P450 enzyme expression patterns in the NCI human tumor cell line panel.
P450 enzyme expression patterns in the NCI human tumor cell line panel.
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发表时间：
2001-03
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通讯作者：
Li J. Yu;J. Matías;D. Scudiero;K. Hite;A. Monks;E. Sausville;D. Waxman
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作者：
Li J. Yu;J. Matías;D. Scudiero;K. Hite;A. Monks;E. Sausville;D. Waxman
细胞色素 P450 (P450) 酶表达模式由 60 个人类肿瘤细胞系（代表九种肿瘤组织类型）确定，由美国国家癌症研究所 (NCI) 抗癌药物筛选计划使用。所有 60 个肿瘤细胞系均显示出显着的 P450 活性以及 P450 还原酶活性（使用通用 P450 底物 7-苄氧基试卤灵测定）。使用其他三种 P450 底物（7-乙氧基香豆素、香豆素和 7-乙氧基试卤灵）观察细胞系特异性 P450 酶模式，每种底物的代谢率都很低。使用模式匹配计算机程序 COMPARE，研究了 P450 活性阵列与大量已证明或潜在临床实用的抗癌药物所表现出的细胞毒性模式之间的相关关系。对于 10 种标准抗癌药物（包括 6 种烷化剂）和 55 种研究化合物，观察到 P450 依赖性 7-苄氧基试卤灵代谢活性模式与细胞系化学敏感性之间存在显着负相关，表明 P450 代谢在这些药物失活中发挥作用。 7-乙氧基香豆素 O-去乙基化与细胞系对一组拓扑异构酶抑制剂的化学敏感性之间也存在负相关性，再次表明 P450 依赖性药物失活。因此，P450 酶谱分析可能有助于解释 NCI 肿瘤细胞组中的药物敏感性和耐药性模式，并且可能有助于鉴定其活性可通过细胞色素 P450 代谢改变的抗癌药物。
Cytochrome P450 (P450) enzyme expression patterns were determined for a panel of 60 human tumor cell lines, representing nine tumor tissue types, used by the National Cancer Institute (NCI) Anticancer Drug Screening Program. All 60 tumor cell lines displayed significant P450 activity, as well as P450 reductase activity, as determined using the general P450 substrate 7-benzyloxyresorufin. Cell line-specific P450 enzyme patterns were observed using three other P450 substrates, 7-ethoxycoumarin, coumarin, and 7-ethoxyresorufin, each of which was metabolized at a low rate. Using a pattern-matching computer program, COMPARE, correlative relationships were investigated between the arrays of P450 activities and the patterns of cytotoxicity exhibited by a large group of anticancer agents of proven or potential clinical utility. Significant negative correlations between the patterns of P450-dependent 7-benzyloxyresorufin metabolism activity and cell line chemosensitivity were observed for 10 standard anticancer agents (including 6 alkylating agents) and 55 investigational compounds, suggesting a role for P450 metabolism in the inactivation of these agents. Negative correlations between 7-ethoxycoumarin O-deethylation and cell line chemosensitivity to a group of topoisomerase inhibitors were also seen, again suggesting P450-dependent drug inactivation. P450 enzyme profiling may thus aid in interpreting the patterns of drug sensitivity and resistance in the NCI tumor cell panel, and may facilitate the identification of anticancer agents whose activity can be altered via cytochrome P450 metabolism.