The expressions of p21 and pRB may be good indicators for the sensitivity of esophageal squamous cell cancers to CPT-11: Cell proliferation activity correlates with the effect of CPT-11.
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.
Nakajima
Yasuaki
Y
Department of Esophago-Gastric Surgery, Tokyo Medical and Dental University, Bunkyou-ku, Tokyo 113-8519, Japan. y.nakaji@cick.jp
Miyake
Satoshi
S
Tanaka
Koji
K
Ogiya
Kazuo
K
Toukairin
Yutaka
Y
Kawada
Kenrou
K
Nishikage
Tetsurou
T
Nagai
Kagami
K
Kawano
Tatsuyuki
T
D017500:Adenovirus E1A Proteins; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001973:Bromodeoxyuridine / Q000493:pharmacokinetics; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology*; D002352:Carrier Proteins / Q000096:biosynthesis*; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins; D002455:Cell Division; D004264:DNA Topoisomerases, Type I / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology*; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D000077146:Irinotecan; D009687:Nuclear Proteins; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis*; D012097:Repressor Proteins; D014407:Tumor Cells, Cultured
D017500:Adenovirus E1A Proteins; D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C416925:EID1 protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; D000077146:Irinotecan; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D004264:DNA Topoisomerases, Type I; D001973:Bromodeoxyuridine; D002166:Camptothecin