Increased tryptophan degradation in patients with bronchus carcinoma

ENGIN A.B., OZKAN Y., FUCHS D. & YARDIM‐AKAYDIN S. (2009) European Journal of Cancer Care
Increased tryptophan degradation in patients with bronchus carcinoma Expression of tryptophan‐degrading enzyme indoleamine (2,3)‐dioxygenase in tumour tissue is proposed to represent an important tumour immunoescape mechanism. To further investigate the potential role of activated indoleamine (2,3)‐dioxygenase in bronchus carcinoma, we examined serum tryptophan and kynurenine concentrations in nine patients with small cell lung cancer and in 27 patients with non‐small cell lung cancer. Tryptophan metabolic changes were compared with markers of inflammation and immune activation namely C‐reactive protein (CRP), erythrocyte sedimentation rate (ESR) and neopterin. Compared with controls, patients presented with lower tryptophan concentrations (P < 0.01) and with higher serum kynurenine to tryptophan ratios (P < 0.01), an index of tryptophan degradation. Also ESR and CRP and neopterin concentrations were increased in the patients (all P < 0.001), and there was a weak correlation between kynurenine to tryptophan ratio and ESR, CRP and neopterin concentrations. We conclude that in the majority of patients with non‐small cell lung cancer and small cell lung cancer, enhanced tryptophan degradation can be observed. It seems to relate to an inflammatory response and may reflect activation of indoleamine (2,3)‐dioxygenase at the tumour site. The capacity of the tumour to escape normal host immune defence may be influenced by tryptophan degradation. Results of this pilot study deserve further confirmation.     

Predictive and prognostic role of serum neopterin and tryptophan breakdown in prostate cancer

The γ‐interferon‐induced enzymes indoleamine 2,3‐dioxygenase and GTP‐cyclohydrolase are key players in tumor immune escape mechanisms. We quantified serum levels of neopterin and tryptophan breakdown (tryptophan, kynurenine, and kynurenine‐to‐tryptophan ratio) in addition to prostate‐specific antigen (PSA) in newly diagnosed prostate cancer (PCa) patients (n = 100) before radical prostatectomy (RP) as well as at time of biochemical recurrence (BCR) after RP (n = 50) in comparison to healthy men (n = 49). Effects of biomarkers on the risk of PCa diagnosis on transrectal biopsy, worse histopathological characteristics of the RP specimens, and cancer‐specific survival (CSS) after BCR were investigated. Neopterin (hazard ratio [HR], 2.46; 95% confidence interval [CI], 1.08–5.61; P = 0.032) and kynurenine (HR, 2.93; 95% CI, 1.26–6.79; P = 0.012) levels were univariately associated with CSS. When adjusted for other biomarkers, only neopterin remained an independent predictor of CSS (HR, 2.56; 95% CI, 1.07–6.12; P = 0.035). Only PSA was associated with an increased risk of PCa diagnosis on biopsy, univariately (odds ratio, 3.14; 95% CI, 1.68–5.88; P < 0.001) as well when adjusted for other biomarkers (odds ratio, 3.29; 95% CI, 1.70–6.35; P < 0.001). Moreover, only preoperative PSA was able to predict positive surgical margin (area under the receiver operating characteristic curve [AUC] = 0.71; 95% CI, 0.59–0.82; P = 0.001), higher Gleason score (AUC = 0.75; 95% CI, 0.66–0.85; P < 0.001) and extraprostatic involvement (AUC = 0.79; 95% CI, 0.69–0.88; P < 0.001) at RP specimens, respectively. Although serum neopterin and tryptophan breakdown cannot be considered as biomarkers in detecting PCa or in predicting worse final pathological findings, neopterin levels are useful for stratifying patients into different prognostic groups after BCR.     

Association between the activation of macrophages, changes of iron metabolism and the degree of anaemia in patients with malignant disorders.

