Dietary intake and resting energy expenditure in relation to weight loss in unselected cancer patients.

Weight loss and anorexia are frequent findings in advanced cancer. The progressive wasting could be attributed to changes in dietary intake and/or energy expenditure mediated by metabolic alterations. In this study, we analyzed dietary intake in generalized malignant disease of solid tumor type in relation to resting energy expenditure (REE) and reported weight loss. In a group of 297 unselected cancer patients from a university hospital outpatient clinic, dietary intake of energy and macronutrients from a 4-day food record, REE by indirect calorimetry, height, weight and weight loss were recorded. Protein intake was validated against 24 hr urine nitrogen in a subgroup (n = 53), and no indication of systematic misreporting was found. Mean daily dietary intake was below maintenance requirements, 26 +/- 10 kcal/kg. Weight loss of more than 10% was present in 43% of patients and elevated REE (>110% of predicted) in 48%. Dietary intake did not differ between normo- and hypermetabolic patients, nor was tumour type or gender related to energy and protein intake. Weight loss could not be accounted for by diminished dietary intake since energy intake in absolute amounts was not different and intake per kilogram body weight was higher in weight-losing patients compared to weight-stable patients. Dietary macronutrient composition did not differ from the general population. Dietary intake of energy and protein was decreased, but dietary macronutrient composition did not appear to be changed. Weight loss and hypermetabolism were frequent and not compensated for by an increase in spontaneous food intake. Our results indicate that an expected up-regulation of dietary intake in response to elevated energy expenditure is frequently lost in cancer patients. This may be the explanation behind cancer cachexia rather than a primary decrease in appetite.

Effects of exercise on insulin distribution and action in testosterone-treated oophorectomized female rats.

Administration of testosterone (T) to oophorectomized (Ovx) female rats is followed by severe insulin resistance, localized to postreceptor cellular events in the muscle. In this study, intervention by exercise was introduced to examine whether circulatory adaptations are involved in insulin resistance. Two groups of Ovx rats were studied: one group was given T (Ovx+T); another group had free access to running wheels (Ovx+T+Ex). In addition, one control group (sham operated) was studied. Insulin sensitivity was measured with the euglycemic hyperinsulinemic clamp technique (submaximal) for 150 min. Muscle interstitial glucose and insulin concentrations were measured by microdialysis. The measurements showed that, in Ovx+T rats, the onset of insulin action was significantly (P < 0.05) slower during the first 95 min of the clamp compared with that in Ovx+T+Ex and controls. Muscle interstitial concentrations of insulin but not glucose were lower in both Ovx+T and Ovx+T+Ex rats than in controls throughout the clamp. It was concluded that physical exercise prevented the slow onset of insulin action in Ovx+T rats without changing the distribution time of muscle interstitial insulin. The results indicate that hyperandrogenicity is characterized by delayed muscle insulin action. Physical exercise reverses these defects without any beneficial effect on muscle interstitial insulin concentrations.

Beta-adrenoceptor activity and resting energy metabolism in weight losing cancer patients.

This study was aimed at comparing the blocking of beta-adrenoceptor activity to changes in the resting energy metabolism of 10 cancer patients with progressive weight loss due to solid malignant tumours. Resting energy expenditure (REE) as well as whole body carbohydrate and fat oxidation were investigated and related to plasma substrate levels (glucose, glycerol, free fatty acids (FFA)) before and after 5 days of oral administration of specific beta1 receptor blocker (atenolol, 50 mg/day) and non-specific beta1,beta2-adrenoceptor (propranolol, 80 mg/day) blockade. The administration order of the drugs was random, and a 3-day washout period was used in all individuals between the provision of the first and the second drug in order to minimise the risk of carry-over effects. Resting measurements in the morning after an overnight fast were performed by indirect calorimetry. Atenolol treatment reduced REE by 77+/-14 kcal/day and propranolol by 48+/-13 kcal/day, respectively (P<0.05 versus pretreatment values). Whole body oxygen uptake and carbon dioxide production were decreased similarly by both atenolol and propranolol treatment (P<0.05). Carbohydrate oxidation was increased by atenolol and decreased by propranolol, whilst fat oxidation was decreased by atenolol and unchanged by propranolol. The decrease in REE, accounting for the decline in heart rate, was significantly more pronounced following treatment with propranolol compared with atenolol (P<0.05). Atenolol and propranolol had no effect on blood glucose, plasma glycerol and FFA. We conclude that wastage in cancer patients is in part explained by increased beta(1) and beta(2)-adrenoceptor activity, in part secondary to elevated cardiovascular activity as a result of anaemia, loss of cardiac contractile capacity and altered host metabolism.

