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Cachexia is a complex syndrome. The main components of this pathological state are anorexia and metabolic abnormalities such as glucose intolerance, fat depletion, and muscle protein catabolism among others. The aim of the present article is to review the different therapeutic approaches that have been designed to fight and counteract muscle wasting in different pathological states such as cancer, AIDS and chronic heart failure.
Melanocortin receptors (MC-R) activated by one of several peptides derived from the pro-opiomelanocortin (POMC) precursor have become leading contenders for a pivotal role in controlling food intake. Evidence has emerged over the last decade to implicate primarily the MC4-R and, to a lesser extent, MC3-R as the key sub-types involved and both are strategically located in those regions within the hypothalamus known to be associated with feeding. The receptors are within class A of the GPCR superfamily and the key electrostatic interaction with the positively charged peptide (Arg) has been mapped to one or more Asp or Glu residues located on helices II and III of the seven helical bundle characteristic of this class of receptor. Sites for secondary interactions from which sub-type selectivity may be derived have also been located in the extracellular and helical domains. Unique amongst GPCRs is the presence of endogenous antagonist peptides, Agouti and Agouti-related peptide (AGRP), which confer an extra level of control on the system. Recently, several reports of potent and selective non-peptide ligands have been published and these are seen as prototypic molecules from which drugs may emerge to treat obesity (agonists) and cachexia (antagonists). The role played by the melanocortin system is the subject of this review and advances in our understanding of the structure of the endogenous ligand(s), non-peptide, small molecule ligands and the receptors at which they interact will be discussed.
This review presents a history of tumor necrosis factor, considers the biology of this pleiotropic mediator, and summarizes the evidence that implicates it as a mediator of cachexia.
Parasitic infections and malnutrition coexist in many tropical and subtropical areas. Studies of Leishmania donovani and of experimentally infected Syrian hamsters have provided important insights into the complex interrelationships between malnutrition and this parasitic disease. Malnutrition, which adversely affects cell-mediated immunity, is associated with the development of visceral leishmaniasis (kala-azar) in children living in endemic areas. In turn, L. donovani can cause wasting as well as hepatosplenomegaly, fever, and anemia. Syrian hamsters infected with L. donovani develop a disease that is comparable to that of humans with kala-azar. Weight loss in infected hamsters is associated with splenic macrophage secretion of potentially catabolic cytokines as measured by the D10.G4.1 assay for interleukin-1 and the L929 cytotoxicity assay for tumor necrosis factor/cachectin. Although decreased food intake contributes to wasting in infected hamsters, studies of skeletal muscle function indicate that it is not the sole factor. Leishmania donovani-infected hamsters have also been used to study drugs with the potential to prevent or reverse cachexia.
OBJECTIVE: To study the effects of a megestrol acetate liquid formulation (800 mg/d) on body weight, body composition, caloric intake, and mental outlook in patients with the acquired immunodeficiency syndrome (AIDS) who had cachexia. DESIGN: Twelve-week, multicenter, randomized, double-blind, placebo-controlled trial. SETTING: Multiple clinical centers. PATIENTS: 100 patients with AIDS who had weight loss of 10% or more of ideal body weight were randomly assigned to placebo (n = 48) or megestrol acetate (n = 52). MEASUREMENTS: Caloric intake, body weight, body composition, and sense of well-being. RESULTS: Most patients receiving megestrol acetate had increased caloric intake resulting in body weight gain (mainly fat mass). From baseline to week 8, the megestrol acetate group increased their daily caloric intake by 608 calories, whereas the placebo group increased intake by 134 calories (difference, 474 calories; 95% CI, -68 to 880 calories). Body weight in the megestrol acetate group increased by 3.86 kg from baseline to week 8, although it decreased by 0.46 kg in the placebo group (difference, 4.32 kg; CI, 2.42 to 6.22 kg). At week 8 in the megestrol acetate group, patients gained 3.68 kg in fat mass and those in the placebo group lost 0.28 kg (difference, 3.96 kg; CI, 2.49 to 5.43 kg). Body water, lean mass, and patient survival were not statistically different between treatment groups. Patients treated with megestrol acetate had an increased sense of well-being when compared with patients who received placebo. CONCLUSIONS: This megestrol acetate liquid formulation is well tolerated, increases food intake, results in body weight gain, and improves the sense of well-being in cachectic patients with AIDS.
