Cisplatin-Induced Inhibition of p34^cdc2 is Abolished by 5-Fluorouracil

Abstract

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 p34^cdc2 is necessary for progression from G₂ to mitosis (Lewin et al., Anti-Cancer Drugs 1995; 6: 465-70). The aim was to study p34^cdc2, cdc25C and wee1 after treatment of mammalian tumour cells in vivo with CDDP as single agent or in combination with 5-FU. CDDP prevented activation of p34^cdc2 by keeping cdc25C inactive and wee1 active. Addition of 5-FU to CDDP decreased the expression of wee1 and promoted cdc25C-activation. p34^cdc2 was dephosphorylated by cdc25C and activated. Alterations in activity of cdc25C and wee1 after drug combination were due to changes in the protein amount, rather than to changes in the phosphorylation degree.