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P.45 Concentration of amino acids in patients with colorectalcarcinoma
and tumor growth was however dependent on gamma-interferon. None of these effects were related to plasma concentrations of prostaglandins (PGE2), as has been repeatedly suggested.
P.42 Increased brain tryptophan (TRP) concentrations may contribute to interleukin-1 (IL-1) induced anorexia A. Fava, A. Laviano, C. Cangiano, M. Muscaritoli, G. F. Tore//i, G. Mulieri and E Rossi Fanelli Department of Clinical Medicine, University 'La Sapienza" Rome, Italy.
P,44 A fish oil-enriched nutritional supplement modulates changes in the acute phase protein response in weight-losing pancreatic cancer patients
IL-1 produces anorexia and reduced food intake (FI) via direct action in the brain and via mechanisms yet to be determined. Data exist showing that during illnesses (i.e., cancer, sepsis) anorexia is: 1) likely to be mediate by IL-1; and 2) related to increased brain concentrations of TRP, the precursor of serotonin. IL-1 is also known to interfere with protein and amino acid metabolism. Aim: We therefore investigated in normal rats whether peripheral IL-1 induces anorexia by increasing brain TRP. Methods: Thirty acclimated, individually caged, male Sprague-Dawley rats were studied. After overnight fasting, rats were assigned to i.p. injections of 1 mg/kg BW rHu IL-lc~ (IL-1 group, n = 10) or normal saline (Control group; n = 10). Ten more rats were pair-fed with IL-1 rats (PF group). After injection, rats received chow and water ad libitum. After 2hrs, FI was measured, while during anesthesia cerebro-spinal fluid (CSF) was collected via cisterna magna puncture. TRP was determined using spectrophotofluorimetry. Data (mean _+ SD) were analyzed using Student's t-test for unpaired data.
M. D. Barber 1, J.A. Ross1, D. C. McMillan 2, T. Preston 2, A. Shenkin 4
and K. C. H. Fearon1 1Department of Surgery, Royal Infirmary of Edinburgh, 2Department of Surge~ Glasgow Royal Infirma~ 3Isotope Biochemistry Laboratory, Scottish Universities Research and Reactor Centre, East Kilbride, 4Department of Clinical Chemistry, University of Liverpool, UK. The acute phase protein response (APPR) has been suggested to contribute to weight-loss in advanced pancreatic cancer. Previous work using fish oil or eicosapentaenoic acid (EPA) in cancer patients has suggested that they may influence the pro-inflammatory state and attenuate weight-loss. We have examined the effect of a fish oilenriched nutritional supplement upon the levels of individual acute phase proteins (APPs) in weight-losing patients with advanced pancreatic cancer. Serum APPs were measured by immunoturbidimetry in 36 patients with advanced pancreatic cancer and 6 healthy subjects of similar age. In a sequential series, 18 patients received a fish oil-enriched nutritional supplement (providing 2 g EPA per day) for 3 weeks while the remainder received full supportive care over a similar period. APPs were measured before and after this interval in both groups. Patients groups were well matched for age, disease stage and acute phase proteins at baseline. Albumin, transferrin and pre-albumin were significantly reduced and fibrinogen, haptoglobin, alpha-l-acid gtycoprotein, alpha-l-antitrypsin, caeruloplasmin and C-reactive protein (CRP) were significantly elevated at baseline compared with controls (P < 0.04) reflecting their roles as negative and positive APPs respectively. In the supplemented group after 3 weeks, there were no significant changes in APPs apart from a rise in transferrin (P= 0.031). In contrast, in the group receiving supportive care alone there were further significant reductions in albumin, transferrin and pre-albumin and significant increases in alpha-l-acid gtycoprotein and CRP concentrations. These results suggest that a wide range of both positive and negative APPs are altered in patients with advanced pancreatic cancer and that the APPR tends to progress in untreated patients. The APPR appears to be stabilized by the administration of a fish oil-enriched nutritional supplement and this may have implications upon the development of cachexia.