We report on a patient with acute painful diabetic neuropathy in whom abdominal pain and severe weight loss mimicked neoplastic disease. Positive recognition of the diabetic neuropathic cachexia syndrome might have avoided extensive invasive investigation. Intensive enteral nutritional support was associated with prompt resolution.
The purpose of this study was to determine the maximum tolerated dose and dose-limiting toxicities of fish oil fatty acid capsules containing omega-3 fatty acid ethyl esters. Twenty-two patients with neoplastic disease not amenable to curative therapy who had lost 2% of body weight over a previous 1 month time period were given an escalating dose of fish oil fatty acids. The maximum tolerated dose was found to be 0.3 g/kg per day of this preparation. This means that a 70-kg patient can generally tolerate up to 21 1-g capsules/day containing 13.1 g of eicosapentaenoic acid + docosahexaenoic acid, the two major omega-3 fatty acids. Dose-limiting toxicity was gastrointestinal, mainly diarrhea, and a poorly described toxicity designated as "unable to tolerate in esophagus or stomach." A patient with chronic lymphocytic leukemia taking the fish oil provided an unusual opportunity to perform a detailed biochemical study of the effect of fish oil capsules on the lipids of malignant cells at several sequential time points in treatment. Studies of the malignant lymphocytes, serum, and whole blood of this one patient revealed an increase in eicosapentaenoic acid, the major component of the fish oil capsules, during fish oil capsule treatment. This study provides a scientific basis for the selection of omega-3 fatty acid doses for future studies in cancer. The maximum tolerated dose found is considerably higher than anticipated from published studies of many human diseases. The observation of a modification of the lipids of leukemic cells, serum, and blood in a patient with chronic leukemia provides a biochemical basis for a possible effect of fish oil supplements on cancer cachexia and tumor growth.
The potential interaction between cyclooxygenase (Cox) and NO metabolic pathways in the control of local tumor growth was evaluated. Mice bearing either a sarcoma-derived tumor (C57B1; MCG 101) or a malignant melanoma (C3H/HeN; K1735-M2) were used. These models were principally different because they demonstrate, in tumor hosts, conditions with and without cancer cachexia, seemingly related to high and low production of prostanoids, respectively. Cox inhibitors (Cox-1 and Cox-2) decreased tumor growth by 35-40% in MCG 101-bearing mice but had no such effect on melanoma-bearing mice, despite the expression of the Cox-2 protein in melanoma cells. Indomethacin reduced prostanoid production in both tumor (MCG 101) and host tissues and reduced tumor cell proliferation, mainly in vivo. Nitric oxide synthase (NOS) inhibitors (N(omega)-nitro-L-arginine methyl ester and N(omega)-nitro-L-arginine) reduced tumor growth in vivo by approximately 50% in both tumor models. Tumor growth reduction, related to NOS inhibition, was unrelated to prostanoid production and was an in vivo phenomenon in both tumor models. Specific inhibitors of inducible NOS activity, unexpectedly, had no effect in any tumor model, although inducible NOS protein was present in tumor tissues in large amounts. A combination of Cox and NOS inhibitors had no additive effect on tumor growth (MCG 101). Cox inhibition increased tumor tissue (MCG 101) expression of cNOS mRNA but had no significant effect on tumor tissue expression of the transferrin receptor, vascular endothelial growth factor, or basic fibroblast growth factor. NOS inhibition increased tumor tissue content of cNOS mRNA but showed as well a trend to increase mRNA content of the transferrin receptor and vascular endothelial growth factor. Our results suggest that NOS inhibitors can decrease the local growth of tumors that are either responsive or unresponsive to Cox inhibition. This effect may reflect cross-talk between Cox and NOS pathways within or among tumor cells, or it may represent unrelated effects on tumor and host cells. Whether NO inhibition may be used therapeutically in clinical tumors that are unresponsive to eicosanoid intervention remains to be evaluated.
