Anderson C P, Tsai J, Chan W, Park C K, Tian L, Lui R M, Forman H J, Reynolds C P
Division of Hematology-Oncology, Childrens Hospital Los Angles, California 90027, USA.
Eur J Cancer. 1997 Oct;33(12):2016-9. doi: 10.1016/s0959-8049(97)00203-7.
Buthionine sulphoximine (BSO) selectively inhibits glutathione (GSH) synthesis and may enhance the antineuroblastoma activity of melphalan (L-PAM). We determined the cytotoxicity of BSO (dose range 0-1000 microM) alone and in combination with L-PAM (dose range 0-0 microM) in a panel of 18 human neuroblastoma cell lines. BSO alone was highly cytotoxic with 16/18 neuroblastoma cell lines having IC90 values (range 2.1- > 1000 microM) below the clinically achievable steady-state plasma level of 500 microM BSO. Maximal cell killing correlated with GSH levels decreased to less than 10% baseline, and was partially reversed by the addition of exogenous anti-oxidants (GSH, vitamin E and ascorbate). Fluorocytometric analysis of DNA fragments by the Tunnel method detected 92% of a BSO sensitive cell line in apoptosis after a 48 h exposure to 500 microM BSO. The combination of L-PAM and BSO synergistically enhanced the cell killing of L-PAM alone by > 1-3 logs (combination index < 1). We conclude that BSO has significant single-agent cytotoxicity against neuroblastoma and enhances cell killing when combined with L-PAM.
丁硫氨酸亚砜亚胺（BSO）可选择性抑制谷胱甘肽（GSH）的合成，并可能增强美法仑（L-PAM）抗神经母细胞瘤的活性。我们测定了单独使用BSO（剂量范围为0 - 1000微摩尔）以及与L-PAM联合使用（剂量范围为0 - 0微摩尔）时，对18种人神经母细胞瘤细胞系的细胞毒性。单独使用BSO具有高度细胞毒性，18种神经母细胞瘤细胞系中有16种的IC90值（范围为2.1 - >1000微摩尔）低于临床可达到的500微摩尔BSO稳态血浆水平。最大细胞杀伤与GSH水平降至低于基线的10%相关，并且通过添加外源性抗氧化剂（GSH、维生素E和抗坏血酸）可部分逆转。通过Tunnel法对DNA片段进行荧光细胞仪分析检测到，在暴露于500微摩尔BSO 48小时后，92%的对BSO敏感的细胞系发生凋亡。L-PAM与BSO联合使用可协同增强单独使用L-PAM时的细胞杀伤作用，增强幅度>1 - 3个对数（联合指数<1）。我们得出结论，BSO对神经母细胞瘤具有显著的单药细胞毒性，与L-PAM联合使用时可增强细胞杀伤作用。
