Biomedical subjects

M J Tisdale

Publications and source records attributed to M J Tisdale.

At least 19 recordsLinked to original sources

PubMed1992

Weight loss in a murine cachexia model is not associated with the cytokines tumour necrosis factor-alpha or interleukin-6.

Daily administration of an escalating dose of tumour necrosis factor-alpha (TNF-alpha) to female NMRI mice caused a progressive loss of body weight representing 12% of the original weight over a 6-day period. Weight loss was associated with a decreased food intake and pair-fed controls exhibited a weight loss of similar magnitude to that caused by TNF-alpha. However, weight loss in animals bearing a murine adenocarcinoma (MAC16) occurred without a change in energy intake and thus differed from that produced by TNF-alpha. Anti-TNF-alpha monoclonal antibodies at levels capable of protecting mice against lethal endotoxaemia were ineffective in reversing weight loss in animals bearing the MAC16 tumour and had no effect on the increase in tumour volume. Circulating levels of interleukin-6 were not elevated in animals bearing the MAC16 tumour and with a weight loss between 1.8 and 5.4 g. These results suggest that these cytokines are not involved in the cachexia produced by this murine tumour.

Adenocarcinoma↗

PubMed1992

Antitumour imidazotetrazines XXVIII 3-methyladenine DNA glycosylase activity in cell lines sensitive and resistant to temozolomide.

The ability of extracts of a range of cell lines to release methylated bases from a DNA substrate, which had been modified with [3H]dimethyl sulphate, has been compared in cell lines with differing sensitivity to the cytotoxic drug, temozolomide. High performance liquid chromatography profiles of the bases released by these extracts showed that the activity was specific for 3-methyladenine. There was little variation in the level of 3-methyladenine-DNA glycosylase between the different cell lines despite a 40-fold difference in sensitivity to temozolomide and no correlation with the level of O6-alkylguanine-DNA alkyltransferase.

Adenocarcinoma↗

PubMed1992

Lipid metabolism in cancer cachexia.

The effect of cancer cachexia on the oxidative metabolism of lipids has been studied in mice transplanted either with the MAC16 adenocarcinoma, which induces profound loss of body weight and depletion of lipid stores, or the MAC13 adenocarcinoma, which is the same histological type, but which grows without an effect on host body weight or lipid stores. While oxidation of D-[U-14C]glucose did not differ between animals bearing tumours of either type and non-tumour bearing controls, oxidation of [1-14C]triolein administered by intragastric intubation was significantly (P less than 0.05) higher in animals bearing the MAC16 tumour than in either non tumour-bearing controls or in animals bearing the MAC13 tumour. Intestinal absorption of [14C]lipid was significantly (P less than 0.05) reduced in animals bearing the MAC13 tumour when compared with either non tumour-bearing animals or MAC16 tumour-bearing animals, but was not significantly different in the latter two groups. The level of labelled lipids in heart and adipose tissue after an oral [14C]lipid load was significantly lower in animals bearing the MAC16 tumour compared with the other two groups. The level of tumour lipids was also higher in the MAC16 than in the MAC13 tumour after both an oral [14C]lipid load or by direct injection of [U-14C]palmitate complexed to albumin into epididymal fat pads. Oxidation of [U-14C]palmitate was also significantly enhanced in liver and heart homogenates from animals bearing the MAC16 tumour. These results suggest that in cachectic tumour-bearing animals mobilisation of body lipids is accompanied by an increased utilisation.

Adenocarcinoma↗

PubMed1992

Tumour-associated hypoglycaemia in a murine cachexia model.

Animals bearing a cachexia-inducing tumour, the MAC16 adenocarcinoma, showed a progressive decrease in blood glucose levels with increasing weight loss, while animals bearing a histologically similar tumour, the MAC13 adenocarcinoma, showed no change in either body weight or blood glucose levels with growth of the tumour. The effect of the MAC16 tumour on blood glucose levels appeared to be unrelated to food intake, glucose consumption by the tumour, or to the production of increased levels of IGF-I and IGF-II mRNA by the tumour cells. The relationship between the induction of cachexia and alteration in blood glucose levels remains unknown.

