Cimetidine amplifies the anti-neoplastic effect of Trichinella spiralis in mice
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Cited by 3 publications
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The role of histamine in the antitumour activity of endotoxin against solid syngeneic Meth-A sarcoma in BALB/c mice was studied. Endotoxin induces haemorrhagic necrosis and regression of this tumour. Histamine and the selective H1 receptor agonist 2-pyridylethylamine mimicked the induction of necrosis but did not cause regression. The selective H2 receptor agonist dimaprit did not cause any tumour damage. The effect of histamine could be inhibited by the H1 receptor antagonists diphenhydramine and promethazine but not by the H2 receptor antagonist cimetidine. Endotoxin-induced necrosis was slightly affected by diphenhydramine, and the incidence of regression was reduced by both H1 antagonists. Cimetidine potentiated endotoxin-induced regression. Similar effects were observed concerning the effects of H-receptor antagonists on necrosis and regression induced by tumour necrosis serum (TNS). Histological examination revealed no marked additional effects of diphenhydramine or cimetidine on endotoxin-induced hyperaemia, haemorrhagic necrosis, and mitotic arrest of the tumour cells. Only cimetidine increased the extent of nonhaemorrhagic necrosis. The endotoxin-induced release of tumour necrosis factor and cytostatic activity in TNS was clearly reduced by diphenhydramine, but hardly affected by cimetidine. Data indicate that intact H1 receptors are required for the induction of tumour regression and antitumour factors by endotoxin. Concomitant H2 blockade may facilitate this by stimulating H1 receptor-mediated processes upon endotoxin-induced histamine release, although a cimetidine-induced inhibition of T-suppressor cell activation might also be involved.
The role of histamine in the antitumour activity of endotoxin against solid syngeneic Meth-A sarcoma in BALB/c mice was studied. Endotoxin induces haemorrhagic necrosis and regression of this tumour. Histamine and the selective H1 receptor agonist 2-pyridylethylamine mimicked the induction of necrosis but did not cause regression. The selective H2 receptor agonist dimaprit did not cause any tumour damage. The effect of histamine could be inhibited by the H1 receptor antagonists diphenhydramine and promethazine but not by the H2 receptor antagonist cimetidine. Endotoxin-induced necrosis was slightly affected by diphenhydramine, and the incidence of regression was reduced by both H1 antagonists. Cimetidine potentiated endotoxin-induced regression. Similar effects were observed concerning the effects of H-receptor antagonists on necrosis and regression induced by tumour necrosis serum (TNS). Histological examination revealed no marked additional effects of diphenhydramine or cimetidine on endotoxin-induced hyperaemia, haemorrhagic necrosis, and mitotic arrest of the tumour cells. Only cimetidine increased the extent of nonhaemorrhagic necrosis. The endotoxin-induced release of tumour necrosis factor and cytostatic activity in TNS was clearly reduced by diphenhydramine, but hardly affected by cimetidine. Data indicate that intact H1 receptors are required for the induction of tumour regression and antitumour factors by endotoxin. Concomitant H2 blockade may facilitate this by stimulating H1 receptor-mediated processes upon endotoxin-induced histamine release, although a cimetidine-induced inhibition of T-suppressor cell activation might also be involved.
