Lasek W, Giermasz A, Kuc K, Wańkowicz A, Feleszko W, Gołab J, Zagozdzon R, Stokłosa T, Jakóbisiak M
Department of Immunology, Institute of Biostructure Medical School, Warsaw, Poland.
Int J Cancer. 1996 May 3;66(3):374-9. doi: 10.1002/(SICI)1097-0215(19960503)66:3<374::AID-IJC18>3.0.CO;2-B.
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.
已经研究了放线菌素D（Act D）和重组人肿瘤坏死因子（TNF）-α对4种已建立的小鼠肿瘤细胞系的抗肿瘤作用：MmB16黑色素瘤、Lewis肺癌（LL/2）、L1肉瘤和L1210白血病。在短期培养（24小时）期间，Act D对MmB16、LL/2和L1肿瘤细胞产生剂量依赖性的细胞生长抑制/细胞毒性作用，但即使在高浓度（10微克/毫升）下，在低于30%-60%的阈值时，也不会降低这些细胞的活力。然而，L1210白血病细胞对Act D高度敏感，在与1微克/毫升Act D一起培养的培养物中未检测到活细胞。在相同培养条件下单独使用TNF-α时，对所有测试的细胞系只有微不足道的影响。然而，这种细胞因子与Act D联合使用时，对MmB16、LL/2和L1细胞产生协同细胞毒性作用，但对L1210白血病细胞没有作用。在一个局部治疗的体内模型中，用Act D和TNF-α处理荷瘤小鼠，观察到与体外结果相关。在荷MmB16黑色素瘤、LL/2癌和L1肉瘤的小鼠中，一起用Act D和TNF-α处理的小鼠观察到最有效的抗肿瘤作用。这种治疗导致肿瘤生长延迟，在某些情况下诱导肿瘤完全消退。相反，TNF-α在注射L1210白血病细胞的小鼠中并没有增强Act D的作用。我们的结果表明，TNF-α可以增强Act D对Act D敏感性较弱的肿瘤的抗肿瘤作用，并且在肿瘤的局部治疗中可能是化疗的有用佐剂。
