Abstract
Background: Recently, homocysteine production was observed in tumour cell lines and homocysteine was proposed as a tumour marker. Furthermore, homocysteine production by activated immunocompetent cells was demonstrated.
Methods: In this study, homocysteine metabolism and immune activation status were investigated in 128 patients suffering from various types of cancer (haematological disorders, lung cancer, gastrointestinal tumours, gynaecological cancer and tumours of other localisation) and healthy age-matched controls.
Results: A high percentage of patients (39.1%) showed moderate hyperhomocysteinaemia, while cysteine, folate and vitamin B12 concentrations were within reference ranges. Most patients were found to have elevated concentrations of the immune activation and inflammation markers neopterin and C-reactive protein (CRP), as well as a higher erythrocyte sedimentation rate (ESR). Patients of different cancer groups differed significantly regarding vitamin B12 and neopterin concentrations; higher B12 levels were also associated with tumour progression. Univariate regression analysis showed that CRP, ESR and neopterin were suited best to predict death. In multivariate analysis, neopterin was best suited to predicting death, while homocysteine and B vitamins were not associated with patient outcome. Homocysteine concentrations were correlated with folate and cysteine levels. Higher neopterin concentrations coincided with lower folate concentrations, but higher vitamin B12 concentrations.
Conclusions: Associations between neopterin and folate concentrations may indicate that cellular immune activation might partly contribute to the development of folate deficiency in cancer patients, thus possibly also impairing homocysteine remethylation.
Clin Chem Lab Med 2007;45:47–53.
References
1. Selhub J, Jacques PF, Rosenberg IH, Rogers G, Bowman BA, Gunter EW, et al. Serum total homocysteine concentrations in the third National Health and Nutrition Examination Survey (1991–1994): population reference ranges and contribution of vitamin status to high serum concentrations. Ann Intern Med1999;131:331–9.10.7326/0003-4819-131-5-199909070-00003Search in Google Scholar
2. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. J Am Med Assoc1995;274:1049–57.10.1001/jama.274.13.1049Search in Google Scholar
3. McCully KS. Homocysteine and vascular disease. Nat Med1996;2:386–9.10.1038/nm0496-386Search in Google Scholar
4. Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet1999;354:407–13.10.1016/S0140-6736(98)11058-9Search in Google Scholar
5. Wu LL, Wu JT. Hyperhomocysteinemia is a risk factor for cancer and a new potential tumor marker. Clin Chim Acta2002;322:21–8.10.1016/S0009-8981(02)00174-2Search in Google Scholar
6. Sun CF, Haven TR, Wu TL, Tsao KC, Wu JT. Serum total homocysteine increases with the rapid proliferation rate of tumor cells and decline upon cell death: a potential new tumor marker. Clin Chim Acta2002;321:55–62.10.1016/S0009-8981(02)00092-XSearch in Google Scholar
7. Rampersaud GC, Bailey LB, Kauwell GP. Relationship of folate to colorectal and cervical cancer: review and recommendations for practitioners. J Am Diet Assoc2002;102:1273–82.10.1016/S0002-8223(02)90281-6Search in Google Scholar
8. Zhang SM, Willett WC, Selhub J, Hunter DJ, Giovannucci EL, Holmes MD, et al. Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer. J Natl Cancer Inst2003;95:373–80.10.1093/jnci/95.5.373Search in Google Scholar PubMed
9. Zhang SM, Willett WC, Selhub J, Manson JE, Colditz GA, Hankinson SE. A prospective study of plasma total cysteine and risk of breast cancer. Cancer Epidemiol Biomarkers Prev2003;12:1188–93.Search in Google Scholar
10. Prinz-Langenohl R, Fohr I, Pietrzik K. Beneficial role for folate in the prevention of colorectal and breast cancer. Eur J Nutr2001;40:98–105.10.1007/PL00007387Search in Google Scholar
