Mags - How did it go this morning?

smokeyjoe said:

Just info. when you google
Just info. when you google cimetidine and colon cancer....sorry it's long....2001; Accepted 1 November 2001.

Top of pageAbstract
Materials and methodsResultsDiscussionReferencesAcknowledgementsFigures and Tables
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 (sLx) and A (sLa). We found that cimetidine treatment was particularly effective in patients whose tumour had higher sLx and sLa antigen levels. For example, the 10-year cumulative survival rate of the cimetidine group with higher CSLEX staining, recognizing sLx, 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 sLx and sLa.

Keywords: colorectal cancer, cancer metastasis, sialyl Lewis antigens, cell adhesion, cimetidine

We demonstrated in a previous randomized control study that cimetidine, a histamine type 2 receptor antagonist, was significantly advantageous in increasing the disease-free period and survival of these patients (Matsumoto, 1995). Cimetidine was given to colorectal cancer patients receiving 5-fluorouracil (5-FU) after operation with the aim of reducing appetite loss and reflux esophagitis. Two other study groups reported similar advantageous effect of cimetidine on colorectal cancer patients (Adams and Morris, 1994; Svendsen et al, 1995). Furthermore, treatment with cimetidine was reported to be beneficial for patients with gastric cancer (Tonnesen et al, 1988), melanoma (Creagan et al, 1985; Hellstrand et al, 1994) or renal cell cancer (Sagaster et al, 1995).

Several studies have suggested various mechanisms underlying the beneficial effect of cimetidine on cancer patients, such as the following: (i) reversal of the pharmacological activity of histamine, tumour growth promoter by blocking histamine receptors on cancer cells (Adams et al, 1994; Reynolds et al, 1996) or affecting histamine metabolism (Garcia-Caballero et al, 1994); (ii) acting as an antioxidant, thus inhibiting tumour growth (Kimura et al, 1986) and (iii) augmentation of anticancer immune reactivity through receptor antagonism of circulatory suppressor T cells (Kumar, 1990), prevention of postoperative alterations of lymphocyte subpopulations (Hansbrough et al, 1986), or by maintenance of natural killer cell activity (Katoh et al, 1996). In our study, we found that cimetidine could block the expression of E-selectin on the surface of human umbilical vein endothelial cells, thus blocking the tumour cell adhesion to endothelium and preventing the liver metastasis in nude mice model (Kobayashi et al, 2000). Such findings were not known when we had planned this prospective randomized control study. But now, it is known that sialyl Lewis-X (sLx) and sialyl Lewis-A (sLa) antigens are ligands to E-selectin, and sLx and sLa expressed on cancer cells mediate adhesion of the cancer cells to vascular endothelial cells expressing E-selectin (Phillips et al, 1990; Takada et al, 1991, 1993). The adhesion of cancer cells to vascular endothelial cells is a key step in invasion and metastasis of cancer cells (Hoff et al, 1989, 1990; Nakamori et al, 1993). Therefore, we decided to classify the subjects according to the level of expression of sLx and sLa on cancer cells and we investigated 10-year survival that was the major objects of this clinical study. We examined whether the effect of cimetidine on cancer patients was correlated with the degree of expression of sLx and sLa on tumour cells in 61 colorectal cancer patients in our randomized control study (Matsumoto, 1995). Treatment with cimetidine markedly reduced the incidence of metastasis and significantly increased survival during a follow-up period of more than 10 years in patients whose tumour cells expressed sLx and sLa epitopes at increased levels.</p>