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

Abstract

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 G 1 -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 IC 50 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 IC 50 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. (Cancer Sci 2004; 95: 464-468) n recent years, many anti-cancer drugs have been developed that show potent anti-tumor activities against various experimental and clinical cancers. Moreover, combination chemotherapy using several anti-cancer drugs plays an important role in improving therapeutic efficacy. For esophageal squamous cell cancers (ESCC), cis-dichlorodiammineplatinum (II) (CDDP) is the key drug used for treatment, with 5-fluorouracil and/or leucovorin mainly used together as biochemical modulators.

Simvastatin enhances irinotecan-induced apoptosis in human non-small cell lung cancer cells by inhibition of proteasome activity

“…Irinotecan is known to arrests cell cycle progression primarily in S or G 2 phases of the cell cycle in a p53-independent manner [24]. Whereas DNA damage-induced arrest in G 1 phase of the cell cycle is dependent on the activation of p53 which induces transcription of the p21 WAF1 , DNA damage-induced S and G 2 phase arrest are triggered in a p53-independent manner.…”

Differential Antiproliferative Effects of Calcitriol on Tumor-Derived and Matrigel-Derived Endothelial Cells

“…The concept of a tissue or cell type selectivity for a nuclear receptor, such as VDR, is not unique; estrogen receptor exerts variable response following estradiol, tamoxifen, and raloxifene depending on tissue type (50). (27). *,P =8.32Â10…”

“…After 48 hours, bromodeoxyuridine labeling solution (Roche, Indianapolis, IN) was added into each well for 4 hours before fixing. Antibody staining and addition of substrate procedures were done as described (27). The absorbance was read with an ELISA reader (Spectra Max 340PC) at 370 nm.…”

The interactive transcript abundance index [c-myc*p73α]/[p21*Bcl-2] correlates with baseline level of apoptosis and response to CPT-11 in human bronchogenic carcinoma cell lines

“…Chemoresistance to CPT-11 is common and several factors responsible for its resistance have been described including inter-tumor variation in carboxylesterase activity, topoisomerase I expression, and drug efflux and transport (14,20). Further, based on knowledge of these resistance mechanisms, some biomarkers for resistance have been identified (21)(22)(23). In spite of this progress, the mechanisms of drug response are still not completely understood (24,25).…”