Previously, we demonstrated that
CPT-11 is an effective agent against esophageal
squamous cell cancers (ESCC), and that the
protein level of
DNA topoisomerase I can be a predictor for sensitivity to
CPT-11 (Jpn J
Cancer Res 2001; 92: 1335-41). Here, we describe our search for additional predictors of sensitivity to
CPT-11, mainly among cell cycle-regulating
proteins, because the cytotoxicity of
CPT-11 is significantly correlated with the percentage of ESCC cells in S-phase. To this end, we selected and examined the expressions of 5
proteins involved in G1-S transition, i.e., p53,
cyclin D1, p21, p27, and pRB, in 14 ESCC cell lines by western blot analysis. Among these
proteins, the expression levels of p21 and pRB showed significant differences that were associated with the IC50 values for
CPT-11 (P = 0.0339 and P = 0.0109, respectively). Namely, the expression of p21 or pRB independently could be a good
indicator of
CPT-11 efficacy in ESCC. In addition, the cell proliferation activities examined by
enzyme-linked
immunosorbent assay (ELISA) using
5-bromo-2'-deoxyuridine (
BrdU) showed a significant correlation with the percentage of total S-phase cells (correlation coefficient = 0.568, P = 0.0324), and an inverse correlation with the IC50 values for
CPT-11 (correlation coefficient =-0.601, P = 0.0213). Because, as in the case of
DNA topoisomerase I, the cell proliferation activity determined using
BrdU shows a close relationship with the MIB-1 labeling index, immunohistochemical studies of p21, pRB, and MIB-1 in resected ESCC specimens and/or biopsy samples could make it possible to predict more precisely the sensitivity of ESCC patients to
CPT-11 prior to treatment.