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Cachexia is a wasting syndrome that can be seen in 20-50% of people with advanced cancer. This wasting syndrome results in rapid weight loss-especially from muscle. The syndrome is caused by immune hormones and a recently-identified molecule that can be found in the urine of cancer patients with cachexia, but not in healthy people or cancer patients without cachexia.
Scientists at ITL have developed a vaccine that targets the cachexia molecule found in the urine of cancer patients. The vaccine is experimental at this stage. Your doctor at ITL will determine whether or not you are a candidate to receive the vaccine.
It is hoped that research of this vaccine will lead to an effective treatment for cachexia syndrome.
In addition to the vaccine, your doctor may prescribe fish oil and an amino acid, L-glutamine, both of which have been shown to help with reversing cachexia syndrome.
Cachexia Definition: (ka-KEK-see-uh) The loss of body weight and muscle mass frequently seen in patients with advanced diseases.
The symptoms of cachexia are the most common symptoms experienced by patients with advanced cancer. They are more common than symptoms such as pain, nausea, and shortness of breath. Many cancer patients identify cachexia symptoms as most troubling to them.
Some types of cancer cause cachexia more often than others.
Cancers that most commonly cause cachexia: gastric, pancreatic
Cancers that often cause cachexia: lung, colon
Cancers that rarely cause cachexia: breast, leukemia, prostate.
Cachexia is estimated to be a major contributing cause of death in between 20-50% of cancer patients. Because many clinical trials and treatment regimens have entrance criteria that include degree of weight loss and functional capacity, patients with cachexia may not qualify for anti-cancer treatments that could be of benefit to them. Furthermore, patients with cachexia are less likely to have a positive response to anti-cancer-treatments, and are more likely to experience adverse effects from such treatments. In these ways, cachexia contributes both directly and indirectly to death from advanced cancer.
Even with adequate nutrition, a patient with cachexia will still lose weight because their body is not able to utilize the nutrients from food properly. Furthermore, the normal body adaptation to starvation (decreased basal metabolic rate and preferential use of fats as an energy source) does not occur in cachexia.
For most cancer patients the total tumor burden is only a small percentage of their total body mass, and the degree of cachexia does not correlate with tumor size. The metabolic rate of tumor tissue has been studied, and is the same as normal body tissues. cachexia also exists in other diseases in which there is no tumor, such as heart failure and AIDS.
Cachexia is thought to be caused by chemical messengers, also called immune cytokines, which are produced by the tumor itself, and by the body's immune system in response to the tumor.
Tisdale MJ.The 'cancer cachectic factor'. Support Care Cancer. 2003 Feb;11(2):73-8. Epub 2002 Nov 05.
Pharmaceutical Sciences Research Institute, Aston University, Birmingham B4 7ET, United Kingdom. M.J.Tisdale@aston.ac.uk
The object of this study was to summarize information on catabolic factors produced by tumours which lead to tissue catabolism in cancer cachexia and to use this information for the development of effective therapy. The study population was made up of patients with cancer cachexia and weight loss greater than 1 kg month(-1). They had a varied range of carcinomas, particularly pancreatic, but also of the breast, ovary, lung, colon and rectum. Cachectic factors were isolated by standard biochemical methods, and the mechanism of tissue catabolism was evaluated in vitro and in vivo. We isolated a 24-kDa sulphated glycoprotein produced by cachexia-inducing murine and human tumours, which induces catabolism of myofibrillar proteins in skeletal muscle and for this reason has been named proteolysis-inducing factor (PIF). PIF was shown to be present in a diverse range of carcinomas in patients whose rate of weight loss exceeded 1.0 kg month(-1). Administration of PIF to normal mice produced a rapid decrease in body weight, which arose primarily from a loss of skeletal muscle, accompanied by increased mRNA levels for ubiquitin, the ubiquitin-carrier protein (E2(14k)), and proteasome subunits. This suggests that PIF induces protein catabolism through an increased expression of the key components of the ATP-ubiquitin-dependent proteolytic pathway. The action of PIF was attenuated both in vitro and in vivo by eicosapentaenoic acid (EPA). Oral EPA has been found to stabilize the body weight of patients with advanced pancreatic cancer and, when combined with an energy- and protein-rich nutritional supplement, to produce weight gain arising solely from an increase in lean body mass. Nutritional supplementation alone is unable to reverse the process of muscle wasting in cancer patients, since this arises from activation of the ubiquitin proteasome pathway by PIF, which is independent of nutrient intake. EPA is able to down-regulate the increased expression of this pathway and prevents muscle wasting in cancer patients.
Induction of cachexia in mice by a product isolated from the urine of cancer patients. Cariuk P, Lorite MJ, Todorov PT, Field WN, Wigmore SJ, Tisdale MJ.cachectic Br J Cancer. 1997;76(5):606-13.
Pharmaceutical Sciences Institute, Aston University, Birmingham, UK.
