Kornmann M, Danenberg K D, Arber N, Beger H G, Danenberg P V, Korc M
Department of Medicine, University of California, Irvine 92697, USA.
Cancer Res. 1999 Jul 15;59(14):3505-11.
Cyclin D1 belongs to a family of protein kinases that have been implicated in cell cycle regulation. Inhibition of cyclin D1 expression has been recently shown (M. Kornmann, et al., J. Clin. Invest, 101: 344-352, 1998) to suppress pancreatic cancer cell growth and increase cytotoxic actions of cisplatinum. The aim of the present study was to determine whether inhibition of cyclin D1 expression also modulates the effects of other antineoplastic drugs and whether it is associated with alterations in the level of expression of drug resistance genes. The suppression of cyclin D1 expression after the stable transfection of a cyclin D1 antisense construct in PANC-1 and COLO-357 human pancreatic cancer cells resulted in a significant increase in sensitivity to the fluoropyrimidines 5-fluorouracil and 5-fluoro-2'-deoxyuridine and to mitoxantrone. All of the antisense-expressing dones exhibited a decrease in thymidylate synthase and an increase in thymidine phosphorylase mRNA expression as determined by reverse transcription-PCR analysis and decreased levels of MDR-1 and MRP mRNA as determined by Northern blotting. These findings demonstrate that the inhibition of cyclin D1, in addition to suppressing the growth of pancreatic cancer cells, enhances their responsiveness to multiple chemotherapeutic agents and suggest that this effect may be due to the altered expression of several chemoresistance genes.
细胞周期蛋白D1属于一类与细胞周期调控有关的蛋白激酶家族。最近有研究表明（M. 科恩曼等人，《临床研究杂志》，101: 344 - 352, 1998），抑制细胞周期蛋白D1的表达可抑制胰腺癌细胞生长，并增强顺铂的细胞毒性作用。本研究的目的是确定抑制细胞周期蛋白D1的表达是否也能调节其他抗肿瘤药物的作用，以及它是否与耐药基因表达水平的改变有关。在PANC - 1和COLO - 357人胰腺癌细胞中稳定转染细胞周期蛋白D1反义构建体后，细胞周期蛋白D1表达受到抑制，结果显示对氟嘧啶类药物5 - 氟尿嘧啶和5 - 氟 - 2'-脱氧尿苷以及米托蒽醌的敏感性显著增加。通过逆转录 - PCR分析确定，所有表达反义的克隆均显示胸苷酸合成酶减少，胸苷磷酸化酶mRNA表达增加，通过Northern印迹法测定，MDR - 1和MRP mRNA水平降低。这些发现表明，抑制细胞周期蛋白D1除了能抑制胰腺癌细胞生长外，还能增强其对多种化疗药物的反应性，并提示这种效应可能是由于几种化疗耐药基因表达改变所致。