Results:
Control IL-1 PF
BW (g)
FI (g)
CSF TRP (#mol/dl)
293 _+12 301 _+19 300+ 16
6.8 _+2.0 1.15 _+2.1" 1.15_+2.1"
0.46 _+0.16 (n= 7) 0.75 _+0.16 (n= 6)# 0.41 _+0.13 (n= 8)
* P< 0.05 vs Control; #P< 0.05 vs Control and PE As expected, IL-1 injection reduced FI. The reduction of FI was paralleled by an increase in CSF TRP concentrations. Conclusions: Since TRP is the precursor of serotonin, we infer that IL-1 may induce anorexia via increased brain serotonergic activity, beside its direct action in the brain.
P,43 Cytokine regulation of tumor growth and development of cancer cachexia in a tumor model with systemic inflammation C. Cahlin, A. K~rner, K. Lundholm and E. Svanberg
Dept of Surgery, Sahlgrenska Sweden.
University Hospital, GSteborg,
Cancer cachexia, with progressive wasting, anorexia and anemia in cancer is related to systemic inflammation. Thus, antiinflammatory treatment (indomethacin) prolongs survival and attenuates cachexia. It is however unclear how cytokines interact and explain the various parts of the cachectic syndrome. The aim of this study was to evaluate how IL-6, gamma-interferon and IL-12 influence on tumor growth and cachexia in a tumor model with systemic inflammation due to increased prostaglandin production (PGE2). Methods: A methylcholantrene induced sarcoma was implanted sc in mice with a knock out of the IL-6 gene or the gamma-interferon gene and normal controls. Normal tumor bearing animals were treated with IL-12 (0.2pg/day) ip. Body weight and food intake were registered daily. Net tumor growth was measured over 10 days treatment and carcass composition was assessed. Results: Normal tumor bearing mice lost 10% body weight over 10 days due to rapid tumor growth. IL-6 knock out mice had reduced tumor growth by 49% (P _<0.05) as compared to wild type controls, and did not reveal any weight loss during the same period of time. Knock out of the gammainterferon gene did not affect tumor size or development of cachexia. IL12 reduced tumor growth by 74% (P_< 0.05), and partially restored cachexia, in wild type control animals, while this effect of IL-12 was abrogated in gamma-interferon knocked out mice. Plasma concentrations of PGE2 did not differ between the knock out groups of mice and normal controls, and was even increased in IL-12 treated animals (6750 pg/mL, P_< 0.05). Conclusion: Cachexia and tumor growth was dependent on IL-6, but ir~dependent of gamma-interferon. The effect of IL-12 to prevent cachexia
P.45 Concentration of amino acids in patients with colorectal carcinoma J. Vecer, L. Sprongi*, H. Kubatova, M. Kvapil and J. Charvat
Department of Internal Medicine and *Department of Biochemist~ University Hospital Motol, Prague, Czech Republic. Each catabolic state appears to have its own unique and reproducible intracellular pattern. The aim of the study is to evaluate and compare the intraceilular concentration of amino acids in cancer and healthy tissue. Plasma, muscle and intracellular concentrations of amino acids in tumor tissue was determined in 29 patients with localized colorectal carcinoma. The biopsies from abdominal muscle and tumor tissue were taken intraoperatively. The specimen was homogenized. High performance liquid chromatography was used to evaluate the concentration of amino acids. A statistical analysis was performed using single sample Ttest. The results showed that the intracellular concentration of taurin (P< 0.05), glutamate (P< 0.05), glycin (P < 0.01), leucin (P < 0.05) and tyrosin (P < 0.01) were significantly increased in tumor tissue compared to intracellular concentration in abdominal muscle. The intracellular tumor tissue concentration of glutamine (P < 0.01 ) was found to be significantly decreased compared to healthy tissue. The plasma concentration of asparagine (P < 0.05), glutamate (P < 0.05), isoleucin (P < 0.05) was found to be significantly decreased. We have concluded that concentration of amino acids differs significantly in tumor and healthy tissue. 41
P.42 Increased brain tryptophan (TRP) concentrations may contribute to interleukin-1 (IL-1) induced anorexia A. Fava, A. Laviano, C. Cangiano, M. Muscaritoli, G. F. Tore//i, G. Mulieri and E Rossi Fanelli Department of Clinical Medicine, University 'La Sapienza" Rome, Italy.