Urine from cancer patients with weight loss showed the presence of an antigen of M(r) 24,000 detected with a monoclonal antibody formed by fusion of splenocytes from mice with cancer cachexia. The antigen was not present in the urine of normal subjects, patients with weight loss from conditions other than cancer or from cancer patients who were weight stable or with low weight loss (1 kg month(-1)). The antigen was present in the urine from subjects with carcinomas of the pancreas, breast, lung and ovary. The antigen was purified from urine using a combination of affinity chromatography with the mouse monoclonal antibody and reversed-phase high-performance liquid chromotography (HPLC). This procedure gave a 200,000-fold purification of the protein over that in the original urine extract and the material isolated was homogeneous, as determined by silver staining of gels. The N-terminal amino acid sequence showed no homology with any of the recognized cytokines. Administration of this material to mice caused a significant (P<0.005) reduction in body weight when compared with a control group receiving material purified in the same way from the urine of a normal subject. Weight loss occurred without a reduction in food and water intake and was prevented by prior administration of the mouse monoclonal antibody. Body composition analysis showed a decrease in both fat and non-fat carcass mass without a change in water content. The effects on body composition were reversed in mice treated with the monoclonal antibody. There was a decrease in protein synthesis and an increase in degradation in skeletal muscle. Protein degradation was associated with an increased prostaglandin E2 (PGE2) release. Both protein degradation and PGE2 release were significantly reduced in mice pretreated with the monoclonal antibody. These results show that the material of M(r) 24,000 present in the urine of cachectic cancer patients is capable of producing a syndrome of cachexia in mice.
Todorov P, Cariuk P, McDevitt T, Coles B, Fearon K, Tisdale M.Characterization of a cancer cachectic factor. Nature. 1996 Feb 22;379(6567):739-42.
CRC Nutritional Biochemistry Research Group, Pharmaceutical Sciences Institute, Aston University, Birmingham UK.
Cancer cachexia is a syndrome of progressive wasting which has been suggested to be mediated by tumour-necrosis factor-alpha, interleukins 1 and 6, interferon-gamma and leukaemia-inhibitory factor. It has proved difficult to correlate levels of tumour-necrosis factor-alpha and interleukin-6 with cancer cachexia, and the weight loss induced by leukaemia-inhibitory factor may be due to toxicity. In the murine adenocarcinoma MAC16, cachexia is mediated by circulatory catabolic factors, which we have now isolated using an antibody cloned from splenocytes of mice transplanted with the MAC16 tumour, with a delayed cachexia. The material is a proteoglycan of relative molecular mass 24K which produces cachexia in vivo by inducing catabolism of skeletal muscle. The 24K material was also present in urine of cachectic cancer patients, but was absent from normal subjects, patients with weight loss due to trauma, and cancer patients with little or no weight loss. This suggests that cachexia in mice and humans may be produced by the same material.
McDevitt TM, Todorov PT, Beck SA, Khan SH, Tisdale MJ. Purification and characterization of a lipid-mobilizing factor associated with cachexia-inducing tumors in mice and humans. Cancer Res. 1995 Apr 1;55(7):1458-63.
A scheme is described for the purification of a lipid-mobilizing factor from a cachexia-inducing murine tumor (MAC16) using a combination of ion exchange (Mono Q), exclusion (Superose), and hydrophobic (C8) chromatography. This process yields an active material with an apparent molecular weight of 24,000 with an overall purification of 3,500 from the tumor homogenate and representing 0.005% of the total protein present. The material tends to aggregate to high molecular mass, is acidic (pI < 4), and displays heterogeneity of charge as evidenced by a broad elution profile on ion exchange and exclusion chromatography and multiple peaks on hydrophobic columns. The purified material was heat and alkali (pH 10.4) labile and activity could be completely inhibited by sulfatase, suggesting that the negative charge could arise from sulfate residues. There was no evidence that the material possessed triglyceride lipase activity. Animals transplanted with the MAC16 tumor and with a delayed weight loss contained in their serum antibodies that recognized a M(r) 24,000 band on Western blots. This material copurified with the lipid-mobilizing factor. Such antibodies were not present in the serum of mice transplanted with the MAC13 tumor, which does not induce cachexia, suggesting that the antibodies were directed to the induction of cachexia rather than the tumor itself. Urine from patients with cancer cachexia also contained a lipid-mobilizing factor which adhered to DEAE-cellulose and gave an apparent M(r) of 24,000 by exclusion chromatography. Western blotting using serum from MAC16 tumor-bearing animals showed the presence of a band of M(r) 24,000 in such fractions, which was not detected using serum from mice bearing the MAC13 tumor. This band was not present in Western blots of urine from normal subjects. The fact that serum from mice bearing the MAC16 tumor can detect the human lipid-mobilizing activity suggests a high degree of structural similarity between the two and raises the possibility that cachexia in
humans may be caused by the same species as in the mouse.
