Lee F Y, Flannery D J, Siemann D W
Department of Radiation Oncology, University of Rochester Cancer Center, New York 14642.
Br J Cancer. 1991 Feb;63(2):217-22. doi: 10.1038/bjc.1991.52.
In an attempt to develop an assay to predict patient tumour response to cyclophosphamide (CP), the feasibility of using a glutathione-targeted assay to assess the in vitro chemosensitivity of tumour cells to 4-hydroperoxycyclophosphamide (4-OOH-CP), an activated congener of CP, was evaluated. A panel of 19 human and three murine tumour cell lines was used. These consisted of three main categories of tumour types, viz. ovarian, lung and squamous cell carcinoma. The major finding was that the occurrence of a significant reduction of tumour cell reproductive capacity was always accompanied by substantial depletion of cellular glutathione (GSH) content, and vice versa. Plots of % GSH depletion versus clonogenic cell survival demonstrated highly significant correlation (r = 0.90-0.91; P less than 0.01). It was determined that for in vitro tumour cell lines, a GSH depletion to 40% of initial content may serve as a cut-off criterion for chemosensitivity to 4-OOH-CP. This degree of GSH depletion is indicative of clonogenic cell survival of approximately 1% (95% confidence limits = 3 x 10(-5)-1.6 x 10(-2)). The relationship between steady state GSH content and intrinsic sensitivity to 4-OOH-CP was also evaluated. The GSH concentration of the tumour cell lines ranged from 1.3-21.2 x 10(-18) moles microns-3; chemosensitivity to 4-OOH-CP, in terms of IC99, was in the range of 5.0-87.1 microM. A good correlation was observed between these two parameters (r = 0.85, P less than 0.02). These results suggest that GSH plays an important role in determining the therapeutic efficacy of 4-OOH-CP in the treatment of cancer. It is uncertain, however, whether a high tumour steady state GSH content in itself is sufficient to cause therapeutic failure in patients.
为了开发一种预测患者肿瘤对环磷酰胺（CP）反应的检测方法，评估了使用谷胱甘肽靶向检测法来评估肿瘤细胞对CP的活化类似物4 - 氢过氧环磷酰胺（4 - OOH - CP）的体外化学敏感性的可行性。使用了一组19种人类和3种鼠类肿瘤细胞系。这些细胞系由三种主要肿瘤类型组成，即卵巢癌、肺癌和鳞状细胞癌。主要发现是肿瘤细胞繁殖能力显著降低的同时总是伴随着细胞内谷胱甘肽（GSH）含量的大量消耗，反之亦然。GSH消耗百分比与克隆形成细胞存活率的曲线显示出高度显著的相关性（r = 0.90 - 0.91；P小于0.01）。已确定对于体外肿瘤细胞系，GSH消耗至初始含量的40%可作为对4 - OOH - CP化学敏感性的临界标准。这种程度的GSH消耗表明克隆形成细胞存活率约为1%（95%置信限 = 3×10⁻⁵ - 1.6×10⁻²）。还评估了稳态GSH含量与对4 - OOH - CP的内在敏感性之间的关系。肿瘤细胞系的GSH浓度范围为1.3 - 21.2×10⁻¹⁸摩尔/微米³；就IC99而言，对4 - OOH - CP的化学敏感性范围为5.0 - 87.1微摩尔。这两个参数之间观察到良好的相关性（r = 0.85，P小于0.02）。这些结果表明GSH在确定4 - OOH - CP治疗癌症的疗效中起重要作用。然而，肿瘤稳态GSH含量本身是否足以导致患者治疗失败尚不确定。
