Artículos de revistas
Anaemia Of Cancer: An Overview Of Mechanisms Involved In Its Pathogenesis
Medical Oncology. , v. 25, n. 1, p. 12 - 21, 2008.
Anaemia is a common complication in cancer patients. The decrease in haemoglobin is associated with an impaired quality of life, poorer response to therapy and worse prognosis. Numerous factors are involved in the physiopathology of cancer-related anaemia. Some factors such as bleeding, bone marrow infiltration, the effects of chemoradiotherapy and associated nutritional deficiencies are related to the disease itself. In addition, the interaction of the immune system with iron metabolism and erythropoiesis has been shown to be an important factor in the development of anaemia in cancer patients and can be seen in the action of several cytokines on different iron-homeostasis and erythrocyte-cell-production pathways. Some inhibitory cytokines, such as tumour necrosis factor-α and interleukin-1, act on the suppression of erythroid precursor cells and erythropoietic production and response; others, such as interleukins 1 and 6 and hepcidin, impair iron metabolism, causing iron to be diverted from erythropoiesis and retained within the reticuloendothelial system. The main mechanisms involved in the development of cancer-related anaemia are discussed in this review. © 2007 Humana Press Inc.2511221Skillings, J.R., An epidemiological review of red cell transfusions in cancer chemotherapy (1999) Cancer Prev Control, 3, pp. 207-12Coiffier, B., Guastalla, J.P., Pujade-Lauraine, E., Bastif, P., Anemia Study Group. Predicting cancer-associated anaemia in patients receiving non-platinum chemotherapy: Results of a retrospective survey (2001) Eur J Cancer, 37, pp. 1617-23Ludwig, H., The European Cancer Anaemia Survey (ECAS): A large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients (2004) Eur J Cancer, 40, pp. 2293-306Birgegard, G., Gascon, P., Ludwig, H., Evaluation of anemia in patients with multiple myeloma and lymphoma: Findings of the European Cancer Anaemia Survey (2006) Eur J Haemaol, 77, pp. 378-86. , 5Kosmidis, P., Krzakowski, M., Prospective data from the European Cancer Anaemia Survey (ECAS): Focus on patients with lung cancer (2003) Lung Cancer, 41, p. 265Schrijvers, D., European Cancer Anaemia Survey (ECAS): Prospective evaluation of anemia in patients (pts) with gastrointestinal (GI) or colorectal (CR) cancer (CA) (2002) Proc Euro School Oncol 2nd Colorectal Cancer Confer, 2, p. 71. , (abstract 18)Richardson, A., Fatigue in cancer patients: A review of the literature (1995) Eur J Cancer Care, 4, pp. 20-32. , 1Stone, P., Richards, M., Hardy, J., Fatigue in patients with cancer (1998) Eur J Cancer, 34, pp. 1670-6. , 11Cella, D., Factors influencing quality of life in cancer patients: Anemia and fatigue (1998) Semin Oncol, 25, pp. 43-6. , 3 Suppl 7Stone, P., Cancer-related fatigue: Inevitable, unimportant and untreatable? Results of a multi-centre patient survey. Cancer Fatigue Forum (2000) Ann Oncol, 11, pp. 971-5Curt, G.A., Impact of fatigue on quality of life in oncology patients (2000) Semin Hematol, 37, pp. 14-7. , 4 Suppl 6Harper, P., Littlewood, T., Anaemia of cancer: Impact on patient fatigue and long-term outcome (2005) Oncology, 69, pp. 2-7. , Suppl 2Dicato, M., Harper, P., The optimal hemoglobin level in the cancer patient (2002) Semin Oncol, 29, pp. 88-91. , 3 Suppl 8Ludwig, H., Strasser, K., Symptomatology of anemia (2001) Semin Oncol, 28, pp. 7-14. , 2 Suppl 8Caro, J.J., Salas, M., Ward, A., Goss, G., Anemia as an independent prognostic factor for survival in patients with cancer: A systemic, quantitative review (2001) Cancer, 91, pp. 2214-21Waters, J.S., O'Brien, M.E., Ashley, S., Management