Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells

Abstract

Cimetidine has been shown to have beneficial effects in colorectal cancer patients. In this study, a total of 64 colorectal cancer patients who received curative operation were examined for the effects of cimetidine treatment on survival and recurrence. The cimetidine group was given 800 mg day(-1) of cimetidine orally together with 200 mg day(-1) of 5-fluorouracil, while the control group received 5-fluorouracil alone. The treatment was initiated 2 weeks after the operation and terminated after 1 year. Robust beneficial effects of cimetidine were noted: the 10-year survival rate of the cimetidine group was 84.6% whereas that of control group was 49.8% (P<0.0001). According to our previous observations that cimetidine blocked the expression of E-selectin on vascular endothelium and inhibited the adhesion of cancer cells to the endothelium, we have further stratified the patients according to the expression levels of sialyl Lewis antigens X (sL(x)) and A (sL(a)). We found that cimetidine treatment was particularly effective in patients whose tumour had higher sL(x) and sL(a) antigen levels. For example, the 10-year cumulative survival rate of the cimetidine group with higher CSLEX staining, recognizing sL(x), of tumours was 95.5%, whereas that of control group was 35.1% (P=0.0001). In contrast, in the group of patients with no or low levels CSLEX staining, cimetidine did not show significant beneficial effect (the 10-year survival rate of the cimetidine group was 70.0% and that of control group was 85.7% (P=n.s.)). These results clearly indicate that cimetidine treatment dramatically improved survival in colorectal cancer patients with tumour cells expressing high levels of sL(x) and sL(a).

Figure 1

Effect of cimetidine on the survival of patients with colorectal cancers. Patients who were treated with cimetidine and 5-FU (‘cimetidine’ group) and 5-FU alone (‘control’ group) were compared by Kaplan-Meier method. The cumulative 10-year survival rate of the cimetidine group (n=34) was 84.6%, whereas that of control group (n=30) was 49.8% (P=0.0015 by log rank test and P=0.0010 by generalized Wilcoxon test).

Figure 2

Effect of cimetidine on the survival of patients with colorectal cancer according to the Dukes classification. Dukes A and B, localized cancer limited to mucosa and submucosa (A) and extending through serosa without lymph node metastasis (B). Dukes C, cancers involving regional lymph nodes. Note that the beneficial effects of cimetidine were greater in patients with Dukes C: the cumulative 10-year survival rate of the cimetidine group (n=13) was 84.6%, whereas that of control group (n=13) was 23.1% (P=0.0016 by log rank test and P=0.0026 by generalized Wilcoxon test).

Figure 3

Effect of cimetidine on cumulative survival rates in the colorectal cancer patients. The tumour tissues from individual patients obtained during curative operations were stained by mAbs to sL^x antigen, including CSLEX (A), KM93 (B), FH6 (C) and sL^a antigen, CA19-9 (D). The level of these epitope expression were semi-quantitated upon microscopic examination by two experienced pathologists: level 1, less than 5% cancer cells stained; level 2, 5–70% cancer cells stained; level 3, 71% or more cancer cells stained. The survival rates of patients with cimetidine treatment (‘Cimetidine’) or without cimetidine treatment (‘Control’) were compared using Kaplan-Meier method. The number of patients (‘n’) in each category was indicated in the figure. The statistical significance was evaluated by log rank test and generalized Wilcoxon test.