11. Storz P. Reactive oxygen species in tumor progression. Front Biosci2005;10:1881–96.10.2741/1667Search in Google Scholar PubMed
12. Nathan CF. Peroxide and pteridine: a hypothesis on the regulation of macrophage antimicrobial activity by interferon γ. Interferon1986;7:125–43.Search in Google Scholar
13. Murr C, Fuith LC, Widner B, Wirleitner B, Baier-Bitterlich G, Fuchs D. Increased neopterin concentrations in patients with cancer: indicator of oxidative stress? Anticancer Res1999;19:1721–8.Search in Google Scholar
14. Luo JL, Maeda S, Hsu LC, Yagita H, Karin M. Inhibition of NF-κB in cancer cells converts inflammation-induced tumor growth mediated by TNFα to TRAIL-mediated tumor regression. Cancer Cell2004;6:297–305.10.1016/j.ccr.2004.08.012Search in Google Scholar
15. Chern CL, Huang RF, Chen YH, Cheng JT, Liu TZ. Folate deficiency-induced oxidative stress and apoptosis are mediated via homocysteine-dependent overproduction of hydrogen peroxide and enhanced activation of NF-κB in human Hep G2 cells. Biomed Pharmacother2001;55:434–42.10.1016/S0753-3322(01)00095-6Search in Google Scholar
16. Odin E, Carlsson G, Frosing R, Gustavsson B, Spears CP, Larsson PA. Chemical stability and human plasma pharmacokinetics of reduced folates. Cancer Invest1998;16:447–55.10.3109/07357909809011698Search in Google Scholar
17. Fuchs D, Jaeger M, Widner B, Wirleitner B, Artner-Dworzak E, Leblhuber F. Is hyperhomocysteinemia due to the oxidative depletion of folate rather than to insufficient dietary intake? Clin Chem Lab Med2001;39:691–4.10.1515/CCLM.2001.113Search in Google Scholar
18. Reibnegger G, Fuchs D, Fuith LC, Hausen A, Werner ER, Werner-Felmayer G, et al. Neopterin as a marker for activated cell-mediated immunity: application in malignant disease. Cancer Detect Prev1991;15:483–90.Search in Google Scholar
19. Hronek M, Zadak Z, Solichova D, Jandik P, Melichar B. The association between specific nutritional antioxidants and manifestation of colorectal cancer. Nutrition2000;16:189–91.10.1016/S0899-9007(99)00285-3Search in Google Scholar
20. Frick B, Rudzite V, Schroecksnadel K, Kalnins U, Erglis A, Trusinskis K, et al. Homocysteine, B vitamins and immune activation in coronary heart disease. Pteridines2003;14:82–7.10.1515/pteridines.2003.14.3.82Search in Google Scholar
21. Schroecksnadel K, Leblhuber F, Frick B, Wirleitner B, Fuchs D. Association of hyperhomocysteinemia in Alzheimer disease with elevated neopterin levels. Alzheimer Dis Assoc Disord2004;18:129–33.10.1097/01.wad.0000127443.23312.31Search in Google Scholar PubMed
22. Schroecksnadel K, Frick B, Wirleitner B, Winkler C, Schennach H, Fuchs D. Moderate hyperhomocysteinemia and immune activation. Curr Pharm Biotechnol2004;5:107–18.10.2174/1389201043489657Search in Google Scholar PubMed
23. Schroecksnadel K, Frick B, Wirleitner B, Schennach H, Fuchs D. Homocysteine accumulates in supernatants of stimulated human peripheral blood mononuclear cells. Clin Exp Immunol2003;134:53–6.10.1046/j.1365-2249.2003.02251.xSearch in Google Scholar PubMed PubMed Central
24. Frick B, Schroecksnadel K, Neurauter G, Leblhuber F, Fuchs D. Increasing production of homocysteine and neopterin and degradation of tryptophan with older age. Clin Biochem2004;37:684–7.10.1016/j.clinbiochem.2004.02.007Search in Google Scholar PubMed
25. Frick B, Schroecksnadel K, Neurauter G, Wirleitner B, Artner-Dworzak E, Fuchs D. Rapid measurement of total plasma homocysteine by HPLC. Clin Chim Acta2003;331:19–23.10.1016/S0009-8981(03)00076-7Search in Google Scholar
26. Almadori G, Bussu F, Galli J, Cadoni G, Zappacosta B, Persichilli S, et al. Serum folate and homocysteine levels in head and neck squamous cell carcinoma. Cancer2002;94:1006–11.10.1002/cncr.10343Search in Google Scholar
27. Refsum H, Wesenberg F, Ueland PM. Plasma homocysteine in children with acute lymphoblastic leukemia: changes during a chemotherapeutic regimen including methotrexate. Cancer Res1991;51:828–35.Search in Google Scholar
