q000188:drug therapy; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use / Q000633:toxicity*
D000903:Antibiotics, Antineoplastic; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin