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Cachexia, a devastating wasting syndrome characterized by severe weight loss with specific losses of muscle and adipose tissue, is driven by reduced food intake, increased energy expenditure, excess catabolism, and inflammation. Cachexia is associated with poor prognosis and high mortality and frequently occurs in patients with cancer, chronic kidney disease, infection, and many other illnesses. There is no effective treatment for this condition. Hypothalamic melanocortins have a potent and long-lasting inhibitory effect on feeding and anabolism, and pathophysiological processes increase melanocortin signaling tone, leading to anorexia, metabolic changes, and eventual cachexia. We used 3 rat models of anorexia and cachexia (LPS, methylcholanthrene sarcoma, and 5/6 subtotal nephrectomy) to evaluate efficacy of TCMCB07, a synthetic antagonist of the melanocortin-4 receptor. Our data show that peripheral treatment using TCMCB07 with intraperitoneal, subcutaneous, and oral administration increased food intake and body weight and preserved fat mass and lean mass during cachexia and LPS-induced anorexia. Furthermore, administration of TCMCB07 diminished hypothalamic inflammatory gene expression in cancer cachexia. These results suggest that peripheral TCMCB07 treatment effectively inhibits central melanocortin signaling and therefore stimulates appetite and enhances anabolism, indicating that TCMCB07 is a promising drug candidate for treating cachexia.

Ghrelin is a novel brain-gut peptide that stimulates food intake and may secondarily increase body weight via a growth hormone secretagogue receptor (GHS-R). Tumor-bearing mice (MCG101), characterized by anorexia, fat loss and muscle wasting due to increased concentration of PGE2 and proinflammatory cytokines (IL-1beta, IL-6, TNF-alpha), were provided ghrelin i.p. at a low (20 microg/day) and high dose (40 microg/day) to examine the ability of ghrelin to counteract tumor-induced anorexia. Immunohistochemical staining and Western blot analyses were used to identify GHS-R expression in the brain as well as its relationship to NPY expression in hypothalamic neurons. GHS-R mRNA in hypothalamus and ghrelin mRNA in gastric fundus were quantified by RT-PCR. Body composition was determined by carcass extractions. GHS-R expression in hypothalamus and plasma ghrelin levels were significantly increased in freely-fed tumor-bearing mice, while gastric fundus expression of ghrelin was unaltered compared to non-tumor-bearing mice (controls). Ghrelin treatment increased food intake, body weight and whole body fat at both low and high doses of ghrelin in normal controls, while tumor-bearing mice showed improved intake and body composition at the high dose of ghrelin only. Exogenous ghrelin normalized the GHS-R expression in hypothalamus from tumor-bearing mice without alterations in the gastric fundus expression of ghrelin. Tumor growth was not altered by exogenous ghrelin. Our results indicate that MCG 101-bearing mice became ghrelin resistant despite upregulation of hypothalamic GHS-R expression, which confirms similar indirect observations in cancer patients. Thus, other factors downstream of the ghrelin-GHS-R system appear to be more important than ghrelin to explain cancer-induced anorexia.

Evidence implies that nitric oxide (NO) in the central nervous systems mediates anorexia in tumor-bearing hosts. We have therefore evaluated, by immunohistochemical image analyses, net alterations of nitric oxide synthases (nNOS, eNOS, iNOS) in brain nuclei [paraventricular hypothalamic nucleus (PVN), medial habenular nucleus (MHB), lateral habenular nucleus (LHB), paraventricular thalamic nucleus (PV), lateral hypothalamic area (LHA), ventromedial hypothalamic nucleus (VMH), nucleus of the solitary tract (NTS)] of tumor-bearing mice (TB) with prostanoid-related anorexia. Pair-fed (PF) and freely fed (FF) non-tumor-bearing mice were used as controls. c-fos was analyzed as indicator of neuronal activation. nNOS was significantly increased in VMH and PVN from TB mice, while eNOS was significantly increased in LHB and LHA. iNOS was significantly increased in LHA and PVN nuclei, but decreased in MHB, LHB and VMH from tumor-bearers. However, several of these alterations were similarly observed in brain nuclei from pair-fed controls. Provision of unspecific NOS-antagonists to TB mice increased nNOS, eNOS and iNOS in several brain nuclei (PVN, LHA, VMH), but left tumor-induced anorexia unchanged. c-fos was significantly increased in all brain nuclei in PF mice except for NTS, LHA and PVN compared to controls, while tumor-bearing mice had increased c-fos in LHA and PVN only compared to controls. Our results demonstrate a complex picture of NOS expression in brain areas of relevance for appetite in tumor-bearing hosts, where most changes seemed to be secondary to stress during negative energy balance. By contrast, NOS content in PVN and LHA nuclei remains candidate behind anorexia in tumor disease. However, nitric oxide does not seem to be a primary mediator behind tumor-induced anorexia. NO may rather secondarily support energy intake in conditions with negative energy balance.

