The ex vivo characterization of XR5944 (MLN944) against a panel of human clinical tumor samples

摘要: XR5944 (MLN944) is a novel DNA targeting agent with potent antitumor activity, both in vitro and vivo, against several murine human tumor models. We have used an ATP-tumor chemosensitivity assay to assess the ex vivo sensitivity of variety solid tumors (n = 90) CCRF-CEM leukemia cell line selected XR5944. Differences gene expression between parental resistant subline were investigated by quantitative reverse transcription-PCR. Immunohistochemistry for topoisomerases I IIalpha multidrug resistance (MDR1) protein was done on those which tissue available 32). The showed increased mRNA levels MDR1, major vault protein, MDR-associated 1 compared line, whereas I, IIalpha, IIbeta essentially unchanged, suggesting that susceptible MDR mechanisms. median IC90 IC50 values tumor-derived cells 68 26 nmol/L, respectively, 6-fold greater than lines. 40- 300-fold more other cytotoxics tested, such as doxorubicin, topotecan, paclitaxel. Breast gynecologic malignancies most sensitive XR5944, gastrointestinal resistance. A positive correlation (r 0.68; P < 0.0001) found P-glycoprotein/MDR1 staining but not either topoisomerase or immunohistochemistry index. These data support rapid introduction clinical trials suggest it may be effective broad spectrum types, especially ovarian breast cancer.