Collard J, Matthew A M, Double J A, Bibby M C
Clinical Oncology Unit, University of Bradford, West Yorkshire, UK.
Br J Cancer. 1995 Jun;71(6):1199-203. doi: 10.1038/bjc.1995.233.
EO9 [3-hydroxy-5-aziridinyl-1-methyl-2(1H-indole-4,7-dione)-prop-beta-en- alpha-ol] was selected for clinical trial in Europe because of its preclinical profile but also because of its distinct mechanism of bioactivation. Several studies have shown that cells rich in DT-diaphorase may be particularly sensitive to EO9. The present study examined the relationship between DT-diaphorase activity and sensitivity to EO9 in a panel of cell lines largely derived from human and rodent leukaemias/lymphoma and solid tumours. A possible relationship between chemosensitivity and enzyme activity was demonstrated (correlation coefficient 0.796). A number of the human cell lines were established as xenografts in nude mice but, with the exception of HT29, DT-diaphorase specific activity was greatly reduced compared with the corresponding cell lines. These data suggest that in vitro studies of bioactivation of drugs by specific enzymes is unlikely to be relevant for the same tumour in vivo. Except for HCLO, all xenografts failed to respond to EO9 as a single dose. HT29 tumours in vivo had similar DT-diaphorase activity [359 nmol of 2,6-dichlorophenol-indophenol (DCPIP) reduced per min per mg of protein] to the cell line (337) but failed to respond to a single dose or daily dose schedule. A preliminary attempt to investigate an hourly dose schedule demonstrated a modest anti-tumour effect accompanied by enhanced toxicity. Attempts to optimise EO9 exposure parameters to potentiate activity in tumours with high DT-diaphorase activity are under way, but as yet the relevance of this particular enzyme for in vivo EO9 activity requires further investigation.
EO9 [3-羟基-5-氮丙啶基-1-甲基-2(1H-吲哚-4,7-二酮)-丙-β-烯-α-醇]因其临床前研究表现以及独特的生物活化机制而被选在欧洲进行临床试验。多项研究表明，富含DT-黄递酶的细胞可能对EO9特别敏感。本研究在一组主要源自人类和啮齿动物白血病/淋巴瘤及实体瘤的细胞系中，检测了DT-黄递酶活性与对EO9敏感性之间的关系。结果证明了化学敏感性与酶活性之间存在可能的关系（相关系数为0.796）。许多人类细胞系被建立为裸鼠异种移植模型，但除HT29外与相应细胞系相比，DT-黄递酶比活性大幅降低。这些数据表明，特定酶对药物进行生物活化的体外研究，可能与同一肿瘤的体内情况无关。除HCLO外，所有异种移植单剂量给药时均未对EO9产生反应。体内HT29肿瘤的DT-黄递酶活性[每毫克蛋白质每分钟还原359 nmol的2,6-二氯酚靛酚（DCPIP）]与细胞系（337）相似，但对单剂量或每日给药方案均无反应。一项初步尝试研究每小时给药方案，结果显示有适度的抗肿瘤作用，但毒性增强。目前正在尝试优化EO9暴露参数，以增强其在DT-黄递酶活性高的肿瘤中的活性，但这种特定酶对EO9体内活性的相关性仍需进一步研究。