Individuals affected with either acute or chronic diseases often show disorders of nutrient balance. In some cases, a devastating state of malnutrition known as cachexia arises, brought about by a synergistic combination of a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass. Stimulation of the hypothalamic melanocortin 4 receptor (MC4-R) produces relative anorexia and increased metabolic rate, even in a relatively starved state. Here we demonstrate that cachexia induced by lipopolysaccharide administration and by tumor growth is ameliorated by central MC4-R blockade. MC4-R knock-out mice or mice administered the MC3-R/MC4-R antagonist, agouti-related peptide, resist tumor-induced loss of lean body mass, and maintain normal circadian activity patterns during tumor growth. The final tumor mass is not affected in these animals, providing further support for the potential role of MC4-R antagonism in the treatment of cachexia in disease states.

MCG 101 tumors were implanted sc. on wild-type C57 Bl and gene knockout mice to evaluate the role of host-produced cytokines [interleukin (IL)-6, IL-12, IFNgamma, tumor necrosis factor (TNF) receptor 1, and TNF receptor 2] to explain local tumor growth, anorexia, and carcass weight loss in a well-defined model with experimental cachexia. Indomethacin was provided in the drinking water to explore interactions between host and tumor-derived prostaglandins and proinflammatory cytokines for tumor growth. Wild-type tumor-bearing mice developed cachexia because of rapid tumor growth, which were both attenuated in IL-6 gene knockouts. Similar findings were observed after provision of anti-IL-6 to wild-type tumor-bearing mice. Alterations in food intake were not directly related to systemic IL-6 but rather secondarily to IL-6-dependent tumor growth. The absence of host-derived IL-12, IFN-gamma, or the TNF receptor 1 or receptor 2 gene did not attenuate tumor growth or improve subsequent cachexia. Thus, carcass weight loss was not improved by the omission of host cytokine (TNF-alpha, IL-12, or IFN-gamma) except for IL-6. Systemic indomethacin provision decreased plasma prostaglandin E2 in five of six groups of gene knockout tumor-bearing mice, which was associated with improved carcass weight in these groups. Indomethacin seemed to improve food intake to a similar extent in both wild-type and gene knockouts, which agree with the speculation that eicosanoids are more important to explain anorexia than host cytokines. Our results demonstrate that host- and tumor-derived cytokines and prostaglandins interact with tumor growth and promote cachexia in a more complex fashion than usually presented based on previous information in studies on either anti-cytokine experiments in vivo or on gene knockouts with respect to a "single cytokine model." Overall, host cytokines were quantitatively less important than tumor-derived cytokines to explain net tumor growth, which indirectly explains subsequent cachexia and anorexia.

Unlabelled: Tumor growth is associated with development of cachexia which includes progressive wasting and anorexia. Our previous studies have indicated that insulin like growth factor-I (rhIGF-I) in complex with its binding protein 3 (IGFBP 3), but not free IGF-I, was a potent stimulator of muscle protein synthesis in rats with chronic undernutrition. The aim of the present study was to evaluate the effect of rhIGF-I/IGFBP-3 on the development of cancer cachexia, and to assess safety data on net tumor growth and progression during treatment., Methods: A methylcholantrene induced sarcoma was implanted s.c. in C 57 bl mice. The animals were provided with rhIGF-I/rhIGFBP-3 (5 microg/g bw) i.v. twice daily (n= 18). Controls were provided with saline (n= 20). Body weight and food intake were registered daily. Net tumor growth was measured over 10 days. Protein synthesis in liver and muscle, as well as plasma concentrations of glucose, insulin, IGF-I and amino acids were measured at the end of the study., Results: tumor size did not differ between control mice and rhIGF-I/rhIGFBP-3 treated mice (1.5 +/- 0.1 g wet tumor weight vs 1.6 +/- 0.2 g respectively). Saline treated tumor bearing controls lost 9.1 +/- 1.3 % body weight over 10 days due to rapid tumor growth while rhIGF-I/rhIGFBP-3 provision attenuated weight loss to 5.6 +/- 1.3% of body weight in study mice (P< 0.05). Food intake was improved and blood glucose concentration was reduced from 7.1 +/- 0.5 to 5.8 +/- 0.2 (P< 0.05) in response to treatment., Conclusion: Our results demonstrate that rhIGF-I/rhIGFBP-3 complex did not affect net tumor growth. Moreover rhIGF-I/rhIGFBP-3 complex improved tumor-host nutritional state by improving food intake, attenuating weight loss and improving glucose metabolism., (Copyright 2000 Harcourt Publishers Ltd.)

