Iwasaki K, Toms S A, Barnett G H, Estes M L, Gupta M K, Barna B P
Department of Neurology, Cleveland Clinic Foundation, OH 44195, USA.
Cancer Immunol Immunother. 1995 Apr;40(4):228-34. doi: 10.1007/BF01519896.
We reported previously that tumor necrosis factor alpha (TNF alpha) inhibited proliferation and invasiveness of human malignant glial cells. Because tamoxifen, an estrogen antagonist, has also been shown to inhibit growth of such cells, we hypothesized that a combination of tamoxifen and TNF alpha might be more effective than either reagent alone. TNF alpha (1-100 ng/ml) or tamoxifen (80 ng/ml-2 micrograms/ml) alone inhibited proliferation of a human glioblastoma cell line (WITG3) in a dose-dependent fashion; in combination, tamoxifen and TNF alpha yielded additive growth inhibition. Apoptotic cells characterized by nuclear fragmentation were detectable after 48 h of TNF alpha or tamoxifen exposure and were significantly increased by combination treatment. In non-neoplastic human astroglia and fibroblasts, proliferation was unaffected by tamoxifen, and enhanced by TNF alpha as previously reported. Staurosporine (2-50 nM), which has been reported to augment the effects of TNF alpha, was less effective than tamoxifen against WITG3 and, in addition, was markedly inhibitory to non-neoplastic glial cells. Binding studies yielded no evidence of WITG3 estrogen or progesterone receptors, nor of tamoxifen effects on TNF alpha receptors. Data suggest that TNF alpha and tamoxifen in combination display growth-regulatory properties, which (a) are more inhibitory to human glioblastoma cells than either agent alone, (b) do not affect non-neoplastic glia, (c) do not require either estrogen/progesterone receptors or alteration of external TNF alpha receptors, and (d) may involve apoptosis.
我们先前报道过肿瘤坏死因子α（TNFα）可抑制人恶性神经胶质细胞的增殖和侵袭能力。由于雌激素拮抗剂他莫昔芬也已被证明能抑制此类细胞的生长，我们推测他莫昔芬与TNFα联合使用可能比单独使用任何一种试剂更有效。单独使用TNFα（1 - 100 ng/ml）或他莫昔芬（80 ng/ml - 2 μg/ml）均以剂量依赖方式抑制人胶质母细胞瘤细胞系（WITG3）的增殖；联合使用时，他莫昔芬和TNFα产生相加的生长抑制作用。在暴露于TNFα或他莫昔芬48小时后可检测到以核碎裂为特征的凋亡细胞，联合处理可使其显著增加。在非肿瘤性人星形胶质细胞和成纤维细胞中，他莫昔芬不影响增殖，而如先前报道的那样，TNFα可增强其增殖。据报道可增强TNFα作用的星形孢菌素（2 - 50 nM）对WITG3的作用不如他莫昔芬有效，此外，它对非肿瘤性神经胶质细胞有明显抑制作用。结合研究未发现WITG3存在雌激素或孕激素受体的证据，也未发现他莫昔芬对TNFα受体有影响。数据表明，TNFα与他莫昔芬联合使用具有生长调节特性，即（a）对人胶质母细胞瘤细胞的抑制作用比单独使用任何一种药物更强；（b）不影响非肿瘤性神经胶质细胞；（c）不需要雌激素/孕激素受体，也不改变细胞表面的TNFα受体；（d）可能涉及细胞凋亡。