P,44 A fish oil-enriched nutritional supplement modulates changes in the acute phase protein response in weight-losing pancreatic cancer patients
IL-1 produces anorexia and reduced food intake (FI) via direct action in the brain and via mechanisms yet to be determined. Data exist showing that during illnesses (i.e., cancer, sepsis) anorexia is: 1) likely to be mediate by IL-1; and 2) related to increased brain concentrations of TRP, the precursor of serotonin. IL-1 is also known to interfere with protein and amino acid metabolism. Aim: We therefore investigated in normal rats whether peripheral IL-1 induces anorexia by increasing brain TRP. Methods: Thirty acclimated, individually caged, male Sprague-Dawley rats were studied. After overnight fasting, rats were assigned to i.p. injections of 1 mg/kg BW rHu IL-lc~ (IL-1 group, n = 10) or normal saline (Control group; n = 10). Ten more rats were pair-fed with IL-1 rats (PF group). After injection, rats received chow and water ad libitum. After 2hrs, FI was measured, while during anesthesia cerebro-spinal fluid (CSF) was collected via cisterna magna puncture. TRP was determined using spectrophotofluorimetry. Data (mean _+ SD) were analyzed using Student's t-test for unpaired data.
M. D. Barber 1, J.A. Ross1, D. C. McMillan 2, T. Preston 2, A. Shenkin 4
and K. C. H. Fearon1 1Department of Surgery, Royal Infirmary of Edinburgh, 2Department of Surge~ Glasgow Royal Infirma~ 3Isotope Biochemistry Laboratory, Scottish Universities Research and Reactor Centre, East Kilbride, 4Department of Clinical Chemistry, University of Liverpool, UK. The acute phase protein response (APPR) has been suggested to contribute to weight-loss in advanced pancreatic cancer. Previous work using fish oil or eicosapentaenoic acid (EPA) in cancer patients has suggested that they may influence the pro-inflammatory state and attenuate weight-loss. We have examined the effect of a fish oilenriched nutritional supplement upon the levels of individual acute phase proteins (APPs) in weight-losing patients with advanced pancreatic cancer. Serum APPs were measured by immunoturbidimetry in 36 patients with advanced pancreatic cancer and 6 healthy subjects of similar age. In a sequential series, 18 patients received a fish oil-enriched nutritional supplement (providing 2 g EPA per day) for 3 weeks while the remainder received full supportive care over a similar period. APPs were measured before and after this interval in both groups. Patients groups were well matched for age, disease stage and acute phase proteins at baseline. Albumin, transferrin and pre-albumin were significantly reduced and fibrinogen, haptoglobin, alpha-l-acid gtycoprotein, alpha-l-antitrypsin, caeruloplasmin and C-reactive protein (CRP) were significantly elevated at baseline compared with controls (P < 0.04) reflecting their roles as negative and positive APPs respectively. In the supplemented group after 3 weeks, there were no significant changes in APPs apart from a rise in transferrin (P= 0.031). In contrast, in the group receiving supportive care alone there were further significant reductions in albumin, transferrin and pre-albumin and significant increases in alpha-l-acid gtycoprotein and CRP concentrations. These results suggest that a wide range of both positive and negative APPs are altered in patients with advanced pancreatic cancer and that the APPR tends to progress in untreated patients. The APPR appears to be stabilized by the administration of a fish oil-enriched nutritional supplement and this may have implications upon the development of cachexia.
