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Vol. 291, Issue 2, 739-748, November 1999
Department of Genomics, Targets and Cancer Research, Pfizer Central
Research, Groton, Connecticut
Phosphorylation of tyrosine residues on the epidermal growth factor
(EGF) receptor (EGFr) is an important early event in signal transduction, leading to cell replication for major human carcinomas. CP-358,774 is a potent and selective inhibitor of the EGFr tyrosine kinase and produces selective inhibition of EGF-mediated tumor cell
mitogenesis. To assess the pharmacodynamic aspects of EGFr inhibition,
we devised an ex vivo enzyme-linked immunosorbent assay for
quantification of EGFr-specific tyrosine phosphorylation in human tumor
tissue specimens obtained from xenografts growing s.c. in athymic mice.
When coupled with pharmacokinetic analyses, this measurement can be
used to describe the extent and duration of kinase inhibition in vivo.
CP-358,774 is an effective, orally active inhibitor of EGFr-specific
tyrosine phosphorylation (ED50 = 10 mg/kg, single
dose). It has a significant duration of action, producing, on average,
a 70% reduction in EGFr-associated phosphotyrosine over a 24-h period
after a single 100 mg/kg dose. Inhibition of EGFr phosphotyrosine in an
ex vivo assay format effectively estimates the potency and degree of
inhibition of EGFr-dependent human LICR-LON-HN5 head and neck carcinoma
tumor growth. Substantial growth inhibition of human tumor xenografts
was achieved with p.o. doses of the compound (ED50 = 10 mg/kg q.d. for 20 days). Combination chemotherapy with
cisplatin produced a significant response above that of cisplatin alone
with no detectable effects on body weight or lethal toxicity. Taken
together, these observations suggest that CP-358,774 may be useful for
the treatment of EGFr-driven human carcinomas.
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R. Nahta, G. N. Hortob |
