K. Takizawa et al., Synergistic induction of ICAM-1 expression by cisplatin and 5-fluorouracilin a cancer cell line via a NF-kappa B independent pathway, BR J CANC, 80(7), 1999, pp. 954-963
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.