A cura della Direzione Scientifica di NBF-Lanes
By the Scientific Director of NBF-Lanes
DEFINITION OF CACHEXIA
In cancer patients it is important to maintain a proper nutritional status. Malnutrition, in fact, affect, directly and / or indirectly, in increasing mortality rate. In humans, it has been reported that cancer cachexia affects 87% of patients hospitalized with cancer and is believed that the same percentage may be present in pets. About 80% of human cancer patients become malnourished during the evolution of the disease. Malnutrition interferes negatively on the immune host defense mechanisms by increasing also the possible side effects of anticancer treatments. Cachexia can be defined as a set of factors that determine alterations in lipid metabolism, protein and glucose resulting in weight loss and deterioration of the organic conditions and the patient’s quality of life of cancer. Cachexia therefore can be defined as the final stage of emaciation associated often to weakness, anorexia, immune and mental depression.
Cachexia seems to hit more subjects with tumors of the gastrointestinal tract due to the systemic action of the tumor as well as for worsening of the digestive functions. In addition to the direct action of the tumor also the different methods of intervention used to treat it (radiation therapy, surgery, chemotherapy and / or in combination) may have a negative impact on the nutritional status of the patient.
CANCER CACHEXIA: A MULTIFACTORIAL PROBLEM
The metabolic abnormalities that develop in the course of cachexia may occur before the onset of clinical signs of the disease itself. What is common to the pathogenesis of cancer cachexia, which is considered a multifactorial problem, is the protein-muscle catabolism (resulting in lean mass loss) induced by the increase of various cytokines and that induces production of acute phase proteins (such as the C-reactive protein). Today in Human Medicine is attributed to this mechanism to the production, by the neoplastic cells, a substance the “proteolysis-inducing factor” (PIF proteolysis Inducing Factor). This factor acts stealing proteins to the muscles to supply the tumor and it can be counteracted by administering eicosapentaenoic acid (EPA). From clinical studies in Human Medicine it seems that administration of EPA permits the correction of metabolic disorders related to damage induced by PIF and by cytokines. Many clinical studies have been conducted in Human Medicine on cancer patients with cachexia to which the diet was enriched with EPA and antioxidants. These studies demonstrated that the use of integrator in cancer patients with weight loss is used to stop the weight loss and regain lean mass, inhibiting the formation of pro-inflammatory cytokines, improve the patient’s quality of life and in later stages allows a lengthening of survival of 2-4 months compared to untreated patients with food supplementation.
METABOLISM OF CARBOHYDRATES, PROTEINS AND LIPIDS IN THE COURSE OF NEOPLASIA
The main alterations that are established in a patient suffering from cancer in the course of cancer cachexia are charged to the metabolism of carbohydrates, proteins and lipids. The neoplastic tissue seems to draw their own food instead of glucose as an energy source of choice, then be able to force the neoplasia to use other energy substrates (such as fats and proteins) would help to reduce cell proliferation. The use of certain amino acids (arginine, glutamine, leucine, valine, etc.) compared to other seems useful to retard tumor growth. In studies performed in animals it has been shown that the increased intake of omega-3 fatty acids can interfere with the growth rate of certain cancers. In fact it seems that EPA and DHA may attenuate tumor growth thanks to their ability to decrease the metabolism of arachidonic acid. Some studies conducted in vivo, have shown that the EPA has a selective effect on tumor cells carrying them to death. Further research has shown that the administration of omega-3 reduces the secretion of tumor necrosis factor- a (TNF-a), interleukin 1-a and interleukin-2, which are important mediators of the cachectic process and play an also critical role as tumor growth factors.
