van der Heyden S, Gheuens E, van de Vrie W, Van Bockstaele D, Van Oosterom A, Eggermont A, De Bruijn E A
Laboratory of Cancer Research & Clinical Oncology, Antwerp University, Wilrijk, Belgium.
Jpn J Cancer Res. 1994 Jan;85(1):13-6. doi: 10.1111/j.1349-7006.1994.tb02880.x.
Most anticancer agents fail to induce clear responses in the treatment of colorectal cancer. This can be explained by involvement of overexpression of the membrane glycoprotein, P-gp 170, which is associated with multidrug resistance (MDR), and/or with involvement of ras. Fluoropyrimidines are amongst the few options in the chemotherapeutic treatment of colorectal cancers. 5'-Deoxy-5-fluorouridine (dFUrd) needs intracellular activation via 5-fluorouracil into 5-fluoro-2'-deoxyuridine-5'-monophosphate and 5-fluorouridine-5'-triphosphate. In the present study, the cytotoxic activity of dFUrd in vitro and dFUrd combined with daunorubicin (DNR) was assessed with the (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium) bromide assay in cells with increased P-gp 170 expression versus controls. Surprisingly, dFUrd was most active in cells with high P-gp 170 expression, a finding which can not be explained by intracellular metabolic activity only. The results also show that dFUrd improves the DNR uptake in MDR-positive cells, and this is related with increased cytotoxicity of the anthracycline.
大多数抗癌药物在治疗结直肠癌时未能诱导出明显的反应。这可以通过膜糖蛋白P - gp 170的过表达来解释，该蛋白与多药耐药性（MDR）相关，和/或与ras的参与有关。氟嘧啶是结直肠癌化疗治疗中的少数选择之一。5'-脱氧-5-氟尿苷（dFUrd）需要通过5-氟尿嘧啶在细胞内激活为5-氟-2'-脱氧尿苷-5'-单磷酸和5-氟尿苷-5'-三磷酸。在本研究中，通过（3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四氮唑）溴化物试验，评估了dFUrd在体外的细胞毒性活性以及dFUrd与柔红霉素（DNR）联合使用时对P - gp 170表达增加的细胞相对于对照细胞的活性。令人惊讶的是，dFUrd在P - gp 170高表达的细胞中活性最高，这一发现不能仅用细胞内代谢活性来解释。结果还表明，dFUrd提高了MDR阳性细胞对DNR的摄取，这与蒽环类药物细胞毒性的增加有关。