Background: Insulin resistance may play an important role in cancer cachexia; however, its mechanisms remain to be clarified., Methods: Cellular mechanisms of insulin resistance in tumor-bearing rats (TBR) were investigated in isolated adipose cells by measuring 3-O-[14C]methyl glucose transport activity and glucose transporter-4 (GLUT4) protein in low-density microsomes at a basal state and in the plasma membrane at an insulin-stimulated state., Results: The insulin-stimulated glucose transport activity in adipose cells from TBR was significantly lower than that of control rats (CTR) (0.51 +/- 0.25 and 2.27 +/- 0.11 fmol/cell/min, respectively). The amount of GLUT4 in low-density microsomes at a basal state and in plasma membrane at an insulin-stimulated state was less in TBR than in CTR., Conclusions: These data suggest that the insulin resistance seen in the adipose cells of these tumor-bearing rats was caused in part by both a decreased amount of GLUT4 protein in a basal state and a decreased translocation of GLUT4 in response to insulin stimulation.

The dynamic metabolic effects of a fructose infusion challenge on hepatic intracellular levels of adenosine 5'-triphosphate (ATP), inorganic phosphate (Pi) and phosphomonoesters (PME) were monitored noninvasively by 31P MRS in a remote tumour-bearing rat model. Fisher male rats were inoculated with a methylcholanthrene-induced sarcoma. Seventeen rats were randomized into three groups: control (n = 6), low tumour burden (LTB, n = 6), or moderate tumour burden (MTB, n = 5). The LTB group had tumour burdens of 0.2-2.0% while the MTB group had tumour burdens of 2.6-5.7%. All rats were in the pre-clinical phase of cancer cachexia as determined by food intake and body weight. Rats were infused with 1.2 g/kg of fructose i.v. and the metabolic response of the liver was monitored with time over 1 h via 31P MRS. In all groups an immediate increase in hepatic levels of PME was noted, which returned to baseline values over the course of the experiment, reflecting the phosphorylation of fructose to fructose 1-phosphate. For the MTB rats, the return to baseline levels was more rapid than in the control or LTB group. All groups experienced a 20% decrease in hepatic ATP levels which did not return to baseline over the 1 h observation period. As well, all groups experienced an initial fall in Pi, which recovered to prefructose levels or greater. MTB rats demonstrated a 30-40% increase in Pi concentration and a 60-70% increase in Pi/ATP ratio after infusion with fructose as compared to LTB and control rats (ANOVA;p<0.05). This is consistent with cachexia-induced enhancement of hepatic gluconeogenic activity, and hence more rapid release of Pi from the phosphorylated metabolites in the MTB rats. Thus fructose infusion and hepatic 31P MRS permit pre-clinical detection of cancer cachexia as reflected by increased Pi generation and more rapid removal of PME.