Adenocarcinoma↗

PubMed1992

Observations on the inhibition of serum and cell surface enzymes by eicosapentaenoic acid.

The relationship between serum and tumour cell surface proteolytic enzymes and the development of muscle breakdown in cancer cachexia has been studied in a murine model of the condition (MAC16). The surface of the MAC16 tumour cells carried a proteolytic enzyme referred to as guanidinobenzoatase (GB). Serum from mice also contained an enzyme (referred to as MSE) which cleaved the trypsin inhibitor 4-methylumbelliferyl-p-guanidinobenzoate as a true substrate, but there was no relationship with weight loss or the presence or absence of tumour and the level of this serum enzyme. Polyunsaturated fatty acids (PUFAs) were shown to be inhibitors of MSE at microM concentrations and one PUFA, eicosapentaenoic acid (EPA) was found to be a non-competitive inhibitor of both MSE and GB. The effect of EPA was specific since other proteolytic enzymes, trypsin, esterase and tissue plasminogen activator were unaffected by concentrations inhibiting GB and MSE. MSE and GB are two different enzymes which possess some common properties. However, GB is likely to be significant for tumour development since MSE is also found in normal mouse serum.

Animals↗

PubMed1991

Anticachectic and antitumor effect of eicosapentaenoic acid and its effect on protein turnover.

The effect of the polyunsaturated fatty acids eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA) on host body weight loss and tumor growth has been investigated in mice bearing a cachexia-inducing colon adenocarcinoma, the MAC16. EPA effectively inhibited both host weight loss and tumor growth rate in a dose-related manner with optimal effects being observed at a dose level of 1.25 to 2.5 g/kg. At these concentrations host body weight was effectively maintained, and there was a delay in the progression of growth of the tumor, such that overall survival was approximately doubled in EPA-treated animals, using the criteria dictated by the United Kingdom Coordinating Committee for the welfare of animals with neoplasms. Even when tumor growth resumed, weight loss did not occur. Animals bearing the MAC16 tumor showed a decreased protein synthesis and an increased degradation in skeletal muscle. Treatment with EPA significantly reduced protein degradation without an effect on protein synthesis. The effect of GLA on both host body weight loss and tumor growth was much less pronounced than that of EPA, with an effect only being seen at a dose of 5 g/kg, at which some toxicity was observed. In vitro studies showed that while EPA was effective in inhibiting tumor-induced lipolysis, GLA was ineffective in this respect. However, prostaglandin E1, which is formed from GLA in vivo, showed partial reversal of tumor-induced lipolysis and probably accounted for the anticachectic effect of GLA. These results suggest that EPA as the pure fatty acid should be considered for clinical investigation as both an anticachectic and antitumor agent, since prior work has shown that the other major component of fish oil docosahexaenoic acid is without pharmacological activity in this system.

Animals↗

PubMed1991

Metabolic substrate utilization by tumour and host tissues in cancer cachexia.

Utilization of metabolic substrates in tumour and host tissues was determined in the presence or absence of two colonic tumours, the MAC16, which is capable of inducing cachexia in recipient animals, and the MAC13, which is of the same histological type, but without the effect on host body composition. Glucose utilization by different tissues was determined in vivo by the 2-deoxyglucose tracer technique. Glucose utilization by the MAC13 tumour was significantly higher than by the MAC16 tumour, and in animals bearing tumours of either type the tumour was the second major consumer of glucose after the brain. This extra demand for glucose was accompanied by a marked decrease in glucose utilization by the epididymal fat-pads, testes, colon, spleen, kidney and, in particular, the brain, in tumour-bearing animals irrespective of cachexia. The decrease in glucose consumption by the brain was at least as high as the metabolic demand by the tumour. This suggests that the tissues of tumour-bearing animals adapt to use substrates other than glucose and that alterations in glucose utilization are not responsible for the cachexia. Studies in vitro showed that brain metabolism in the tumour-bearing state was maintained by an increased use of lactate and 3-hydroxybutyrate, accompanied by a 50% increase in 3-oxoacid CoA-transferase. This was supported by studies in vivo which showed an increased metabolism of 3-hydroxybutyrate in tumour-bearing animals. Thus ketone bodies may be utilized as a metabolic fuel during the cancer-bearing state, even though the nutritional conditions mimic the fed state.