of anemia inpatients receiving chemotherapy (2002) J Clin Oncol, 20, pp. 601-3. , 2Obermair, A., Impact of hemoglobin levels before and during concurrent chemotherapy on the response to treatment in patients with cervical cancer: Preliminary results (2001) Cancer, 92, pp. 903-8Grogan, M., The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix (1999) Cancer, 86, pp. 1528-36. , 8Vaupel, P., Kelleher, D.K., Thews, O., Modulation of tumor oxygenation (1998) Int J Radiat Oncol Biol Phys, 42, pp. 843-8Vaupel, P., Kelleher, D.K., Höckel, M., Oxygenation status of malignant tumours: Pathogenesis of hypoxia and significance for tumor Therapy (2001) Semin Oncol, 28, pp. 29-35. , 2 Suppl 8Dunst, J., Hemoglobin level and anemia in radiation oncology: Prognostic impact and therapeutic implications (2000) Semin Oncol, 27, pp. 4-8. , 2 Suppl 4Teicher, B.A., Holden, S.A., Al Achi, A., Herman, T.S., Classification of antineoplastic treatments by their differential toxicity toward putative oxygenated and hypoxic tumor subpopulations in vivo in the FSaIIC murine fibrosarcoma (1990) Cancer Res, 50, pp. 3339-44. , 11Green, S.L., Giaccia, A.J., Tumor hypoxia and the cell cycle: Implications for malignant progression and response to therapy (1998) Cancer J Sci Am, 4, pp. 218-23Harris, A.L., Hypoxia-a key regulatory factor in tumour growth (2002) Nat Rev Cancer, 2, pp. 38-47Graeber, T.G., Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours (1996) Nature, 379, pp. 88-91Littlewood, T.J., Impact of hemoglobin levels on treatment outcomes in patients with cancer (2001) Semin Oncol, 28, pp. 49-53. , 2 Suppl 8(1998) Common Toxicity Criteria, , NCI. Cancer therapy evaluation program, version 2.0. Published April 1998 by National Institute of Health, National Cancer Institute. Bethesda, MD [NLM 9810879]Montserrat, E., Bosch, F., Rozman, C., B-cell chronic lymphocytic leukaemia: Recent progress in biology, diagnosis, and therapy (1997) Ann Oncol, 8, pp. 93-101. , Suppl 1Mercadante, S., Gebbia, V., Marrazzo, A., Filosto, S., Anaemia in cancer: Pathophysiology and treatment (2000) Cancer Treat Rev, 26, pp. 303-11Groopman, J.E., Itri, L.M., Chemotherapy-induced anemia in adults: Incidence and treatment (1999) J Natl Cancer Inst, 91, pp. 1616-34Tas, F., Anemia in oncology practice: Relation to disease and their therapies (2002) Am J Clin Oncol, 25, pp. 371-9. , 4Okamoto, H., Chemotherapy-induced anemia in patients with primary lung cancer (1992) Ann Oncol, 3, pp. 819-24Tanvetyanon, T., Choudhury, A.M., Severity, risk factors, and physician practices in the management of anemia during concurrent chemoradiation for head and neck carcinoma (2006) Cancer, 106, pp. 1554-9. , 7Doll, D.C., Weiss, R.B., Hemolytic anemia associated with antineoplastic agents (1985) Cancer Treat Rep, 69, pp. 777-82. , 7-8Barrett-Lee, P.J., Bailey, N.P., O'Brien, M.E., Wager, E., Large-scale UK audit of blood transfusion requirements and anaemia in patients receiving cytotoxic chemotherapy (2000) Brit J Cancer, 82, pp. 93-7Faquin, W.C., Schneider, T.J., Goldberg, M.A., Effect of inflammatory cytokines on hypoxia-induced erythropoietin production (1992) Blood, 79, pp. 1987-94Nairz, M., Weiss, G., Molecular and clinical aspects of iron homeostasis: From anemia to hemochromatosis (2006) Wien Klin Wochenschr, 118, pp. 442-462. , 15-16Ponka, P., Beaumont, C., Richardson, D.R., Function and regulation of transferrin and ferritin (1998) Semin Hematol, 35, pp. 35-54Wardrop, S.L., Richardson, D.R., Interferon-gamma and lipopolysaccharide regulate the expression of Nramp2 and increase the uptake of iron from low relative molecular mass compleses by macrophages (2000) Eur J Biochem, 267, pp. 