The introduction of HAART has changed the nutritional status of HIV patients. In the pre-protease inhibitor (PI) era, more than 60% of HIV-positive persons presented with protein energy malnutrition (PEM) and vitamin and mineral deficit. This caused progressive physical-metabolic wasting (wasting syndrome/cachexia) and increased susceptibility to opportunistic infections and drug toxicity. PEM was a concurrent cause in 80% of deaths attributed to AIDS. Since 1996, the year in which PIs were introduced, the number of patients dying as a result of AIDS has decreased by two thirds, and cachexia is no longer the AIDS terminal phase in developed countries. But different patterns of nutritional status changes have appeared in association with the use of newer anti-HIV therapies and with longer survival of HIV-infected patients. A new clinical and laboratory syndrome--lipodystrophy syndrome--now affects patients receiving PI-based therapy. This syndrome consists of changes in body shape that are caused by an abnormal redistribution of fat. Fat accumulates in the abdominal area (truncal and visceral obesity), in the axillary pads (bilateral symmetric lipomatosis), and in the dorsocervical pads ("buffalo hump," "bull neck") but decreases in the legs, arms, and nasolabial and cheek pads (peripheral lipodystrophy). Hyperlipidemia and insulin resistance are also frequently present (metabolic syndrome X). Pathogenic mechanisms of lipid and fat tissue disturbances are discussed in this article, and the clinical approach to patient management and therapeutic options for lipodystrophy and lipid dysmetabolism is evaluated.
In 81 patients with circulatory insufficiency of the IIB-III stage some in dices of the lipids and protein metabolism along with the blood sugar level were studied. Changes in the lipids metabolism values are more pronounced in patients with mitral defects than in those with atherosclerotic cardiosclerosis. The authors attach definite importance to these derangements in the pathogenesis of cardiac cachexia secondary to the developing circulatory insufficiency.
The expression of cyclin T1 in an autoptic case of AIDS-related cachexia was investigated by immunohistochemistry. When contrasted with normal human tissues, a very similar pattern of expression was found. However, a peculiar distribution of cyclin T1 was noticed in the brown fat and in lymph nodes affected by AIDS-associated lymphadenopathy.
During the last days of life, patients experience a myriad of symptomatology. While the exact percentage of patients with cancer affected by anorexia may be subject to debate, there is a clear indication that a significant portion of patients with cancer will at some point in the course of his or her illness suffer the ravages of anorexia and the related progressive weight loss that accompanies it. Anorexia is often related to the tissue wasting process of cachexia, a more severely debilitating condition that may be a contributing factor, or even the primary cause of death, in approximately 20% of cancer patients. Clinicians involved in oncology and hospice/palliative care should have a clear understanding of this process and appropriate interventions for patients experiencing anorexia/cachexia.
Previous studies have shown that five human cancer cell lines, LS180, MKN-1, MMG-1, C32 and LX-1, induced remarkable weight loss in tumor-bearing nude mice. With the aim of identifying novel molecules involved in lipid catabolism, conditioned media of these cancer cell lines were analyzed in terms of lipoprotein lipase (LPL)-inhibiting or lipolytic activities. All conditioned media from the five cell lines significantly suppressed LPL activity in 3T3-L1 cells, while media from LX-1 and C32 promoted lipolytic activity in a dose-dependent manner. RT-PCR and ELISA demonstrated that the major factors responsible for LPL inhibition and lipolysis were not IL-1beta, IL-6, IL-11, TNF-alpha, TGF-beta1 or LIF in all the cancer cell lines except for MMG-1 cells. Preliminary biochemical analysis showed that the LPL-inhibiting factor produced by LX-1 cells was approximately 65 kD and vulnerable to heat, whereas the lipolytic factor was less than 1 kD and heat stable. These results suggested that unknown factors are partially involved in the pathogenesis of cancer cachexia in tumor-bearing nude mice and further purification will be needed.
Cancer cachexia, defined as involuntary weight loss and tissue wasting due to cancer, negatively influences physical condition, quality of life and prognosis. Well known causes, such as ileus or hypercalcemia, do not suffice to explain the entire phenomenon. Metabolic changes induced by the tumor and/or host are supposed to play a deciding role. In the present review current insights into the etiology and treatment are discussed.
Many patients with life-threatening diseases such as cancer experience severe symptoms that compromise their health status and deny them quality of life. Patients with cancer often experience cachexia, pain, and depression,which translate into an unacceptable quality of life. The discovery of the endocannabinoid system has led to a renewed interest in the use of cannabinoids for the management of nausea, vomiting, and weight loss arising either from cancer or the agents used to treat cancer. The endocannabinoid system has been found to be a key modulator of systems involved in pain perception, emesis, and reward pathways. As such, it represents a target for development of new medications for controlling the symptoms associated with cancer. Although the cannabinoid receptor agonist tetrahydrocannabinol and one of its analogs are currently the only agents approved for clinical use, efforts are under way to devise other strategies for activating the endocannabinoid system for therapeutic uses.