Protection of metabolic and exercise capacity in unselected weight-losing cancer patients following treatment with recombinant erythropoietin: a randomized prospective study.

This study was aimed at evaluating whether anemia could be prevented in unselected weight-losing cancer patients on anti-inflammatory treatment by early and prophylactic treatment with recombinant human erythropoietin (rhEPO) and whether such a benefit could be translated into improved physical function and metabolic efficiency. One hundred eight cancer patients who experienced progressive cachexia due to solid, mainly gastrointestinal tumors were randomized to receive twice daily a cyclo-oxygenase inhibitor (controls; indomethacin, 50 mg twice a day) or indomethacin and erythropoietin, provided on individual basis to prevent development of progressive anemia (study patients; indomethacin, 50 mg twice a day plus rhEPO; range, 12,000-30,000 units per week). All patients were treated and followed up until death or to preterminal stage. Biochemical tests (blood, liver, kidney, and thyroid), nutritional state assessment (food intake and body composition), and exercise testing with simultaneous measurements of respiratory gas exchanges before and during exercise were performed before institution of treatments and then at regular intervals during the treatment period (2-30 months after start). Study and control patients did not differ in survival. rhEPO prevented development of anemia during the entire observation period. This was associated with a significantly more preserved maximum exercise capacity in study patients compared to control patients during the follow-up period (101 +/- 10 versus 66 +/- 6 W; P < 0.0001), based on more effective ventilation and whole-body respiratory gas exchanges. These improvements were also evident when exercise performance was normalized to lean body mass, an indirect measure of the skeletal muscle mass. The metabolic efficiency, expressed as oxygen uptake per watt produced, was also significantly preserved in rhEPO-treated patients compared to controls (14.1 +/- 1.1 versus 16.3 +/- 0.9 ml O2/W, P < 0.05). Our results demonstrate that institution of early and prophylactic rhEPO treatment to patients with progressive cancer prevents development of tumor-induced anemia. This achievement was associated with a better preserved exercise capacity, which is explained in part by improved whole-body metabolic and energy efficiency during work load.

Purine nucleotides and phospholipids in ischemic and reperfused rat skeletal muscle: effect of ascorbate.

The effect of intravenously administered ascorbate on the ischemic and reperfused rat skeletal muscle was investigated. Purine nucleotides and phospholipids in skeletal muscle from rats subjected to 4 h of ischemia followed by 1-h reperfusion were analyzed by high-performance liquid chromatography. In addition, ATP, phosphocreatine (PCr), Pi, and phosphomonoesters (PME) were analyzed by 31P-nuclear magnetic resonance at 202.4 MHz, and individual PME such as glucose-6-phosphate and IMP were quantified. PCr and ATP were exhausted after 4 h of ischemia and recovered poorly upon reperfusion in the soleus and tibialis muscle of untreated rats. Postischemic reperfusion resulted in significant loss of cardiolipin. Treatment with 55 mM ascorbate resulted in total restoration of PCr during reperfusion, and ATP recovered to 42% of control in the soleus. Recovery was improved in the tibialis as well, and the cardiolipin decrease was limited. A lower ascorbate concentration (5 mM) did not enhance postischemic recovery. Our findings show that a high dose of ascorbate improves the energetic state of rat skeletal muscle during postischemic reperfusion, probably due to its antioxidant function.

Tumour purine nucleotides and cell proliferation in response to exercise in rats.

Voluntary physical exercise can delay the onset of anorexia and cachexia in tumour-bearing rats. A substrate deviation in the host which has been hypothesised as tumour burden is reduced despite an increase in food intake. Therefore, we determined the levels of purine nucleotides, the energy charge and the cell division rate in tumours from exercising animals in the postexercise period. Tumour content of purine nucleotides was analysed by HPLC. Tumour cell kinetics was studied by flow cytometry after incorporation of bromodeoxyuridine (BrdU) into DNA. Exercising animals demonstrated a 34.4% reduction in tumour volume (P < 0.05) but a 1.31-fold increase in energy charge in tumour tissue (P < 0.05). Labelling index (LI), DNA synthesis time (Ts) and potential doubling time (Tpot) were not significantly altered. These results suggest that the influence on tumour growth is closely related to the exercise period.

Coenzymes Q9 and Q10 in skeletal and cardiac muscle in tumour-bearing exercising rats.