Animals↗

PubMed1991

Enzymatic methylation of cytosine in DNA is prevented by adjacent O6-methylguanine residues.

The effect of O6-alkylation of guanine residues on the enzymic methylation of cytosine has been studied using synthetic oligonucleotides in which all guanines in cytosine-guanine sequences at potentially methylatable sites are replaced by O6-methylguanine. In contrast with the unmodified forms, which showed high acceptance activity for methyl-3H-labeled groups from S-adenosyl-L-[methyl-3H]methionine in the presence of DNA methylase, the modified oligonucleotides were not substrates for the enzyme either in the single-stranded or annealed forms. In view of the importance of cytosine methylation in the down-regulation of certain genes, the potential to affect gene expression by this mechanism may be a contributory factor in the toxic and carcinogenic effects of chemical methylating agents.

Base Sequence↗

PubMed1991

Importance of the O6 position of guanine residues in the binding of DNA methylase to DNA.

Methylation of Micrococcus lysodeikticus DNA by purified DNA methylase isolated from L1210 leukaemia cells is potently and specifically inhibited by both hetero and homoribo and deoxyribopolynucleotides containing guanine residues. The inhibitory effect is unaffected by chain length, but is abolished when the O6 residue of guanine is substituted as in poly[d(O6MeG)]20. Potent inhibition is also shown by polyinosinic and polyxanthylic acids, but not by polyadenylic acid or by heteropolymers containing adenine and thymine. These results suggest that the 6-position of the purine nucleus is important in binding of the DNA methylase to a particular region of the DNA duplex and that the hydrogen bonding properties of this group are important in enzyme recognition.

Binding Sites↗

PubMed1991

Antitumour imidazotetrazines--XXIV. Growth suppression by DNA from cells treated with imidazotetrazinones.

Transfection of a murine colon adenocarcinoma cell line (MAC13) with DNA extracted from GM892 or Raji cells previously treated with either the methyl- (temozolomide) or ethyl-(CCRG82019) imidazotetrazinones caused a dose-related suppression of cell growth. The effect was proportional to the concentration of DNA transfected and the time of incubation of the donor cell lines with the drugs. It was not shown with X-irradiated DNA suggesting that the effect did not arise from non-specific damage to the DNA. Transfection of MAC13 cells with DNA extracted from GM892 cells was more effective in inhibiting growth than DNA from Raji cells, and temozolomide treated cellular DNA was a more potent growth inhibitor than that from CCRG 82019 treated cells. For both agents the growth inhibitory effect was most marked with DNA extracted 6 hr after drug addition and thereafter the effect decreased up to 24 hr after drug addition. This suggests that the growth inhibitory effect is due to a repairable lesion, and that the terminal mechanism of action of these agents involves targets after DNA.

Animals↗

PubMed1991

Inhibition of tumour-induced lipolysis in vitro and cachexia and tumour growth in vivo by eicosapentaenoic acid.