ROLE OF CLA IN THE PATIENT WITH NEOPLASIA
In recent years numerous studies in Human Medicine and, more recently, in Veterinary Medicine have highlighted the role of conjugated linoleic acid (CLA) in the anticancer activity, especially for dependent tumors of the mammary gland, skin, stomach and colon. The conjugated linoleic acid (CLA) is a long-chain fatty acid consisting of several isomers, they have been identified two forms (cis-9, trans-11 and trans-10, cis-12) particularly biologically active. The conjugated linoleic acid is a product of natural origin, especially in bovine-derived products. From numerous studies it appears that the mechanism by which CLA is able to modulate the proliferation of neoplastic cells in both the blocking of DNA synthesis and the proteins responsible for oncogenesis. Some studies show that CLA inhibits tumor proliferation promoting the signals that determine the apoptosis of tumor cells in many tissues (breast, liver, adipose). The results of a recent study (Park HS, 2001) have demonstrated that the administration of CLA in the diet significantly decreases the incidence of colon cancer in the mice treated with 1,2- dimethylhydrazine and the apoptotic index. Modulation of carcinogenesis is bsed in complex cellular mechanisms that seems lead to change the metabolism of fatty acids in the phospholipids favoring the inhibition of eicosanoids derived from arachidonic acid, such as PGE2 and PGE2 a. Eicosanoids seem to modulate carcinogenesis in several tissues (mammary gland, skin, prostate, and colon). Some stages of the process of carcinogenesis, such as cell proliferation, local and systemic inflammation, platelet aggregation, and cell differentiation, are particularly sensitive to the effect of eicosanoids. The CLA appears to act on the incorporation in the phospholipids of the arachidonic acid thus reducing the presence of inflammatory eicosanoids. Another mechanism that promotes the reduction of eicosanoids through the CLA is the inhibition of the expression or activity of the enzyme constitutive cyclooxygenase (COX-1) and the inducible form (COX-2). COX-2 is produced as a response to inflammatory stimuli and leads to the formation of PGE2 (mediators of inflammation). Some studies have shown that a high level of COX-2 is associated with tumor progression and inhibition of apoptosis of the tumor cells. The occurrence or the overexposure of COX-2 found in many types of cancer are believed responsible for the production of factors that promote angiogenesis, tumor proliferation, tumor cell of numerous alterations and apoptosis block (indispensable mechanism that leads to death programmed cell). In the genesis of the tumor it is also implicated nitric oxide in response to the action of certain classes of cytokines. The excess nitric oxide reacts with superoxide radicals to form a compound that leads to subsequent dependent oxidative damage of cell membranes, proteins and DNA. The inhibition of the enzyme (iNOS), which leads to the formation of nitric oxide in response to the action of certain classes of cytokines, determines a reduction of angiogenesis. The CLA appears to suppress the production of PGE2 is that of nitric oxide in activated macrophages reducing the levels of messenger RNA for COX-2 and iNOS.
CLA AND MAMMARY GLAND
In the last five years the activity of CLA on breast tissue from tumor affection has been extensively studied. The mouse model is the most used and several studies have evaluated the lowest effective dose of CLA can act by modulating and reducing various parameters related to the neoplastic activity. The results of a study (Ip et al. 2002) have shown that a diet enriched in CLA taken from mice treated only once with methylnitrosourea, has allowed the reduction of 33-36% of premalignant lesions and 35-40% of cancer breast. A retrospective study (Hubbard et al, 2000) also showed that the administration of CLA at 0.5-1% induces a reduction of 20% of metastatic breast cancers in mice.
CLA AND LIVER CANCER
Several studies (Lu M et al. 2002; Moya-Camarena et al. 1999) showed that the CLA isomers are potent ligands for a nuclear receptor (PPAR- a) acting in the pathogenesis of liver cancer in rodents. One of these studies compared the apoptotic index, an important factor inhibiting the neoplastic process, in mice fed with a CLA-enriched diet compared to a control group that did not receive this supplement. In the first group there has been a significant increase in apoptosis liver.
From all the studies, in animal models in vivo, on animals and human cancer cell cultures in vitro, it showed that conjugated linoleic acid (CLA) has a role in antineoplastic for the many effects on cellular mechanisms.
The role of the different components of the feed ration, both macronutrients (fats, proteins and carbohydrates) and / or micronutrients (vitamins, minerals, fatty acids and amino acids), it is increasingly being studied and it starts to show how the nutritional treatment can positively and greatly affect the quality of life of animals suffering from cancer.
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