Effects of cimetidine and indomethacin on the growth of dimethylhydrazine-induced or transplanted intestinal cancers in the rat
Summary The effects of cimetidine and indomethacin on the growth of dimethylhydrazine induced or transplanted intestinal tumours in the rat have been studied. Cimetidine is a histamine type 2 receptor antagonist and indomethacin is an inhibitor of prostaglandin synthesis. Two models of rat intestinal tumours were used: a colon carcinoma line transplantable in syngeneic animals and intestinal tumours induced by dimethylhydrazine treatment of Sprague-Dawley rats. Cimetidine and indomethacin were given in drinking water, alone or in combination. Cimetidine had no effect on the growth of transplanted colon cancer but significantly increased the incidence of chemically-induced tumours, with a tendency toward more invasive and metastatic tumours than in the control animals. Indomethacin did not significantly modify the incidence or other characteristics of the tumours in any of the models. This result is at variance with a protective effect of indomethacin on chemically-induced rat colon cancer previously reported by others.In spite of numerous attempts, treatment of advanced or residual colorectal cancer by cytotoxic agents can be considered a failure. Since surgery is efficient only in the early forms of disease, other methods of treatment need to be found. Two groups have recently reported that indomethacin, a potent inhibitor of prostaglandin synthesis, was able to inhibit the growth of intestinal tumours indiced by a,variety of carcinogenec agents in the rat (Pollard & Luckert, 1980;Kudo et al., 1980). It has also been reported that cimetidine, a histamine type-2 receptor antagonist widely used in the treatment of peptic ulcer, could inhibit the growth of experimental tumours in rodents. This could perhaps occur through its blocking effect on histamine H-2 receptors at the surface of suppressor T lymphocytes (Gifford et al., 1981;Osband et al., 1981).Because indomethacin and cimetidine could have a cooperative effect on tumour growth, the efficiency of both drugs was tested individually or in combination, on experimental intestinal cancer. Two models were used in this work: a colon carcinoma line transplantable in syngeneic BDIX strain rats and intestinal tunours induced by dimethylhydrazine in Sprague-Dawley rats. Materials and methods AnimalsTwo strains of syngeneic rats were used in this Correspondence: A. Caignard Received 28 March 1984; accepted 16 July 1984. work: BDIX rats, bred in our laboratory by brother-sister mating, and Sprague-Dawley rats (IFFA-Credo, L'Arbresle, France). They were kept in an air-conditioned, humidity-controlled room, with a Light-dark cycle of 12h. They were allowed drinking water ad libidum and fed Extralabo biscuits (Sainte-Colombe, France). To determine the lipidic composition of the biscuits, lipids were extracted according to Folch et al., (1957) and the fatty acids were analyzed by gas-liquid chromatography as their methyl ester derivatives. The mean fatty acid content was 4.3% of the biscuit weight, unsaturated fatty acids and linoleic acid being respectively 60% and 21%...
To date, the efficacy of replacement therapy by means of autologous stem cells is hindered by at least 3 factors: (i) the lack of sufficient number of autologous stem cells; (ii) the existence of stem cells with aged-phenotype of reduced repair capacity; (iii) the reduced potential of replacement therapy to repair non-or slow-turnover tissues. Lately, groundbreaking research has shown that somatic cells may be reprogrammed to a pluripotent state by the induction of a specific set of genes in vitro -creating induced pluripotent stem cells (iPS). Moreover, there is evidence that the increased expression of specific genes is able to reverse/rejuvenate the aged-phenotype of stem cells. Remarkably, these two methods operate at the epigenetic level as well. Considering the reversibility of cell potency and aged-phenotype, the next logical step toward the goal of organismal rejuvenation is to test the possibility of inducing the pluripotent state in somatic cells in vivo. Such an approach will not only provide enough autologous stem cells to replace old cells as in standard replacement therapy, but may also have the additional beneficial effects of (i) reversing the possible aged-phenotype of iPS and (ii) rejuvenating nonor slow-turnover tissues that otherwise would benefit less from standard replacement therapy.Recent advances have highlighted the crucial role played by mitochondria in the etiology of a variety of rare maternally inherited disorders, in common complex diseases, as well as in normal physiological processes such as aging. One approach to the management of mitochondrial diseases would be to develop reagents to modulate mitochondrial function in vivo. Work in our laboratory is focused on the characterization of a multi-protein complex (the RNA Import Complex or RIC) from the kinetoplastid protozoon Leishmania tropica that transports tRNAs across mitochondrial membranes. The purified complex was efficiently taken up by human cells through a caveolin 1-depedent endocytotic pathway and targeted to mitochondria. The mitochondrial function of cybrid lines carrying the tRNA mutation that causes Myoclonic Epilepsy with Ragged Red Fibers (MERRF) was upregulated following administration of RIC. Conversely, RIC could be used to deliver signal-tagged antisense RNAs to mitochondria, resulting in degradation of the targeted mRNA and downregulation of respiration. This regime will be useful to study mitochondrial metabolism in cultured cells as well as in animal models.Human memory T cell pools proliferate and differentiate at varying rates that are determined by the frequency of lifelong antigenic re-encounter with different specific antigens. An important question is whether certain specific pools of memory T cells may be driven to exhaustion in elderly subjects, a pertinent point in view of the increasing human life expectancy. An emerging consensus is that cytomegalovirus (CMV), a b-herpesvirus with a prevalence of 60-90% worldwide, is an agent that induces specific T cells to extreme differentiation. The question t...
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