Stimulation of lipolysis in murine adipocytes in response to a lipid-mobilizing factor produced by a cachexia-inducing murine adenocarcinoma was inhibited by eicosapentaenoic acid (EPA) with a Ki value of 104 microM. The inhibitory effect was strictly structurally specific, since other related fatty acids of both the (n-3) and (n-6) series were ineffective as inhibitors of the lipolytic process. Induction of lipolysis by both salbutamol and ACTH was also inhibited by EPA, suggesting that the effect is exerted on a step central to the process of lipolysis. Lipolysis induced with the tumour lipid-mobilizing factor was associated with a prolonged elevation of the intracellular level of cyclic AMP in adipocytes, in contrast with ACTH and salbutamol. The elevation of adipocyte cyclic AMP in response to the tumour lipid-mobilizing factor and lipolytic hormones was inhibited by EPA. In vivo, administration of pure EPA to weight losing mice bearing the MAC16 adenocarcinoma completely prevented weight loss and tumour growth rate. In contrast both the other (n-3) fatty acid present in fish oil, docosahexaenoic acid (DHA), and linoleic acid were ineffective in inhibiting weight loss or the growth of the MAC16 tumour. This suggests that inhibition of tumour lipolytic activity accounts for the anticachectic effect of EPA, and that a correlation may exist between the inhibition of cachexia and the inhibition of tumour growth.

Adenocarcinoma↗

PubMed1991

Changes in activity of lipoprotein lipase, plasma free fatty acids and triglycerides with weight loss in a cachexia model.

The effect of weight loss during cancer cachexia on the plasma levels of free fatty acids (FFA) and triglycerides, and on the tissue levels of lipoprotein lipase (LPL), has been studied in mice bearing an experimental colon adenocarcinoma (MAC16). Despite extensive mobilisation of host body fat reserves, plasma levels of triglycerides were reduced irrespective of the extent of weight loss. The plasma levels of FFA also showed an initial decrease with weight loss, followed by a rise peaking at a weight loss of about 2 g, and thereafter the levels decreased with increasing weight loss. The level of LPL in both heart and adipose tissue showed an initial rise with increasing weight loss also peaking at a weight loss of approximately 2.5 g, followed by a decrease with further weight loss. The increased LPL would provide an increased level of fatty acids for oxidation in the cachectic state and would account for the effect on plasma FFAs and triglycerides.

Adenocarcinoma↗

PubMed1991

Lipogenesis in tumour and host tissues in mice bearing colonic adenocarcinomas.

Although animals bearing the MAC16 colon adenocarcinoma showed progressive weight loss, the average food consumption (15.1 +/- 0.6 Kcal day-1) did not differ from non tumour-bearing controls (15.3 +/- 0.3 Kcal day-1), while animals bearing a related colon adenocarcinoma, MAC13, which had no effect on body weight had a significantly (P less than 0.01) elevated food intake (16.4 +/- 0.3 Kcal day-1) above controls. Weight loss in animals bearing the MAC16 tumour was associated with a significant reduction in the percentage contribution of the kidneys, colon and epididymal fat pads to the total body weight. Although loss of body fat occurred only in the MAC16 model, both tumours were capable of synthesising lipids from glucose both in vitro and in vivo at the same rate. In addition both tumours increased the rate of lipogenesis from glucose in kidney, liver and epididymal fat pads of the host. Lipogenesis from glucose would be expected to result in a loss of utilisable carbohydrate energy and thus would be expected to increase the overall energy requirements in the tumour-bearing state leading to catabolism of host body tissues if the energy intake is not increased.

Acetyl-CoA Carboxylase↗

PubMed1991

Lipid mobilising factors specifically associated with cancer cachexia.

Both urine and plasma from mice and humans with cancer cachexia have been shown to contain higher levels of lipid mobilising activity than normal controls, even after acute starvation. There was no significant increase in the urinary lipid mobilising activity of either mice or humans after acute starvation, suggesting that the material in the cachectic situation was probably not due to an elevation of hormones normally associated with the catabolic state in starvation. Further characterisation of the lipid mobilising activity in the urine of cachectic mice using Sephadex G50 exclusion chromatography showed four distinct peaks of activity of apparent molecular weights of greater than 20, 3, 1.5 and less than 0.7 kDa. No comparable peaks of activity were found in the urine of a non tumour-bearing mouse. The high molecular weight activity was probably formed by aggregation of low molecular weight material, since treatment with 0.5 M NaCl caused dissociation to material with a broad spectrum of molecular weights between 3 and 0.7 kDa. Lipolytic species of similar molecular weights were also found in the urine of cachectic cancer patients, but not in normal urine even after 24 h starvation. The lipid mobilising species may be responsible for catabolism of host adipose tissue in the cachectic state.