In this study, we investigated a possible association between the degree of macrophage activation - as measured by serum neopterin concentrations - and disturbances of iron metabolism, determined by the concentrations of ferritin and serum iron, in patients with malignant disorders. Additionally we evaluated correlations between these factors and the degree and type of anaemia. Seventy-three patients, who suffered from non-Hodgkin's lymphoma (NHL) (n = 43), Hodgkin's disease (n = 11), myeloma or monoclonal gammopathy of unknown significance (n = 9), myelodysplastic syndrome (n = 1), and solid tumours (n = 9), were examined. Mean neopterin levels were raised in all groups, patients with NHL showing the highest concentrations. Ferritin but not neopterin concentrations were higher in males than in females. A significant correlation was found between neopterin and ferritin concentrations (p less than 0.01). Considering only female patients the strength of the correlation was the same (p less than 0.02). In addition, we found inverse correlations of neopterin with haemoglobin and iron concentrations (all p less than 0.01). Similar relationships existed in patients during follow-up. Our results support the hypothesis of an association between the degree of activation of macrophages and the development of anaemia by a shift or iron towards the storage sites.     

Urinary biopterin and neopterin excretion and pituitary-adrenal activity in psychiatric patients

The urinary excretion of biopterin and neopterin, pterin compounds related to tetrahydrobiopterin, the cofactor for the initial steps in monoamine synthesis, was serially measured in a heterogeneous group of psychiatric patients and compared to excretion in control subjects, to state of illness, and to the results of the dexamethasone suppression test. Patients with major depression had increased excretion of biopterin compared to normal subjects. There was no relationship between biopterin or neopterin excretion and postdexamethasone cortisol levels. Pterin excretion did not significantly change with improvement in mood or with conversion from nonsuppressor to suppressor status. The meaning of increased urinary biopterin is presently unclear, although its relation to hormonal state and sympathoadrenal tone deserves further study.     

Neopterin levels and dexamethasone suppression test in posttraumatic stress disorder

Neopterin has recently gained growing importance as an immunological marker in psychiatric disorders. In the present study, we aimed to evaluate whether the dexamethasone suppression test (DST) and neopterin were associated with posttraumatic stress disorder (PTSD). Fourteen patients with PTSD and 14 controls were enrolled in the study. A clinical evaluation and measurements of cortisol and neopterin levels before and after DST were performed. Additionally, all patients were assessed by Clinician Administered PTSD Scale (CAPS). There was a significantly higher DST nonsuppression in the patient group than control group. There were positive correlations between the duration of illness and CAPS, basal cortisol or postdexamethasone cortisol levels in the patient group. The mean neopterin levels for both before and after DST were significantly lower in the patient group than control group. In conclusion, our results suggest that not only the patients with PTSD have considerable DST nonsuppression but also PTSD may be associated with neopterin. Received: 13 February 2002 / Accepted: 13 June 2002     

Is serum neopterin level a marker of responsiveness to interferon beta‐1a therapy in multiple sclerosis?

BACKGROUND: Interferon beta (INFbeta) may induce the expression of several proteins, including neopterin, considered a biological marker of INFbeta activity. OBJECTIVES: The aim of this study was to determine the serum neopterin concentration at the beginning of, and during, IFNbeta-1a therapy in relapsing-remitting multiple sclerosis (r-r MS) patients, and to look for a possible correlation between protein synthesis and the clinical course of the disease. METHODS: Thirteen r-r MS patients were treated with INFbeta-1a (i.m. 6 MIU/week) for 2 years. Blood samples for neopterin determinations were taken daily over a period of 1 week at the end of each 6 months of therapy, and tested for neutralizing antibodies (NABs). RESULTS: Neopterin levels peaked 24-48 h post-injection and returned to baseline after 120 h. After 1 year of therapy, four patients dropped out of the study because of progression of the disease: in these subjects a significant decrement of neopterin was observed. CONCLUSION : Neopterin baseline values were not found to decrease over the 2 years of therapy, and neopterin may be considered to be a useful marker of responsiveness to IFNbeta.     

