Watanabe N, Okamoto T, Tsuji N, Sasaki H, Akiyama S, Kobayashi D, Sato T, Yamauchi N, Niitsu Y
Fourth Department of Internal Medicine, Sapporo Medical University, School of Medicine.
Jpn J Cancer Res. 1995 Apr;86(4):395-9. doi: 10.1111/j.1349-7006.1995.tb03069.x.
Tumor necrosis factor (TNF) and various chemotherapeutic drugs show synergistic antitumor effects in vitro and in vivo, though the mechanism is not clear. Based on our previous finding that endogenous TNF (enTNF) acts as an intracellular resistance factor against exogenous TNF by scavenging oxygen free radicals (OFR) with induced manganous superoxide dismutase (MnSOD), we examined the suppression of these resistance factors by chemotherapeutic drugs and the resulting increase in TNF cytotoxicity. Pretreatment of HeLa cells, which produce an appreciable amount of enTNF and show apparent TNF resistance, with TNF followed by adriamycin (ADM) resulted in an additive effect, whereas pretreatment with ADM followed by TNF resulted in a synergistic effect. After treatment of HeLa cells with ADM, the expression of enTNF was remarkably suppressed and MnSOD activity was decreased by one-half. These results indicate that suppression of the intracellular resistance factors, i.e., enTNF and MnSOD, by ADM plays an important role in the mechanism of the synergistic antitumor effect of TNF in combination with ADM.
肿瘤坏死因子（TNF）与多种化疗药物在体外和体内均显示出协同抗肿瘤作用，但其机制尚不清楚。基于我们之前的发现，即内源性TNF（enTNF）通过诱导锰超氧化物歧化酶（MnSOD）清除氧自由基（OFR），作为对外源性TNF的一种细胞内抗性因子，我们研究了化疗药物对这些抗性因子的抑制作用以及由此导致的TNF细胞毒性增加。用TNF预处理能产生大量enTNF且表现出明显TNF抗性的HeLa细胞，随后给予阿霉素（ADM），产生了相加效应，而先用ADM预处理HeLa细胞，随后给予TNF，则产生了协同效应。用ADM处理HeLa细胞后，enTNF的表达明显受到抑制，MnSOD活性降低了一半。这些结果表明，ADM对细胞内抗性因子（即enTNF和MnSOD）的抑制作用在TNF与ADM联合应用的协同抗肿瘤作用机制中起重要作用。
