Cisplatin-induced inhibition of p34cdc2 is abolished by 5-fluorouracil

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.