Overexpression of the proto-oncogene c-ski in mice results in the development of a hypertrophic phenotype, characterized by increases in body and muscle weights. It has been previously shown in our laboratories that down-regulation of muscle protein breakdown associated with reduced expression of genes pertaining to different proteolytic systems likely account for this hypertrophic pattern. The aim of the present study was to evaluate the resistance of c-ski transgenic mice to catabolic stimuli such as those induced by the growth of the Lewis lung carcinoma. The tumor elicited a loss of body weight either in transgenic or in non-transgenic animals, although it was less pronounced in the former. The mass of gastrocnemius, tibialis and extensor digitorum longus (EDL) muscles were significantly reduced in non-transgenic tumor-bearing mice. Despite the anabolic setting displayed by the transgenic animals, the EDL only is completely protected against wasting. Indeed, gastrocnemius, tibialis and soleus show a reduction in weight, the latter two being significantly more depleted when compared to the non-transgenic tumor bearers. Similarly, the perigenital white adipose tissue presented a reduced mass which was more marked in the transgenic group. The quantitation of gene expression for ubiquitin, E2, C8 and calpain in the EDL showed marked differences between the transgenic and the non-transgenic groups of tumor hosts. As expected from previous results, in the latter group most of the transcripts examined increased with respect to controls as a consequence of tumor growth; by contrast, in the transgenic tumor hosts there was a significant reduction of ubiquitin, E2, C8 subunit, and calpain mRNA levels in comparison with the transgenic tumor-free animals. These results show that c-ski hyperexpression prevents tumor-induced muscle wasting in the EDL muscle, likely by impairing the state of activation of different proteolytic systems. However, the lack of effectiveness in the other muscles examined suggests that the achievement of a significant interference with the development of cachexia at the molecular level is not an easy task and probably should be designed taking into consideration more than one target.
The mRNA content of both TNF-alpha and its receptors (TNFR1 and TNFR2) in skeletal muscle and adipose tissue from cachectic rats has been assessed. The implantation of the Yoshida AH-130 ascites hepatoma resulted in substantial decrease in skeletal muscle TNF-alpha expression as early as at day 2 following tumour implantation. However, the mRNA content for the two receptors followed a different pattern, being significantly increased at day 7. In adipose tissue the expression of the TNF-alpha gene was significantly increased at all the time points studied, whereas TNF-alpha receptors expression followed a similar pattern to that observed in skeletal muscle. Western blot analysis indicated that the TNFR1 protein followed an identical pattern to that observed in the mRNA content both in muscle and adipose tissue. It is concluded that, during experimental cancer cachexia, the contribution of muscle-produced TNF-alpha is decreased; however, significant changes were observed in relation with TNF-alpha receptors at the skeletal muscle level that could possibly be related to the muscle wasting process associated with tumour growth.
The maximal expression of hyponutrition in cancer is tumoral cachexia, which will direct or indirectly account for mortality in one third of cancer patients. Causes of hyponutrition in cancer are related with the tumor, the patient, or therapies, and summarily we may differentiate four main mechanisms by which hyponutrition may occur in cancer patients: Poor energy and nutrients intake; Impairments of nutrient digestion and/or absorption; Increased demands; Impairments of nutrient metabolism; Any modality of oncologic therapy induces hyponutrition occurrence, especially in those cases in which several therapies are administered to cure cancer (surgery, radiotherapy, chemotherapy). Hyponutrition in cancer patients produces a decrease in muscle mass, which leads to strength loss, having important consequences on functional status of the individual since it increases dependence on others (relatives, caregivers) and decreases quality of life. Besides, hyponutrition is associated to poorer response to radiotherapy and chemotherapy, or poorer tolerability of such therapies. Hyponutrition also impairs scarring mechanisms and increases the risk for surgical complications such as suture dehiscence or infections. Both infectious complications and surgically derived complications entail longer hospital staying, which contributes to increase management costs. Finally, effects of hyponutrition on mortality should not be neglected, with severe weight loss being associated to lower survival.