Adipose Tissue↗

PubMed1991

Effect of the lipid-lowering agent bezafibrate on tumour growth rate in vivo.

The growth rate of the MAC16 tumour in cachectic animals was significantly enhanced by the hypolipidemic agent bezafibrate, while the growth rate of a histologically similar tumour, the MAC13, which grows without an effect on host body compartments was unaffected. Growth of the MAC16 in vitro was unaffected by bezafibrate, suggesting that it was an in vivo phenomenon only. The stimulatory effect of bezafibrate correlated with the maximum plasma levels of free fatty acids (FFA) arising from the catabolism of adipose tissue. Accumulation of 14C-lipid from 1-14C-triolein administered by intragastric intubation was enhanced in heart, gastrocnemius muscle and tumour of bezafibrate treated animals, while the total lipid absorption did not differ from solvent treated controls. The increased lipid accumulation in the heart, but not the tumour correlated with an increased tissue lipoprotein lipase level. The increased tumour level may arise from an increased uptake of FFA arising from a weakening of the bonds between FFA and albumin. These results suggest that growth of certain tumours is dependent on maintaining sufficient lipid levels and that the lipid mobilising effect of the tumour may be necessary to sustain tumour growth.

Animals↗

PubMed1991

Cancer cachexia.

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Body Weight↗

PubMed1990

Lipolytic factors associated with murine and human cancer cachexia.

We have identified a lipolytic factor in extracts of a cachexia-inducing murine carcinoma (MAC16) that shows characteristics of an acidic peptide and appears to be composed of three fractions of apparent molecular weights corresponding to 3 kd, 1.5 kd, and 0.7 kd, as determined by exclusion chromatography. Material with identical chromatographic and molecular weight characteristics was also present in the serum of patients with clinical cancer cachexia but absent from normal serum, even under conditions of starvation. The MAC16 lipid factor, when injected into animals bearing the non-cachexia-inducing tumor MAC13, was capable of inducing weight loss without a significant reduction in food intake. Similar lipolytic material, although in lower concentration, was also found in the MAC13 tumor extracts. These findings suggest that cachexia may arise from the enhanced expression of a lipolytic factor associated with tumor cells.

Adenocarcinoma↗

PubMed1990

Inhibition of weight loss by omega-3 fatty acids in an experimental cachexia model.

The effect of substitution of the carbohydrate component of the diet by calories derived from fish oil on host body weight loss and tumor growth rate has been studied in an experimental colon adenocarcinoma (MAC16). This tumor produces extensive host weight loss and reductions in both total body fat and muscle dry weight, without a reduction in food intake. Diets containing fish oil significantly reduced host body weight loss, with almost complete protection occurring when the fish oil comprised 50% of the calories, without an alteration of total calorie consumption or nitrogen intake. There was also a significant reduction in tumor growth rate, although the reduction in host weight loss was greater than might be expected from a smaller tumor burden. The reduction of host body weight loss was associated with an increase in total body fat and muscle mass. The effect appears specific to the type of fat since comparable results were not obtained with a gamma-linolenic acid-enriched diet. When compared with cyclophosphamide and 5-fluorouracil the fish oil diet exerted a similar antitumor effect at the maximum dose. Whereas the antitumor effect of the former agents was achieved with considerable host toxicity, the latter produced no toxicity and almost completely abolished the cachectic effect of the tumor. These results suggest that fish oil is a nontoxic, highly effective anticachectic agent with the added advantage of antitumor activity.

Adenocarcinoma↗