6586-93Aigner, E., Weiss, G., Regulation of iron transport by inflammatory cytokines in human monocytic cells (2001) 13th European Macrophage Conference, , Vienna. Aug 31th-Sept 1st, abstractByrd, T., Horwitz, M.A., Regulation of transferrin receptor expression and ferritin content in human mononuclear macrophages. Coordinate upregulation by iron transferrin and downregulation by interferon gamma (1993) J Clin Invest, 91, pp. 969-76Ludwiczek, S., Aigner, E., Theurl, I., Weiss, G., Cytokine-mediated regulation of iron transport in human monocytic cells (2003) Blood, 101, pp. 4148-54. , 10Rafferty, S.P., Domachowske, J.B., Malech, H.L., Inhibition of hemoglobin expression by heterologous production of nitric oxide synthase in the K562 erythroleukemic cell line (1996) Blood, 88, pp. 1070-8Furukawa, T., Kohno, H., Tokynaga, R., Taketani, S., Nitric oxide mediated inactivation of mammalian ferrochelatase in vivo and in vitro: Possible involvement of the iron-sulphur cluster of the enzyme (1995) Biochem J, 310, pp. 533-8MacIejewski, J.P., Nitric oxide suppression of human hematopoiesis in vitro. Contribution to inhibitory action of interferon-gamma and tumor necrosis factor-alpha (1995) J Clin Invest, 96, pp. 1085-92Ponka, P., Tissue specific regulation of iron metabolism and heme synthesis: Distinct control mechanism in erythroid cells (1997) Blood, 89, pp. 1-25Murr, C., Widner, B., Wirleitner, B., Fuchs, D., Neopterin as a marker for immune system activation (2002) Curr Drug Metab, 3, pp. 175-87. , 2Reibnegger, G.J., Bichler, A.H., Dapunt, O., Neopterin as a prognostic indicador in patients with carcinoma of the uterine cervix (1986) Cancer Res, 46, pp. 950-5Sheldon, J., Plasma neopterin as an adjunct to C-reactive protein in assessment of infection (1991) Clin Chem, 37, pp. 2038-42Fuchs, D., Association between immune activation, changes of iron metabolism and anaemia in patients with HIV infection (1993) Eur J Haematol, 50, pp. 90-4Grotto, H.Z.W., Costa, F.F., Carneiro, M.V., Galiza Neto, G.C., Serum neopterin in patients with Chagas disease (1994) Trans R Soc Trop Med Hyg, 88, p. 75. , 1Muller, T.F., Noninvasive monitoring using serum amyloid a and serum neopterin in cardiac transplantation (1998) Clin Chim Acta, 276, pp. 63-74Hamerlinck, F.F., Neopterin: A review (1999) Exp Dermatol, 8, pp. 167-76Weiss, G., Neopterin and prognosis in patients with adenocarcinoma of the colon (1993) Cancer Res, 53, pp. 260-65Reibnegger, G.J., Predictive value of interlukin-6 and neopterin in patients with multiple myeloma (1991) Cancer Res, 51, pp. 6250-3Birk, D., Gansauge, F., Gansauge, S., Schwarz, A., Berger, H.G., Levels of serum neopterin are increased in pancreatic cancer patients and correlate with the prognosis (1999) Eur J Med Res, 4, pp. 156-60Berdowska, A., Zwirska-Korczala, K., Neopterin measurement in clinical diagnosis (2001) J Clin Pharm Ther, 26, pp. 319-29Weiss, G., Neopterin modulates toxicity mediated by reactive oxygen and chloride species (1993) FEBS Lett, 321, pp. 89-92Barak, M., Gruener, N., Neopterin augmentation of tumor necrosis factor production (1991) Immunol Lett, 30, pp. 101-6Denz, H., Weight loss in patients with haematological neoplasia is associated with immune system stimulation (1993) Clin Invest, 71, pp. 37-41Denz, H., Association between the activation of macrophages, changes of iron metabolism and the degree of anaemia in patients with malignant disorders (1992) Eur J Haematol, 48, pp. 244-8Pagel, H., Fandrey, J., Schobersberger, W., Fuchs, D., Jelkmann, W., Effects of neopterin and 7, 8-dihydroneopterin on hypoxia-induced renal erythropoietin production (1999) Eur J Haematol, 62, pp. 341-5Johnson, C.S., Cook, C.A., Furmanski, P., In