Inappropriate hepatic lipogenesis, hypertriglyceridaemia, decreased fatty acid oxidation and muscle protein wasting are common in patients with sepsis, cancer or AIDS. Given carnitine's role in the oxidation of fatty acids (FAs), we anticipated that carnitine might promote FA oxidation, thus ameliorating metabolic disturbances in lipopolysaccharide (LPS)- and methylcholanthrene-induced sarcoma models of wasting in rats. In the LPS model, rats were injected with LPS (24 mg kg-1 i.p.), and treated with carnitine (100 mg kg-1 i.p.) at -16, -8, 0 and 8 h post LPS. Rat health was observed, and plasma inflammatory cytokines and triglycerides (TG) were measured before and 3 h post LPS. In the sarcoma model, rats were implanted subcutaneously with tumour, and treated continuously with carnitine (200 mg kg-1 day-1 i.p.) via implanted osmotic pumps. Tumour burden, TG and cytokines were measured weekly for 4 weeks. Carnitine treatment significantly lowered the tumour-induced rise in TG (% rise) in the sarcoma model (700 +/- 204 vs 251 +/- 51, P < 0.03) in control and carnitine groups respectively. Levels of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) (pg ml-1) were also lowered by carnitine in both LPS (IL-1 beta: 536 +/- 65 vs 378 +/- 44: IL-6: 271 +/- 29 vs 222 +/- 32; TNF-alpha: 618 +/- 86 vs 367 +/- 54, P < or = 0.02) and sarcoma models (IL-1 beta: 423 +/- 33 vs 221 +/- 60; IL-6: 222 +/- 18 vs 139 +/- 38; TNF-alpha: 617 +/- 69 vs 280 +/- 77, P < or = 0.05) for control and carnitine groups respectively. We conclude that carnitine has a therapeutic effect on morbidity and lipid metabolism in these disease models, and that these effects could be the result of down-regulation of cytokine production and/or increased clearance of cytokines.

We studied the tumor host response to excessive doses of an anabolic steroid (nandrolone propionate, 2.5 mg 20 g intraperitoneally every second day for 11 days) with respect to body composition and tumor cell kinetics in MCG 101 sarcoma-bearing mice (C57BL/6J) with progressive cachexia. Although survival and food intake were not affected, a significant weight gain was observed that was essentially attributed to water retention. Net protein content was increased only to a minor extent (15%), of which only the liver accounted for a significant part of the body compartments. Hepatic protein accumulation was obviously caused by decreased protein degradation, since hepatic RNA content was unchanged. After anabolic steroid administration, reduced histochemical staining of succinate dehydrogenase was observed in skeletal muscles rich in oxidative type 1 fibers, but it was not different from that of tumor-bearing control animals, which was also confirmed by measurements of citrate synthase and cytochrome c oxidase activities in skeletal muscle and liver tissue. The anabolic steroid had no significant effect on tumor growth in terms of weight progression, energy state, polyamine synthesis rate, cell division rate, and cell cycle cytocompartments. We conclude that anabolic steroid supplementation is not therapeutically beneficial in counteracting progressive weight loss in experimental cancer.

Morphologic changes in the hepatocytes of tumour-bearing rats at the pre-cachectic and cachectic stages were studied by electron microscopy and were quantitatively analysed by a morphometric method. Ten male F-344 rats, subcutaneously inoculated with methylcholanthrene-induced sarcoma cells (TBR) were compared with ten pair-fed controls (CTR). There was no significant difference in the size of the cells or their nuclei, the number of mitochondria, or the number of lysosomes, between TBR and CTR at either the pre-cachectic or cachectic stage. Although the size of mitochondria of TBR was already significantly enlarged at the pre-cachectic stage, before the food intake of the TBR had decreased, the micro-structure within the mitochondria was unaltered. Marked differences were observed in the number, arrangement and distribution of the rough endoplasmic reticulum, all of which decreased significantly in TBR compared with CTR at both the pericentral and periportal zones. Changes at the periportal region were further pronounced at the cachectic stage. These results, distinct from the changes seen in simple starvation, may confirm a part of the biochemical evidence specific to tumour induced metabolic alterations.

The development of cachexia may complicate cancer therapy, yet controversy exists concerning its nutritional management. For example, use of total parenteral nutrition (TPN) may not be appropriate because of gut atrophy, possible stimulation of tumor growth, and lack of total host protein repletion. In the present experiment, host and tumor responses were compared after identical parenteral or enteral nutritional supplementation (EN). Eighteen days after subcutaneous inoculation of adult male Fischer-344 rats with fresh methylcholanthrene-induced sarcoma (tumor-bearing [TB] rats), catheters were placed into either the external jugular vein or the stomach. Four days later, rats were started on an 11-day course of either TPN or EN with a Freamine-III-based formula (amino acids = 6%, dextrose = 21.5%, lipid = 1.5%). When the rats were killed, there was no difference in tumor weight between the various TB groups. Carcass weight was increased significantly in both the TB-TPN and TB-EN groups, and there was an elevation in gastrocnemius protein content in both groups compared with the TB-rat food group. Small intestine protein was preserved in the TB-EN group to the level observed in the control-rat food animals. Total lipids in the liver were increased in both TB-TPN and TB-EN groups; however, the magnitude of the increase was less in the TB-EN animals. Neither treatment resulted in complete protein repletion of tumor-bearing rats. EN may be more appropriate than TPN in that gut mass is preserved. The maintenance of gut mucosa may prove to be beneficial in the treatment of the depleted, immunocompromised, and metabolically stressed host.