Physical exercise increases metabolic rate, and induces both adaptational biogenesis of mitochondria in skeletal muscle and an increase in antioxidant capacity. The onset of experimental anorexia and cachexia can be delayed by voluntary exercise. As skeletal muscle is the main target for cancer cachexia, we determined the levels of coenzymes Q9 and Q10 in skeletal muscle from tumour-bearing exercising rats, and compared them to those of sedentary tumour-bearers and controls. Both tumour-bearing groups had increased levels of coenzymes Q9 and Q10 in the anterior tibial muscle (P < 0.05 for exercised animals). In the soleus muscle, only the tumour-bearing exercising animals demonstrated an increase in the levels of both coenzymes (P < 0.05). In cardiac muscle, the presence of tumour and exercise reduced the levels of coenzymes below that of sedentary controls. Exercise counteracted the anaemia in the tumour-bearing host (P < 0.05). In conclusion, the increase in antioxidant capacity in skeletal muscle indicates a defence mechanism in the tumour-bearing hosts which is augmented by physical exercise.

Insulin sensitivity, hormonal levels and skeletal muscle protein metabolism in tumour-bearing exercising rats.

We have previously shown that spontaneous physical exercise can delay onset of experimental anorexia and cachexia, and retard tumour growth; we now report the effects on insulin sensitivity, hormonal levels and skeletal muscle protein metabolism. Insulin sensitivity determined with a euglycaemic hyperinsulinaemic clamp revealed a normalised glucose disposal rate in tumour-bearing exercising (TBE) versus sedentary (TBS) animals (TBE 15.55 +/- 2.71 versus TBS 2.47 +/- 2.12 mg/kg/min; P < 0.05). Both TBE and TBS animals had decreased levels of corticosterone during the clamp. Serum levels of insulin during tumour progression were unaffected by exercise, but the insulin: glucagon ratio increased and the progressive decrease in rT3 was attenuated. The concentration of glucagon decreased in both tumour-bearing groups during the experiment, while TBE animals showed a relative reduction in corticosterone. Capacity for skeletal muscle protein synthesis, expressed as RNA: protein ratio, was normalised in TBE animals in two tumour protocols (TBE 5.9 +/- 0.6 versus TBS 4.7 +/- 0.3; TBE 2.9 +/- 0.4 versus TBS 1.8 +/- 0.2; P < 0.05, respectively). Incorporation rate of 14C-phenylalanine into skeletal muscle protein was increased in the TBE group in vitro and in vivo. In the postexercise period, protein degradation evaluated by tyrosine release in vitro was increased, but decreased over time. This study has confirmed a positive skeletal muscle protein balance in exercising tumour-bearing animals, partly explained by the increased insulin sensitivity. This conclusion was further supported by the less catabolic pattern indicated by hormonal levels.

Influence of zymosan (a non-specific macrophage stimulator) and of indomethacin on liver tumours--an experimental study in rats.

Zymosan--a non-specific macrophage-stimulating agent--reduces tumour take in the liver. The mechanism for this effect is not clear, but it may be mediated via the Kupffer cells and prostaglandins. On the other hand, the Prostaglandin-synthesis inhibitor, indomethacin, inhibits tumour growth. Pretreatment with zymosan (3 mg 100 g-1) for 3 days of two different strains of rats, inoculated in the liver with a hepatoma or an adenocarcinoma cell suspension respectively, reduced tumour take and also initial tumour growth. The effect on tumour take and initial growth was inhibited by concomitant administration of indomethacin (0.2 mg 100 g-1). When zymosan was administered after tumour cell inoculation the growth rate of the hepatoma was retarded, but this effect was not abrogated by indomethacin. Pretreatment with indomethacin had no significant effect on tumour take or initial growth. When given after the tumour was established in the liver, indomethacin reduced the growth rate of the hepatoma, but not of the adenocarcinoma. These results suggest that there are different mechanisms for the effects of zymosan on tumour take and on growth of an established tumour. In immunoincompetent nude mice the effect on the hepatoma was similar to the effect in the rat. In vitro both tumours were insensitive to zymosan and indomethacin. This study confirms that pretreatment with a non-specific macrophage stimulator (zymosan) diminishes tumour take and growth in the liver, that the effect of zymosan on tumour take in the liver is abrogated by indomethacin and that the zymosan effect on tumour take in the liver is at least partly mediated by the Kupffer cells and prostaglandins.

In vivo 31P nuclear magnetic resonance evidence of the salvage effect of ascorbate on the postischemic reperfused rat skeletal muscle.

