Di Nicolantonio Federica, Knight Louise A, Whitehouse Pauline A, Mercer Stuart J, Sharma Sanjay, Charlton Peter A, Norris David, Cree Ian A
Translational Oncology Research Centre, Department of Histopathology, Queen Alexandra Hospital, Portsmouth, United Kingdom.
Mol Cancer Ther. 2004 Dec;3(12):1631-7.
XR5944 (MLN944) is a novel DNA targeting agent with potent antitumor activity, both in vitro and in vivo, against several murine and human tumor models. We have used an ATP-tumor chemosensitivity assay to assess the ex vivo sensitivity of a variety of solid tumors (n = 90) and a CCRF-CEM leukemia cell line selected with XR5944. Differences in gene expression between the parental CCRF-CEM and the resistant subline were investigated by quantitative reverse transcription-PCR. Immunohistochemistry for topoisomerases I and IIalpha and multidrug resistance (MDR1) protein was done on those tumors for which tissue was available (n = 32). The CCRF-CEM XR5944 line showed increased mRNA levels of MDR1, major vault protein, and MDR-associated protein 1 compared with the parental line, whereas the expression of topoisomerases I, IIalpha, and IIbeta was essentially unchanged, suggesting that XR5944 is susceptible to MDR mechanisms. The median IC90 and IC50 values for XR5944 in tumor-derived cells were 68 and 26 nmol/L, respectively, 6-fold greater than in resistant cell lines. XR5944 was 40- to 300-fold more potent than the other cytotoxics tested, such as doxorubicin, topotecan, and paclitaxel. Breast and gynecologic malignancies were most sensitive to XR5944, whereas gastrointestinal tumors showed greater resistance. A positive correlation (r = 0.68; P < 0.0001) was found between the IC50 values of XR5944 and P-glycoprotein/MDR1 staining but not with either topoisomerase I or IIalpha immunohistochemistry index. These data support the rapid introduction of XR5944 to clinical trials and suggest that it may be effective against a broad spectrum of tumor types, especially ovarian and breast cancer.
XR5944（MLN944）是一种新型的DNA靶向药物，在体外和体内对多种小鼠和人类肿瘤模型均具有强大的抗肿瘤活性。我们使用ATP肿瘤化疗敏感性测定法评估了多种实体瘤（n = 90）以及用XR5944筛选出的CCRF - CEM白血病细胞系的体外敏感性。通过定量逆转录 - PCR研究了亲代CCRF - CEM细胞和耐药亚系之间的基因表达差异。对有可用组织的肿瘤（n = 32）进行了拓扑异构酶I和IIα以及多药耐药（MDR1）蛋白的免疫组织化学检测。与亲代细胞系相比，CCRF - CEM XR5944细胞系中MDR1、主要穹窿蛋白和MDR相关蛋白1的mRNA水平升高，而拓扑异构酶I、IIα和IIβ的表达基本未变，这表明XR5944易受多药耐药机制影响。XR5944在肿瘤来源细胞中的中位IC90和IC50值分别为68和26 nmol/L，比耐药细胞系高6倍。XR5944的效力比其他测试的细胞毒性药物（如阿霉素、拓扑替康和紫杉醇）强40至3百倍。乳腺和妇科恶性肿瘤对XR5944最敏感，而胃肠道肿瘤表现出更大的耐药性。发现XR5944的IC50值与P - 糖蛋白/MDR1染色之间存在正相关（r = 0.68；P < 0.0001），但与拓扑异构酶I或IIα免疫组织化学指数无关。这些数据支持将XR5944迅速引入临床试验，并表明它可能对广泛的肿瘤类型有效，尤其是卵巢癌和乳腺癌。