Temporal patterns of the cachectic effects of tumor growth and their relation to systemic levels of tumor necrosis factor (TNF) and IL-6 (interleukin-6) were examined in a rat model of experimental cancer cachexia employing the methylcholanthrene (MCA) sarcoma. Fischer 344 rats, implanted with biotelemeters for measuring temperature and activity, were implanted subdermally with tumor tissue fragments. Ad libitum-fed and pair-fed controls were sham incised. Bioassays for TNF and IL-6 were performed on serial plasma samples, obtained via jugular vein at 3- to 6-day intervals throughout the experimental period. Tumor growth induced significant anorexia, weight loss, and a decline in motor activity corresponding to an increase in mean plasma IL-6 levels, independent of reduced food intake or weight loss alone as shown in pair-fed controls. A significant lowering of body temperature then developed, followed by a two- to threefold increase in water consumption. The patterns of weight loss and temperature reduction differed in rate and degree from those seen with pair feeding.

The cause of cancer cachexia is unclear. Tumors may be competing with the host for ingested nutrients or may be releasing some factor that actively inhibits energy utilization. To explore these questions, plasma was sterilely collected and pooled from 103 terminally cachectic Fischer 344 rats implanted with an experimental sarcoma. Control plasma was collected in similar fashion from 138 nontumor-bearing rats (NTBP). Plasma from tumor-bearing rats (TBP) or NTBP was continuously infused in a randomized, blinded fashion for 4 days into 20 normal rats. During infusion, food intake and nitrogen excretion were measured daily. At sacrifice, body weight and organ masses were determined. Rats receiving TBP demonstrated an immediate and profound anorexia compared with those receiving NTBP. Total food intake during treatment was 31.2 +/- 3.3 (g +/- SEM) in the TBP group versus 48.2 +/- 2.8 in the NTBP group (P less than 0.001 by t test). Likewise, the total decline in body weight was greater in the TBP group as compared with the NTBP group (-35.2 +/- 3.4 versus -14.6 +/- 4.0, P less than 0.001). Mean daily nitrogen balance during treatment was negative in the rats receiving TBP (-14.5 +/- 20.1 mg +/- SEM) while remaining highly positive in the rats receiving NTBP (110.7 +/- 19.3, P less than 0.002). Finally, cardiac and gastrocnemius muscle masses were decreased, while hepatic mass was unaffected. These data demonstrate that the syndrome of cancer-associated cachexia is transmissible in plasma and therefore may be mediated by a circulating molecule or molecules. Identification and purification of the molecule(s) responsible for this effect would have obvious clinical benefits.

Tumor necrosis factor may be a mediator of the syndrome of cancer cachexia. Tachyphylaxis or tolerance to the cachectic effects of recombinant tumor necrosis factor (rTNF) has been previously described. In this study, we investigate whether repetitive exposure to rTNF can induce similar tolerance in tumor-bearing (TB) rats and ameliorate cachexia induced by the tumor. In experiment 1, non-tumor-bearing (NTB) and TB rats were randomized to either escalating low doses of rTNF or saline i.p. twice daily for 9 consecutive days. NTB rats treated with rTNF demonstrated a significant decline in food intake and weight change (P less than 0.00001) but soon developed tolerance to the cachectic effects of rTNF; they consumed significantly more food than on the first day of treatment and had weight change similar to NTB rats treated with saline. TB rats treated with rTNF showed a similar significant decline in food intake and weight change (P less than 0.0001) and also demonstrated similar tolerance to the cachectic effects of rTNF with continued treatment. Following treatment, TB rats that had been treated with rTNF ate significantly more and lost less weight than TB rats that had been treated with saline (P less than 0.00001). rTNF treatment of TB rats also demonstrated antineoplastic activity, as estimated tumor weight of tumors from rats treated with rTNF were significantly less than controls (P = 0.003). The anticachexia and antineoplastic effects of rTNF resulted in prolonged survival of TB rats treated with rTNF compared to control TB rats (P = 0.015). Experiment 2 utilized two different rTNF treatment regimens in TB rats: one group received 12 days of escalating doses of rTNF, and another group received 15 days of rTNF treatment. TB rats treated with rTNF again had a significantly greater food intake (P less than 0.00001) and delayed weight loss (P = 0.0001) posttreatment that was further augmented by additional doses of rTNF. Antineoplastic activity of rTNF was less clear, and overall tumor growth curves were not affected by rTNF treatment. Survival of TB rats treated with rTNF was again significantly increased in a dose-dependent manner (P = 0.006). Repeated administration of low doses of rTNF to TB rats induces mild reduction in tumor growth, tolerance to the cachectic effects of rTNF that results in tolerance to the cachectic effects of tumor, and prolongation of survival.