28. Piyathilake CJ, Johanning GL, Macaluso M, Whiteside M, Oelschlager DK, Heimburger DC, et al. Localized folate and vitamin B-12 deficiency in squamous cell lung cancer is associated with global DNA hypomethylation. Nutr Cancer2000;37:99–107.10.1207/S15327914NC3701_13Search in Google Scholar
29. Fuith LC, Artner-Dworzak E, Daxenbichler G. Tumor markers in gynecology. Wien Klin Wochenschr1989;101:489–91.Search in Google Scholar
30. Reibnegger G, Hetzel H, Fuchs D, Fuith LC, Hausen A, Werner ER, et al. Clinical significance of neopterin for prognosis and follow-up in ovarian cancer. Cancer Res1987;47:4977–81.Search in Google Scholar
31. Reibnegger GJ, Bichler AH, Dapunt O, Fuchs DN, Fuith LC, Hausen A, et al. Neopterin as a prognostic indicator in patients with carcinoma of the uterine cervix. Cancer Res1986;46:950–5.Search in Google Scholar
32. Murr C, Bergant A, Widschwendter M, Heim K, Schrocksnadel H, Fuchs D. Neopterin is an independent prognostic variable in females with breast cancer. Clin Chem1999;45:1998–2004.10.1093/clinchem/45.11.1998Search in Google Scholar
33. Lewenhaupt A, Ekman P, Eneroth P, Eriksson A, Nilsson B, Nordstrom L. Serum levels of neopterin as related to the prognosis of human prostatic carcinoma. Eur Urol1986;12:422–5.10.1159/000472672Search in Google Scholar
34. Weiss G, Kronberger P, Conrad F, Bodner E, Wachter H, Reibnegger G. Neopterin and prognosis in patients with adenocarcinoma of the colon. Cancer Res1993;53:260–5.Search in Google Scholar
35. Kronberger P, Weiss G, Tschmelitsch J, Fuchs D, Salzer GM, Wachter H, et al. Predictive value of urinary neopterin in patients with lung cancer. Eur J Clin Chem Clin Biochem1995;33:831–7.10.1515/cclm.1995.33.11.831Search in Google Scholar
36. Ikeda M, Natsugoe S, Ueno S, Baba M, Aikou T. Significant host- and tumor-related factors for predicting prognosis in patients with esophageal carcinoma. Ann Surg2003;238:197–202.10.1097/01.sla.0000080822.22415.cbSearch in Google Scholar
37. de Mello J, Struthers L, Turner R, Cooper EH, Giles GR. Multivariate analyses as aids to diagnosis and assessment of prognosis in gastrointestinal cancer. Br J Cancer1983;48:341–8.10.1038/bjc.1983.198Search in Google Scholar
38. Nozoe T, Matsumata T, Kitamura M, Sugimachi K. Significance of preoperative elevation of serum C-reactive protein as an indicator for prognosis in colorectal cancer. Am J Surg1998;176:335–8.10.1016/S0002-9610(98)00204-9Search in Google Scholar
39. Terpos E, Szydlo R, Apperley JF, Hatjiharissi E, Politou M, Meletis J, et al. Soluble receptor activator of nuclear factor κB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index. Blood2003;102:1064–9.10.1182/blood-2003-02-0380Search in Google Scholar PubMed
40. Carmel R, Eisenberg L. Serum vitamin B12 and transcobalamin abnormalities in patients with cancer. Cancer1977;40:1348–53.10.1002/1097-0142(197709)40:3<1348::AID-CNCR2820400352>3.0.CO;2-QSearch in Google Scholar
41. Cortelezzi A, Fracchiolla NS, Bamonti-Catena F, Motta M, Cighetti G, Carrabba M, et al. Hyperhomocysteinemia in myelodysplastic syndromes: specific association with autoimmunity and cardiovascular disease. Leuk Lymphoma2001;41:147–50.10.3109/10428190109057963Search in Google Scholar
42. Schroecksnadel K, Frick B, Kaser S, Wirleitner B, Ledochowski M, Mur E, et al. Moderate hyperhomocysteinaemia and immune activation in patients with rheumatoid arthritis. Clin Chim Acta2003;338:157–64.10.1016/j.cccn.2003.09.003Search in Google Scholar
43. Frick B, Neurauter G, Diez-Ruiz A, Schroecksnadel K, Wirleitner B, Leblhuber F, et al. Neopterin and oxidation products in the blood of patients with various forms of dementia. Pteridines2003;13:88–93.10.1515/pteridines.2003.14.3.88Search in Google Scholar
©2007 by Walter de Gruyter Berlin New York
