LE Magazine July 2002
Cimetidine
Cimetidine increases survival of
colorectal cancer patients with high levels of sialyl Lewis-X
and sialyl Lewis-A epitope expression on tumour cells.
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 the 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 the 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).
Br J Cancer 2002 Jan
21;86(2):161-7
Clinical improvement in advanced
cancer disease after treatment combining histamine and
H2-antihistaminics (ranitidine or cimetidine).
In a randomized study 31 patients with advanced cancer
disease in whom classical anticancer therapy had been
abandoned received a daily combination of subcutaneous
histamine and oral H2-antihistaminics. In 27 patients,
treatment induced a marked clinical improvement as shown by a
large rise in performance status (Karnofsky scale). Ten
patients were still alive 3-14 months after initiation of
treatment. Average survival in the 31 treated patients (172
+/- 113 days) was significantly longer than in 34 non-treated
patients with similar advanced cancer (26 +/- 16 days, P less
than 0.00001). In six treated patients, the size of liver and
lung metastases decreased. Histamine was perfectly tolerated
up to 4 mg/day.
Eur J Cancer Clin Oncol 1988
Feb;24(2):161-7
Effect of cimetidine on survival after
gastric cancer.
The effect of cimetidine on survival was investigated in
181 patients with gastric cancer. Immediately after operation
or the decision not to operate, the patients were randomized
in double-blind fashion to placebo or cimetidine 400 mg twice
daily for two years or until death, with review every three
months. Median survival in the cimetidine group was 450 days
(range 1-1826) and in the placebo group 316 days (1-1653). The
relative survival rates (cimetidine/placebo) were 45%/28% at 1
year, 22%/13% at 2 years, 13%/7% at 3 years, 9%/3% at 4 years,
and 2%/0% at 5 years. Survival in the cimetidine group was
significantly longer than in the placebo group.
Lancet 1988 Oct 29;2(8618):990-2
Prevention of alterations in
postoperative lymphocyte subpopulations by cimetidine and
ibuprofen.
Surgical procedures probably result in a temporary state of
immunosuppression. Identification of functional lymphocyte
subclasses using appropriate monoclonal antibodies appears to
serve as a sensitive, accurate, and reproducible measure of
immune status in patients in many disease states. Using
monoclonal antibodies specific for lymphocyte surface markers
and immunofluorescent assay, we quantitated lymphocyte
subpopulations in patients undergoing surgical procedures.
Cholecystectomy, colon surgery, and coronary bypass procedures
all resulted in postoperative decreases in helper and inducer
populations and increases in cytotoxic suppressor populations,
with resultant depressions in the helper to suppressor
lymphocyte ratio. Studies in an additional group of patients
who underwent cholecystectomy demonstrated that these changes
could be prevented by perioperative administration of
ibuprofen and cimetidine. These results suggest that
prostaglandins and histamines are involved in immunoregulatory
events after major operation. The ability of specific
pharmacologic therapy to prevent alterations in lymphocyte
populations suggest that postoperative immunity may be
preserved, hopefully leading to greater host resistance
against infection and tumor dissemination.
Am J Surg 1986 Feb;151(2):249-55
Cimetidine preserves non-specific
immune function after colonic resection for cancer.
Fifty consecutive patients undergoing resection of
colorectal cancer were randomized to either receive cimetidine
at a dose of 400 mg bd for a minimum of 5 pre-operative days,
then intravenously for 2 postoperative days, or to act as
controls. Baseline immune function was determined in all
patients by in vitro testing of lymphocyte proliferation (LP)
in response to mitogen, skin testing for cell mediated
immunity (CMI) and measurement of lymphocyte subsets. Immune
function was retested in both groups on the second
postoperative day. In control patients the mean postoperative
LP value was 41% of pre-operative levels (P < 0.0001) and
the mean CMI reduced to 29% (P < 0.0001). Patients treated
with cimetidine had no significant fall in these parameters.
Numbers of T and natural killer (NK) cells fell after surgery
in both groups, and B cell numbers were maintained in the
cimetidine group. It is concluded that cimetidine reduces the
immunosuppression that follows colonic resection.
Aust N Z J Surg 1994
Dec;64(12):847-52
The growth of carcinogen-induced colon
cancer in rats is inhibited by cimetidine.
Colon cancer was induced in 40 Sprague Dawley rats using a
10-week course of 1,2 dimethylhydrazine (DMH). Twenty animals
received cimetidine in their drinking water, commencing 5
weeks after concluding the course of DMH. After five weeks
treatment of the animals were sacrificed and the colon and
rectum excised. Tumours were assessed histologically for depth
of invasion, inflammatory cell response and stained for
Proliferating Cell Nuclear Antigen (PCNA), as a measure of
tumour proliferative index. PCNA staining was measured using a
computerized image analysis system. There were 25 tumours in
the cimetidine treated group and 20 in controls. In the
control group, 10% of the tumours were benign, 35% malignant
polyps, 40% invading through submucosa and 15% invading
through the bowel wall, as opposed to 40%, 44%, 8% and 8%,
respectively in the cimetidine group (Chi squared test: P =
0.002). The mean proliferative index for control tumours was
27.9% and for the cimetidine tumours 23.1% t test: P = 0.002).
It is concluded that cimetidine inhibits colon cancer cellular
proliferation and slows early tumour invasion in this animal
model.
Eur J Surg Oncol 1993
Aug;19(4):332-5
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