C57BL/6 mice bearing either a transplantable methylcholanthrene-induced sarcoma or Lewis lung adenocarcinoma were passively immunized every other day with a rabbit immunoglobulin fraction raised against murine cachectin/tumor necrosis factor-alpha. Mice bearing methylcholanthrene-induced sarcoma developed tumor-associated hypophagia that was attenuated by anticachectin immunoglobulin treatment. In the same tumor-bearing animals, anticachectin treatment also significantly reduced the extent of carcass protein and fat loss, and reduced tumor weight. Mice bearing Lewis lung adenocarcinoma did not develop significant anorexia or carcass lean tissue depletion as tumor growth progressed, but they lost carcass lipid. Treatment of Lewis lung adenocarcinoma bearing mice with anticachectin antibodies diminished the degree of carcass lipid depletion and prevented plasma hypertriglyceridemia. However, in both tumor models, anticachectin treatment did not affect either the development of anemia, hypoalbuminemia or the increase in serum amyloid P concentrations seen with increasing tumor burden. We conclude that an endogenous cachectin response, inhibitable by exogenously administered antibody, contributes to anorexia and to changes in body fat and protein metabolism in these tumor-bearing animals. Neutralizing endogenous cachectin production with antibodies offers the potential to reduce tissue wasting that is frequently associated with neoplastic disease, but it does not appear to affect all of the hematologic and acute phase responses in these murine tumor models.

As a model of surgical stress in the cancer-bearing animal, we resected large flank sarcomas from cachectic rats under ether anesthesia and closed wounds primarily. The metabolic cost of tumor resection was measured using a long-term continuous indirect calorimeter. In the immediate postresection period energy balance decreased and host energy expenditure increased significantly (P less than 0.005). In animals with similar tumor weights, mortality following resection was determined by the degree of cachectic depletion. We then considered whether improvement of preoperative host nutritional status with insulin treatment might improve a subsequent surgical outcome. Insulin, when administered exogenously to cachectic tumor-bearing rats, has been shown to stimulate food intake and preserve host weight and does not stimulate tumor growth. When individual rats bearing a cachexia-producing flank sarcoma demonstrated a decline in food intake to less than 75% of predicted (approximately 25 days after tumor implantation), they were randomized to receive either daily injections of NPH insulin (2 units/100 g/day) for 5 days or no treatment for 5 days. Animals then underwent tumor resection and 14-day survival was measured. All resections were performed in an unbiased manner without the surgeon's knowledge of each rat's treatment status. In an experiment using 59 rats, insulin-treated rats had a threefold higher 5-day preoperative food intake and did not lose weight in the preoperative period, while untreated rats lost 17 g (P less than 0.001). Mortality in the insulin-treated group was 10% versus 28% in the untreated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Cancer bearing is frequently accompanied by weight loss, yet the factors causing cancer cachexia remain unclear. This study compares how tumor type and tumor burden affect host carcass fat depletion. Nude mice were inoculated with human malignant melanoma, human colon adenocarcinoma, or murine sarcoma cells, or were noninjected controls. Body weights, tumor burdens, and carcass lipid contents were measured. Carcass weights of melanoma-bearing mice were significantly lower than those of sarcoma-bearing mice, mice exposed to colon cancer antigens but without tumor growth, or control mice (all p less than 0.02). The degree of carcass lipid loss in melanoma-bearing mice (mean tumor burden 3.5% of total body weight [TBW]) was almost three times that of sarcoma-bearing mice (p less than 0.05), which had more than twice the tumor burden (mean tumor burden 7.8% TBW). Exposure to colon cancer antigens without tumor growth resulted in essentially no carcass lipid depletion compared with control mice. These findings argue against a mass effect of tumor as being solely responsible for host fat mobilization and suggest that carcass lipid depletion in tumor-bearing nude mice is more a function of tumor type than of tumor burden.

