Prognostic Significance of the Expressions of Metallothionein, Glutathione-S-Transferase-π, and P-Glycoprotein in Curatively Resected Gastric Cancer

Abstract

Although experimental studies indicate that overexpression of metallothionein (MT), glutathione-S-transferase-π; (GST-π;), or P-glycoprotein (P-GP) is related to the drug resistance of cancer cells, the clinical significance of the overexpression remains to be elucidated. The expressions of MT, GST-ti, and P-GP were evaluated immunohistochemically in 74 specimens of gastric adenocarcinoma in T_1-3N_1-2 stages which were resected with curative intent. Fluorinated pyrimidines, mitomycin C, and Adriamycin were prescribed in 73, 54, and 2 patients, respectively. The staining characteristics were investigated in relation to the clinical results. The cell-proliferative activity was studied with anti-proliferating cell nuclear antigen antibody. Expressions of GST-rc and P-GP correlated with the staining intensity of normal mucosa. Five-year disease-free survival rates (DFSRs) of GST-π-negative and GST-π-positive groups were 75.0 and 49.0%. The 5-year DFSRs of P-GP-negative and P-GP-positive groups were 68.2 and 38.6%. Concurrent expression among the three proteins was associated with the survival: 5-year DFSR of no- or one-protein-positive group was 75.0%, while those of 2- and 3-protein-positive groups were 56.0 and 38.9%, respectively. Tumors concurrently expressing 2 or 3 proteins have a high proliferative activity. Expressions of MT, GST-π, and P-GP by the tumor are associated with a poorer prognosis of the patients.

Expression of multidrug resistance-associated protein1,P-glycoprotein, and thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection

“…Similar proportion of high expression of P-gp and correlation with well differentiated tumour have been reported in other studies (Mizoguchi et al, 1990;Fujii et al, 1995;Monden et al, 1997;Motoo et al, 1998). One interesting finding was a strong association between MRP1 and P-gp expression.…”

“…In other studies that investigated the clinical relevance of MRP1 or P-gp, the patients usually received fluoropyrimidine with or without mitomycin-C, in which neither MRP1 nor P-gp is associated with drug resistance (Goldstein et al, 1989;Cole et al, 1992;Gottesman and Pastan, 1993;Endo et al, 1996a;Monden et al, 1997;Hipfner et al, 1999). Our results suggest the possibility that the expression of drug resistance-related proteins has little clinical significance in gastric cancer patients who received adjuvant chemotherapy.…”

“…In gastric cancer, the prognostic significance of TS, MRP1, and P-gp expression has been showing conflicting results (Endo et al, 1996a;Monden et al, 1997;Kuniyasu et al, 1998;Takebayashi et al;Suda et al, 1999;Choi et al, 2001). While TS expression predicted increased risk of recurrence and poor survival in patients treated with adjuvant chemotherapy after surgical resection in two studies, our previous study showed no significant differences in DFS and OS between high TS and low TS group (Kuniyasu et al, 1998;Suda et al, 1999;Choi et al, 2001).…”

“…There are two studies that investigated the association between MRP1 expression and survival of patients treated with surgery, which failed to demonstrate the prognostic significance of MRP1 expression (Endo et al, 1996a;Takebayashi et al;. On the other hand, a study suggested that high expression of P-gp was poor prognostic factor in gastric cancer patients who underwent surgical resection followed by adjuvant chemotherapy (Monden et al, 1997). There were no significant differences in DFS and OS of gastric cancer patients according to the expression of MRP1, P-gp, and TS in the present study.…”

“…In gastric cancer patients who underwent surgical resection with or without adjuvant chemotherapy, several investigators have reported the prognostic significance of TS, MRP1, and P-gp with conflicting results (Endo et al, 1996a;Monden et al, 1997;Kuniyasu et al, 1998;Takebayashi et al;Suda et al, 1999;Choi et al, 2001). We have recently reported that expression of TS did not predict poor survival in 103 gastric cancer patients treated with 5-FU and doxorubicin-based adjuvant chemotherapy after curative resection (Choi et al, 2001).…”