血清新蝶呤对冠心病患者的临床诊断价值

目的:探讨检测新蝶呤(Npt)及C-反应蛋白(CRP)对冠心病(CAD)患者的临床价值。方法:观察30例稳定性心绞痛(SAP)、32例不稳定性心绞痛(UAP)、28例急性心肌梗死(AMI)和40例健康体检者(对照组)血清中Npt及CRP的水平,按冠状动脉(冠脉)造影狭窄病变支数分为3组,进行相应比较,并观察冠脉病变支数及其狭窄程度与Npt和CRP的相关性。结果:CAD组血清Npt、CRP水平高于对照组,差异均有统计学意义(均P<0.05),AMI及UAP组Npt、CRP水平明显高于SAP组(均P<0.05),CAD组血清Npt、CRP水平与冠脉狭窄病变支数及狭窄程度无直线相关性(均P>0.05)。结论:血清Npt、CRP的升高可作为CAD患者发生急性冠脉事件的预测指标。     

中研2号治疗HIV/AIDS的临床和实验研究

目的：观察中研2号对HIV／AIDS患者和猴艾滋病毒SIV mac25l感染猴的疗效,评价该方抗艾滋病毒和对机体的保护作用。方法：根据统一的诊断标准,对确诊的HIV／AIDS患者给予中研2号治疗,疗程为3个月,从免疫功能、病毒载量和临床症状体征等方面进行疗效判定;采用猴艾滋病模型,以病毒分离、酶联免疫法及流式细胞仪检测SIV水平、CD4^+、CD8^+细胞及新喋呤水平,并进行病理学检查。结果：中研2号对治疗HIV／AIDS患者临床有效率为45％～55％;对猴艾滋病模型不仅能降低感染猴病毒血症及SIV p27抗原水平,同时能持续提高CD4^+细胞数量,降低血清新喋呤含量,与叠氮胸苷阳性药对照结果近似,与生理盐水比较,差异有显著性。病理检查显示中研2号能激活并促进淋巴结中心细胞的增殖。结论：中研2号具有一定的临床效果,可抑制感染猴血浆病毒血症及保护机体免疫功能。     

Atorvastatin suppresses interferon-gamma -induced neopterin formation and tryptophan degradation in human peripheral blood mononuclear cells and in monocytic cell lines

Inhibitors of 3-hydroxy-3methylglutaryl-co-enzyme A (HMG-CoA) reductase, so-called statins, are used in medical practice because of their lipid-lowering effect and to reduce the risk of coronary heart disease. Recent findings indicate that statins also have anti-inflammatory properties and can modulate the immune response. In vitro, we investigated the effect of atorvastatin on the T cell/macrophage system in peripheral blood mononuclear cells (PBMC) and in the human monocytic cell lines THP-1 and MonoMac6. We monitored neopterin production and tryptophan degradation in PBMC after treatment with 10 micro m and 100 micro m atorvastatin in the presence or absence of 100 U/ml IFN-gamma, 10 micro g/ml phytohaemagglutinin (PHA) or 10 micro g/ml concanavalin A (ConA) and in monocytic cell lines THP-1 and MonoMac6 with or without stimulation with 100 U/ml IFN-gamma or 10 ng/ml to 1 micro g/ml lipopolysaccharide (LPS). In stimulated PBMC 100 micro m atorvastatin inhibited neopterin formation and tryptophan degradation completely, whereas 10 micro m atorvastatin was only partially effective. Also in monocytic cell lines THP-1 and MonoMac6, atorvastatin was able to suppress IFN-gamma- and LPS-induced formation of neopterin and degradation of tryptophan. Our data from PBMC agree well with previous investigations that statins inhibit T cell activation within the cellular immune response. In addition we demonstrate that atorvastatin directly inhibits IFN-gamma-mediated pathways in monocytic cells, suggesting that both immunoreactivity of T cells and of monocyte-derived macrophages are down-regulated by this statin.     

非霍奇金淋巴瘤患者血清和尿新喋呤的表达与疗效的关系

目的研究血清和尿新喋呤表达水平与非霍奇金淋巴瘤疗效的相关性。方法采用ELISA法，检测27例非霍奇金淋巴瘤患者治疗前后血清和尿中的新喋呤含量，并分析治疗前血清和尿中的新喋呤水平与患者疗效的关系。结果完全缓解和部分缓解患者的治疗前后的血清和尿新喋呤水平均低于稳定和进展组（P〈0．05）；治疗前后血清与尿新喋呤水平均高度相关（r=0．80、0．82，P〈0.05）。结论治疗前血清和尿新喋呤水平可作为非霍奇金淋巴瘤疗效的预测指标，尿液检测更加方便。