vivo suppression of erythropoiesis by tumour necrosis factor alfa (TNF-alfa): Reversal with exogenous erythropoietin (EPO) (1990) Exp Hematol, 18, pp. 109-13Ulich, T.R., Del Castilho, J., Yin, S., Tumor necrosis factor exerts dose-dependent effects on erythropoiesis and myrlopoiesis in vivo (1990) Exp Hematol, 18, pp. 311-5Moldawer, L.L., Marano, M.A., Wei, H., Cachectin/tumor necrosis factor-alpha alters red blood cell kinetics and induces anemia in vivo (1898) FASEB J, 3, pp. 1637-43. , 5Trey, J.E., Kushner, I., The acute phase response and the hematopoietic system: The role of cytokines (1995) Crit Rev Oncol Hematol, 21, pp. 1-18Weiss, G., Modification of iron regulation by the inflammatory response (2005) Best Pract Res Clin Haematol, 18, pp. 183-201Miller, L.L., Miller, S.C., Torti, S.V., Tsuji, Y., Torti, F.M., Iron-independent induction of ferritin H-chain by tumor necrosis factor (1991) Proc Natl Acad Sci USA, 88, pp. 4946-50. , 11Weiss, G., Pathogenesis and treatment of anaemia of chronic disease (2002) Blood Rev, 16, pp. 87-96Rogers, J.T., Translational control during the acute phase response. Ferritin synthesis in response to interleukin-1 (1990) J Biol Chem, 265, pp. 14572-8. , 24Means Jr., R.T., Dessypris, E.N., Krantz, S.B., Inhibition of human erythroid colony-forming units by interleukin-1 is mediated by gamma interferon (1992) J Cell Physiol, 150, pp. 59-64Jelkmann, W., Pagel, H., Wolff, M., Fandrey, J., Monokines inhibiting erythropoietin production in human hepatoma cultures and in isolated perfused rat kidney (1991) Life Sci, 50, pp. 301-8Salvarani, C., The role of interleukin 1, erythropoietin and red cell bound immunoglobulins in the anaemia of rheumatoid arthritis (1991) Clin Exp Rheumatol, 9, pp. 241-6. , 3Maury, C.P., Anaemia of chronic disease in AA amyloidosis is associated with allele 2 of the interleukin-1beta-511 promoter gene and raised levels of interlukin-1beta and interleukin-18 (2004) J Intern Med, 256, pp. 145-52. , 2Graziadei, I., Gaggl, S., Kaserbacher, R., Braunsteiner, H., Vogel, W., The acute-phase protein alpha 1-antitripsin inhibits growth and proliferation of human early erythroid progenitor cells (BFU-E) and of human erythroleukemic cells (K562) in vitro by interfering with transferrin iron uptake (1994) Blood, 83, pp. 260-8Peetre, C., Gullberg, U., Nilsson, E., Olsson, I., Effects of recombinant tumor necrosis factor on proliferation and differentiation of leukemic and normal hemopoietic cells in vitro. Relationship to cell surface receptors (1986) J Clin Invest, 78, pp. 1694-700Torti, F.M.S.V., Regulation of ferritin genes and protein (2002) Blood, 99, pp. 3505-16Graversen, J.H., Madsen, M., Moestrup, S.K., CD163: A signal receptor scavenging haptoglobin-hemoglobin complexes from plasma (2002) Int J Biochem Cell Biol, 34, pp. 309-14. , 4Weiss, G., Iron and anemia of chronic disease (1999) Kidney Int Suppl, 69, pp. 12-7Krause, A., LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity (2000) FEBS Lett, 480, pp. 147-50Park, C.H., Valore, E.V., Waring, A.J., Ganz, T., Hepcidin, a urinary antimicrobial peptide synthesized in the liver (2001) J Biol Chem, 276, pp. 7806-10Ganz, T., Hepcidin-a regulator of intestinal iron absorption and iron recycling by macrophages (2005) Best Pract Res Clin Haematol, 18, pp. 171-82Zasloff, M., Antibiotic peptides as mediators of innate immunity (1992) Curr Opin Immunol, 4, pp. 3-7Singh, P.K., Parsek, M.R., Greenberg, E.P., Welsh, M.J., A component of innate immunity prevents bacterial biofilm development (2002) Nature, 417, pp. 552-5. , 6888Pigeon, C., A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload (2001) J Biol Chem, 276, pp. 