The effect of 32 mM ascorbate on the time courses of phosphocreatine (PCr), inorganic phosphate (Pi), adenosine triphosphate (ATP) and intracellular pH in rat skeletal muscle during ischemia and reperfusion was investigated in vivo using 31P nuclear magnetic resonance (NMR) spectroscopy. Ascorbate was administered intravenously prior to induction of ischemia and at the time of reperfusion. The changes in PCr/(PCr+Pi), ATP and pH were similar in the non-treated and in the treated groups during ischemia. PCr/(PCr+Pi) fell to < 10% and ATP to approximately 30% of the preischemic values after 4 hours of arrested circulation, and pH decreased considerably. Postischemic reperfusion was followed continuously for 150 minutes. At the time of reflow, treatment with ascorbate had an immediate, positive effect on the recovery of high energy phosphates and pH. The level of PCr/(PCr+Pi) was 86% higher (p < 0.001) and the ATP level was 40% higher (p < 0.001) in the treated group than in the control group by the end of the reperfusion period. The results provide in vivo evidence for a salvaging effect of ascorbate on ischemia-reperfusion injury in skeletal muscle, probably owing to its antioxidant function and other ancillary effects, mainly its provision of additional buffer capacity.

Cytochrome c oxidase and purine nucleotides in skeletal muscle in tumour-bearing exercising rats.

We have previously shown that spontaneous physical exercise can delay the onset of experimental anorexia and cachexia and retard tumour growth and we now report the effects on the energy metabolism in skeletal muscle. Exercising tumour-bearing animals (TBE) had an increased maximal capacity for oxygen uptake expressed as Vmax of the cytochrome c oxidase compared with their tumour-bearing sedentary controls (TBS) [mean (S.E.) 289.9 (30.7) vs. 141.6 (11.0); P less than 0.05] but an unchanged Km value. The TBS animals had a depressed Vmax as compared with non-tumour-bearing sedentary controls (CS) [141.6 (11.0) vs. 210.1 (15.1); P less than 0.05]. Most of the purine nucleotides in the 'glycolytic' anterior tibial muscle were significantly altered in the TBE animals compared with the TBS animals, but in the mainly 'oxidative' soleus muscle only the level of inosine monophosphate (IMP) was changed. The results indicate that physical exercise can normalise the oxidative capacity and improve the energy state in skeletal muscle in the tumour-bearing host.

Effects of spontaneous physical exercise on experimental cancer anorexia and cachexia.

The aim of this study was to evaluate whether spontaneous physical exercise can modify cancer anorexia and cachexia in tumour-bearing rats. Two transplantable experimental tumours were evaluated. Tumour-bearing Wistar Furth rats fed ad libitum and with free access to a running wheel had a delayed onset of anorexia compared with their non-exercised tumour-bearing controls, retained normal behaviour and were able to run the same daily distance as non-tumour controls until the onset of cachexia. Exercise resulted in a decreased carcass wet weight and lipid stores but in an increased carcass dry weight in the tumour-bearing animals. Despite increased food intake, physical exercise resulted in a reduced final tumour weight without any change in water content. Skeletal and cardiac muscle tissue did not show any difference in water content but there was an increased RNA/protein quotient in the exercising tumour-bearing animals. Thus the deleterious alterations induced by the malignancy on tumour host metabolism are not inevitable but can be modified by spontaneous physical exercise.

Trace element changes in serum and skeletal muscle compared to tumour tissue in sarcoma-bearing rats.

Cancer cachexia is characterized by wasting of the lean tissue and profound changes in the body composition of the tumour host. These changes are partly explained by an inefficient energy production but other factors may also be important, such as deficiency of essential nutritional components. In the present study the changes of trace elements in serum and skeletal muscle were compared to those in tumour tissue during tumour progression in sarcoma--bearing rats. Trace element analysis was performed directly on serum specimens and frozen sections from skeletal muscle and tumour tissue. The samples were analysed by energy dispersive X-ray fluorescence spectrometry (EDXRF) without any other pre-treatment such as homogenization and extraction. In skeletal muscle an increased content of zinc was found during tumour progression. The iron concentration was unchanged, but since muscle wasting is part of the cachexia this means that iron was transferred to other compartments. Thus the iron content of serum was doubled and tumour tissue had a high concentration of iron. Selenium was below detection limits in skeletal muscle but well detectable in tumour tissue and it increased during tumour growth. Rubidium and potassium content correlated in all tissues (R:0.98) as did bromine and sodium (R:0.98). Copper behaved differently from the other trace elements and showed large variability. This was also true when tissue copper was individually correlated to all other trace elements in the same tissue.