Nylén U, He Q, Welander I, Lewin F, Skog S
Department of Medical Radiobiology, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
Acta Oncol. 1998;37(4):355-63. doi: 10.1080/028418698430575.
Clinical (Dimery and Hong, J Nat Cancer Inst 1993; 85: 95- 111) and experimental studies (Scanlon et al., Proc Natl Acad Sci USA 1986; 83: 8923-5; Lewin et al., In Vivo 1990; 4: 277-82) have indicated an increased cytotoxic effect, when cisplatin (CDDP) is combined with 5-fluorouracil (5-FU). Addition of 5-FU abolishes the G2-arrest induced by CDDP (Lewin et al., In Vivo 1990; 4: 277-82; Nylén et al., Acta Oncol 1996; 35: 229 35). The mechanism for the synergy is unclear. Activation of p34cdc2 is necessary for progression from G2 to mitosis (Lewin et al., Anti-Cancer Drugs 1995; 6: 465-70). The aim was to study p34cdc2, cdc25C and weel after treatment of mammalian tumour cells in vivo with CDDP as single agent or in combination with 5-FU. CDDP prevented activation of p34cdc2 by keeping cdc25C inactive and weel active. Addition of 5-FU to CDDP decreased the expression of weel and promoted cdc25C-activation. p34cdc2 was dephosphorylated by cdc25C and activated. Alterations in activity of cdc25C and weel after drug combination were due to changes in the protein amount, rather than to changes in the phosphorylation degree.
临床研究（迪梅里和洪，《国家癌症研究所杂志》1993年；85: 95 - 111）和实验研究（斯坎伦等人，《美国国家科学院院刊》1986年；83: 8923 - 8925；莱温等人，《体内》1990年；4: 277 - 282）表明，顺铂（CDDP）与5-氟尿嘧啶（5-FU）联合使用时，细胞毒性作用增强。添加5-FU可消除CDDP诱导的G2期阻滞（莱温等人，《体内》1990年；4: 277 - 282；尼伦等人，《肿瘤学学报》1996年；35: 229 - 235）。协同作用的机制尚不清楚。p34cdc2的激活是从G2期进入有丝分裂所必需的（莱温等人，《抗癌药物》1995年；6: 465 - 470）。目的是研究在体内用CDDP单药或与5-FU联合处理哺乳动物肿瘤细胞后p34cdc2、cdc25C和wee1的情况。CDDP通过使cdc25C无活性和wee1有活性来阻止p34cdc2的激活。在CDDP中添加5-FU可降低wee1的表达并促进cdc25C的激活。p34cdc2被cdc25C去磷酸化并激活。药物联合后cdc25C和wee1活性的改变是由于蛋白量的变化，而非磷酸化程度的变化。
