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 71 of cimetidine orally together with 200 mg day 71 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% (P50.0001). 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 .

Binding Sites for Lewis Antigens Are Expressed by Human Colon Cancer Cells and Negatively Affect Their Migration

“…Prognostic evaluations point to a functional impact of both determinants, and an increased expression of sialyl Lewis x correlated with the extent of malignancy and the high incidence of recurrence (and consequently with survival) of colon carcinoma patients (Nakamori et al, 1993). However, recent studies disagree with this conclusion, pinpointing a correlation of sialyl Lewis x (but not the Lewis a isomer) expression with progression of lymph node metastasis and dedifferentiation but not its status as an independent prognostic factor in colorectal adenocarcinomas (Baldus et al, 2002;Matsumoto et al, 2002). An important point to be noted for comparison is the nature of the mAb used as fine-specificity differences are encountered between various preparations (Matsumoto et al, 2002).…”

“…However, recent studies disagree with this conclusion, pinpointing a correlation of sialyl Lewis x (but not the Lewis a isomer) expression with progression of lymph node metastasis and dedifferentiation but not its status as an independent prognostic factor in colorectal adenocarcinomas (Baldus et al, 2002;Matsumoto et al, 2002). An important point to be noted for comparison is the nature of the mAb used as fine-specificity differences are encountered between various preparations (Matsumoto et al, 2002). At any rate, these clinical studies provide reason to pursue a delineation of functions of these oligosaccharides in models.…”

Anti-tumor effects of cimetidine on hepatocellular carcinomas in diethylnitrosamine-treated rats

“…In 1988, it was reported that post-operative treatment with cimetidine improved survival in a gastric cancer patient (10). Since that time, several studies have reported survival advantages with cimetidine treatment, mainly in patients with gastrointestinal cancer (11)(12)(13)(14). Further, positive effects have also been demonstrated in non-gastrointestinal cancer patients, such as those with renal cell carcinoma (15), malignant melanoma (16) and glioblastoma (17).…”

Carbohydrate‐mediated cell adhesion in cancer metastasis and angiogenesis

“…A remarkable improvement in 10-year survival from 49.8% to 84.6% was reported. 56) When the cancer cells strongly expressed sialyl Lewis x or sialyl Lewis a , the beneficial effect of cimetidine administration was even more prominent. The most pronounced effect was observed with sialyl Lewis a expression; 10-year sur- vival was improved from 20.1% to 90.9% in patients with cancer cells strongly expressing sialyl Lewis a by cimetidine treatment, whereas there was virtually no observable effect (90.9% vs. 80.0%) in patients with cancer cells exhibiting little or no expression of sialyl Lewis a .…”

“…The most pronounced effect was observed with sialyl Lewis a expression; 10-year sur- vival was improved from 20.1% to 90.9% in patients with cancer cells strongly expressing sialyl Lewis a by cimetidine treatment, whereas there was virtually no observable effect (90.9% vs. 80.0%) in patients with cancer cells exhibiting little or no expression of sialyl Lewis a . 56) The prophylactic effect is proposed to be due to the suppression of E-selectin expression in vascular endothelial cells. 57) The above-mentioned therapeutic applications involve inhibition of E-selectin-mediated cell adhesion.…”