Wang Z, Corey E, Hass GM, Higano CS, True LD, Wallace D Jr, Tisdale MJ, Vessella RL.Expression of the human cachexia-associated protein (HCAP) in prostate cancer and in a prostate cancer animal model of cachexia. Int J Cancer. 2003 May 20;105(1):123-9.
Department of Urology, University of Washington, Seattle, WA 98195, USA.
Prostate cancer (CaP) patients with disseminated disease often suffer from severe cachexia, which contributes to mortality in advanced cancer. Human cachexia-associated protein (HCAP) was recently identified from a breast cancer library based on the available 20-amino acid sequence of proteolysis-inducing factor (PIF), which is a highly active cachectic factor isolated from mouse colon adenocarcinoma MAC16. Herein, we investigated the expression of HCAP in CaP and its potential involvement in CaP-associated cachexia. HCAP mRNA was detected in CaP cell lines, in primary CaP tissues and in its osseous metastases. In situ hybridization showed HCAP mRNA to be localized only in the epithelial cells in CaP tissues, in the metastatic foci in bone, liver and lymph node, but not in the stromal cells or in normal prostate tissues. HCAP protein was detected in 9 of 14 CaP metastases but not in normal prostate tissues from cadaveric donors or patients with organ-confined tumors. Our Western blot analysis revealed that HCAP was present in 9 of 19 urine specimens from cachectic CaP patients but not in 19 urine samples of noncachectic patients. HCAP mRNA and protein were also detected in LuCaP 35 and PC-3M xenografts from our cachectic animal models. Our results demonstrated that human CaP cells express HCAP and the expression of HCAP is associated with the progression of CaP and the development of CaP cachexia. Copyright 2003 Wiley-Liss, Inc.
Barber MD, Fearon KC, Tisdale MJ, McMillan DC, Ross JA.Effect of a fish oil-enriched nutritional supplement on metabolic mediators in patients with pancreatic cancer cachexia. Nutr Cancer. 2001;40(2):118-24.
University Department of Surgery, Royal Infirmary of Edinburgh, Edinburgh EH3 9YW, UK.
Weight loss in advanced cancer patients is refractory to conventional nutritional support. This may be due to metabolic changes mediated by proinflammatory cytokines, hormones, and tumor-derived products. We previously showed that a nutritional supplement enriched with fish oil will reverse weight loss in patients with pancreatic cancer cachexia. The present study examines the effect of this supplement on a number of mediators thought to play a role in cancer cachexia. Twenty weight-losing patients with pancreatic cancer were asked to consume a nutritional supplement providing 600 kcal and 2 g of eicosapentaenoic acid per day. At baseline and after 3 wk, patients were weighed and samples were collected to measure serum concentrations of interleukin (IL)-6 and its soluble receptor tumor necrosis factor receptors I and II, cortisol, insulin, and leptin, peripheral blood mononuclear cell production of IL-1 beta, IL-6, and tumor necrosis factor, and urinary excretion of proteolysis inducing factor. After 3 wk of consumption of the fish oil-enriched nutritional supplement, there was a significant fall in production of IL-6 (from median 16.5 to 13.7 ng/ml, P = 0.015), a rise in serum insulin concentration (from 3.3 to 5.0 mU/l, P = 0.0064), a fall in the cortisol-to-insulin ratio (P = 0.0084), and a fall in the proportion of patients excreting proteolysis inducing factor (from 88% to 40%, P = 0.008). These changes occurred in association with weight gain (median 1 kg, P = 0.024). Various mediators of catabolism in cachexia are modulated by administration of a fish oil-enriched nutritional supplement in pancreatic cancer patients. This may account for the reversal of weight loss in patients consuming this supplement.
Klimberg VS, McClellan JL.Claude H. Organ, Jr. Honorary Lectureship. Glutamine, cancer, and its therapy. Am J Surg. 1996 Nov;172(5):418-24.
Arkansas Cancer Research Center, Little Rock, USA.
OBJECTIVE: This overview on glutamine, cancer and its therapy discusses some of the in vitro and in vivo work on glutamine and tumor growth, and summarizes animal and human data on the potential benefits of glutamine in the tumor-bearing host receiving radiation or chemotherapy. BACKGROUND: Glutamine is the most abundant amino acid in the body. A tumor can act as a "glutamine trap," depleting host glutamine stores and resulting in cachexia. In vitro evidence of the dependence of tumor growth on glutamine has deterred its use in the clinic setting. METHODS: Data from a variety of investigations studying glutamine's interaction with the tumor-bearing host receiving radiation or chemotherapy were compiled and summarized. RESULTS: A large body of evidence in vivo suggests that supplemental glutamine does not make tumors grow but in fact results in decreased growth through stimulation of the immune system. When given with radiation or chemotherapy, glutamine protects the host and actually increases the selectivity of therapy for the tumor. CONCLUSION: Further prospective randomized trials are needed to demonstrate the safety and efficacy in humans undergoing radiation and chemotherapy.
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