7811-9Nicolas, G., Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice (2001) Proc Natl Acad Sci USA, 98, pp. 8780-5. , 15Nemeth, E., Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization (2004) Science, 306, pp. 2090-3Donovan, A., Roy, C.N., Andrews, N.C., The ins and outs of iron homeostasis (2006) Physiology, 21, pp. 115-23Kemna, E., Pickkers, P., Nemeth, E., Van Der Hoeven, H., Swinkels, D., Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in human injected with LPS (2005) Blood, 106, pp. 1864-6. , 5Nieken, J., Recombinant human interleukin-6 induces a rapid and reversible anemia in cancer patients (1995) Blood, 86, pp. 900-5Nemeth, E., Valore, E.V., Territo, M., Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein (2003) Blood, 101, pp. 2461-3Nemeth, E., IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin (2004) J Clin Invest, 113, pp. 1271-6Cartwright, G.E., The anemia of chronic disorders (1966) Semin Hematol, 3, pp. 351-75Fuchs, D., Immune activation and the anemia associated with chronic inflammatory disorders (1991) Eur J Haematol, 46, pp. 65-70Spivak, J.L., Iron and the anemia of chronic disease (2002) Oncology, 16, pp. 25-33. , 9 Suppl 10Practice Guidelines in Oncology. Version 1.2007. Cancer- and Treatment-related Anemia, , http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf, Available at Accessed May 18, 2007Blumberg, N., Heal, J.M., Effects of transfusion on immune function. Cancer recurrence and infection (1994) Arch Pathol Lab Med, 118, pp. 371-9Cella, D., Quality of life and clinical decisions in chemotherapy-induced anemia (2006) Oncology, 20, pp. 25-8. , 8 Suppl 6Littewood, T.J., Effects of epoetin alfa on hematologic parameters and quality of life in patients receiving nonplatinum chemotherapy: Results of a randomized, double-blind, placebo-controlled clinical trial (2001) J Clin Oncol, 19, pp. 2865-74Hedenus, M., Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: A randomized, double-blind, placebo-controlled study (2003) Br J Haematol, 122, pp. 394-403Seidenfeld, J., Epoetin treatment of anemia associated with cancer therapy: A systematic review and meta-analysis of controlled clinical trials (2001) J Natl Cancer Inst, 93, pp. 1204-14Bohlius, J., Recombinant human erythropoietins and cancer patients: Updated meta-analysis of 57 studies including 9353 patients (2006) J Natl Cancer Inst, 98, pp. 708-14Henke, M., Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotheraphy: Randomized, double-bind, placebo-controlled trial (2003) Lancet, 362, pp. 1255-60Leyland-Jones, B., BEST Investigators and Study Group. Breast cancer trial with erythropoietin terminated unexpectedly (2003) Lancet Oncol, 4, pp. 459-60(2006) Interim Analysis of DAHANCA, 10. , http://www.dahanca.dk/get_media_file.php?mediaid=125, December 1. Avaiable at Accessed May 21, 2007Weiss, M.J., New insights into erythropoietin and epoetin alfa: Mechanisms of action, target tissues, and clinical applications (2003) Oncologist, 8, pp. 18-29. , Suppl 3Lappin, T.R., Maxwell, A.P., Johnston, P.G., Warning flags for erythropoiesis-stimulating agents and cancer-associated anemia (2007) Oncologist, 12, pp. 362-5Parganas, E., Jak2 is essential for signaling through a variety of cytokine receptors (1998) Cell, 93, pp. 385-95Yasuda, Y., Erythropoietin regulates tumor growth of human malignancies (2003) Carcinogenesis, 24, pp. 1021-9(2007) Information for Healthcare Professionais, , http://www.fda.gov/cder/drug/InfoSheets/HCP/RHE2007HCP.htm, Erytropoiesis Stimulating Agents (ESA). FDA Alert, February 16, Avaiable at Accessed May 15, 2007Bokemeyer, C., EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 Update (2007) Eur J Cancer, 43 (2), pp. 258-270