Results:
Control IL-1 PF
BW (g)
FI (g)
CSF TRP (#mol/dl)
293 _+12 301 _+19 300+ 16
6.8 _+2.0 1.15 _+2.1" 1.15_+2.1"
0.46 _+0.16 (n= 7) 0.75 _+0.16 (n= 6)# 0.41 _+0.13 (n= 8)
* P< 0.05 vs Control; #P< 0.05 vs Control and PE As expected, IL-1 injection reduced FI. The reduction of FI was paralleled by an increase in CSF TRP concentrations. Conclusions: Since TRP is the precursor of serotonin, we infer that IL-1 may induce anorexia via increased brain serotonergic activity, beside its direct action in the brain.
P,43 Cytokine regulation of tumor growth and development of cancer cachexia in a tumor model with systemic inflammation C. Cahlin, A. K~rner, K. Lundholm and E. Svanberg
Dept of Surgery, Sahlgrenska Sweden.
University Hospital, GSteborg,
Cancer cachexia, with progressive wasting, anorexia and anemia in cancer is related to systemic inflammation. Thus, antiinflammatory treatment (indomethacin) prolongs survival and attenuates cachexia. It is however unclear how cytokines interact and explain the various parts of the cachectic syndrome. The aim of this study was to evaluate how IL-6, gamma-interferon and IL-12 influence on tumor growth and cachexia in a tumor model with systemic inflammation due to increased prostaglandin production (PGE2). Methods: A methylcholantrene induced sarcoma was implanted sc in mice with a knock out of the IL-6 gene or the gamma-interferon gene and normal controls. Normal tumor bearing animals were treated with IL-12 (0.2pg/day) ip. Body weight and food intake were registered daily. Net tumor growth was measured over 10 days treatment and carcass composition was assessed. Results: Normal tumor bearing mice lost 10% body weight over 10 days due to rapid tumor growth. IL-6 knock out mice had reduced tumor growth by 49% (P _<0.05) as compared to wild type controls, and did not reveal any weight loss during the same period of time. Knock out of the gammainterferon gene did not affect tumor size or development of cachexia. IL12 reduced tumor growth by 74% (P_< 0.05), and partially restored cachexia, in wild type control animals, while this effect of IL-12 was abrogated in gamma-interferon knocked out mice. Plasma concentrations of PGE2 did not differ between the knock out groups of mice and normal controls, and was even increased in IL-12 treated animals (6750 pg/mL, P_< 0.05). Conclusion: Cachexia and tumor growth was dependent on IL-6, but ir~dependent of gamma-interferon. The effect of IL-12 to prevent cachexia
P.45 Concentration of amino acids in patients with colorectal carcinoma J. Vecer, L. Sprongi*, H. Kubatova, M. Kvapil and J. Charvat
Department of Internal Medicine and *Department of Biochemist~ University Hospital Motol, Prague, Czech Republic. Each catabolic state appears to have its own unique and reproducible intracellular pattern. The aim of the study is to evaluate and compare the intraceilular concentration of amino acids in cancer and healthy tissue. Plasma, muscle and intracellular concentrations of amino acids in tumor tissue was determined in 29 patients with localized colorectal carcinoma. The biopsies from abdominal muscle and tumor tissue were taken intraoperatively. The specimen was homogenized. High performance liquid chromatography was used to evaluate the concentration of amino acids. A statistical analysis was performed using single sample Ttest. The results showed that the intracellular concentration of taurin (P< 0.05), glutamate (P< 0.05), glycin (P < 0.01), leucin (P < 0.05) and tyrosin (P < 0.01) were significantly increased in tumor tissue compared to intracellular concentration in abdominal muscle. The intracellular tumor tissue concentration of glutamine (P < 0.01 ) was found to be significantly decreased compared to healthy tissue. The plasma concentration of asparagine (P < 0.05), glutamate (P < 0.05), isoleucin (P < 0.05) was found to be significantly decreased. We have concluded that concentration of amino acids differs significantly in tumor and healthy tissue. 41