The relationship between circulating thyroid hormones and nutritional status was studied in sarcoma-bearing inbred C57BL/6J mice and control mice. Supplementation with exogenous thyroxine (T4) was also evaluated. Tumor-bearing animals had depressed levels of circulating thyroid hormones. This was also found in food-restricted (pair-fed and pair-weighed) controls. Plasma levels of thyroid hormones decreased with increased tumor burden. Thyrotropin-releasing hormone caused an increased response of thyroid-stimulating hormone in tumor-bearing animals. Low levels of thyroid hormones in sarcoma-bearing mice were due to depressed hormone production by the thyroid gland rather than to increased clearance rate of hormones. Plasma levels of triiodothyronine (T3) correlated to the amount of whole-body nitrogen among sarcoma-bearing mice and food-restricted controls. Exogenous T4 increased food intake by 20% in sarcoma-bearing mice. The benefit of this was probably counteracted by an increased metabolic rate, since reversal of plasma levels of T3 and free T4 had no net effect on body composition of freely eating sarcoma-bearing mice, although it had a negative effect on body and muscle composition in food-restricted controls. Exogenous T4 did not stimulate tumor growth. The results indicate that low circulating levels of thyroid hormones in experimental cancer cachexia are probably caused by the reduced food intake (anorexia), which is in agreement with findings in clinical cancer. Depression of thyroid hormones is probably a physiological means to reduce energy expenditure and to preserve substrates in progressive cancer disease.

This study was designed to ascertain whether the overall availability of whole-body lipids and nitrogen is a limiting factor for survival in tumor-bearing mice suffering from anorexia and cachexia. Three-month-old nongrowing mice (C57BL/6J) were given s.c. transplants of a methylcholanthrene-induced sarcoma. Freely fed, starved, and pair-fed animals were used. Body and lipid composition, tumor growth, and survival time were measured. Freely fed sarcoma-bearing mice died with profoundly altered body composition. This was not explained by the anorexia assessed in pair-feeding experiments. Starvation had caused a more severe depletion in body composition in both tumor-bearing and nontumor-bearing animals than the tumor alone did in freely fed tumor-bearing mice. Freely fed tumor-bearing animals had normal proportions of whole-body triglycerides, cholesterol, and polar lipids, but they lost palmitic acid quantitatively more than any other fatty acid. It is unlikely that any single fatty acid became limiting during tumor growth. The results show that the overall availability of lipids, nitrogen, and glucose precursors is not a limiting factor for survival in experimental tumor cachexia. Other factors considered to be more likely as determining factors for the death of tumor-bearing animals are discussed.

The present study was performed to determine if a host nutritional treatment, insulin, in the absence of antitumor treatment could improve survival of cachectic tumor-bearing (TB) rats. Initially food intake and host weight were correlated with survival of untreated rats with similar size sarcomas (45-50 cm3). TB rat food intake (r = 0.69, p less than 0.0001) and host weight (r = 0.47, p less than 0.004) correlated positively with subsequent survival. Once daily neutral protamine hagedorn (NPH) insulin treatment (2 units/100 g) significantly improved food intake (p less than 0.01) and host weight (p less than 0.01) of cachectic TB rats without increasing tumor growth. Twice daily NPH insulin (2 units/100 g) maintained normal food intake of cachectic TB rats and turned a host weight loss into a host weight gain which was significantly greater than untreated controls (p less than 0.001) and all other methods of insulin administration including once daily (p less than 0.001). Twice daily NPH insulin maintained mild hypoglycemia (glucose = 84 +/- 12 mg/dl) compared to once daily NPH insulin which resulted in hyperglycemia (glucose = 140 +/- 8 mg/dl, p less than 0.001) prior to next dose. In addition, twice daily NPH insulin did not increase tumor growth. Once daily NPH insulin for 5 days during cachectic decline was well tolerated (no treatment deaths), and improved median survival of TB rats randomized to insulin (15 days) compared to controls (13 days, p = 0.06). However, twice daily NPH insulin during cachectic decline failed to improve survival because of treatment deaths.(ABSTRACT TRUNCATED AT 250 WORDS)