Synergistic induction of ICAM-1 expression by cisplatin and 5-fluorouracilin a cancer cell line via a NF-kappa B independent pathway

Cisplatin (CDDP) and 5-fluorouracil (5-FU) are common anti-tumour agents, a nd the anti-tumour effect of CDDP and 5-FU are synergistically enhanced by combined treatment. To clarify the mechanisms of this synergism, we examine d the effect of CDDP and 5-FU on the expression of cell adhesion molecules involved in recognition of cancer cells by T lymphocytes. When NA cells, a squamous cell carcinoma cell line, were exposed to CDDP and 5-FU for 18 h, the expression of intercellular adhesion molecule-1 (ICAM-1) was synergisti cally induced, whereas CDDP or 5-FU alone did not induce the expression of ICAM-1, as determined by flow cytometry. Expression of ICAM-2 and ICAM-3, w hich are recognized by the same counter receptor on T-cells, were not up-re gulated by CDDP and 5-FU, RT-PCR analysis showed that the induction of ICAM -1 on NA cells might be due to transcriptional induction of ICAM-1 mRNA, Tr eatment with genistein, a protein tyrosine kinase (PTK) inhibitor, inhibite d the induction of ICAM-1 on NA cells by CDDP and 5-FU, whereas staurospori n, a protein kinase C inhibitor, did not. Although CDDP and 5-FU induced bi nding at the nuclear factor kappa B (NF-kappa B) site in the ICAM-1 promote r, pretreatment with genistein did not prevent CDDP and 5-FU-induced bindin g at the NF-kappa B site. Moreover, a NF-h B nuclear translocation inhibito r did not inhibit the induction of ICAM-1 expression by treatment with CDDP and 5-FU, The synergistic effect of CDDP and 5-FU was not specific to NA c ells, since ICAM-1 was synergistically induced by CDDP and 5-FU on HSC-4 ce lls, a squamous cell carcinoma cell line. These findings indicate that trea tment with CDDP and 5-FU induces ICAM-1 expression by a NF-kappa B independ ent regulatory mechanism involving PTK.