Epidemiological and nonclinical studies investigating effects of iron in carcinogenesis-A critical review

[en] The efficacy and tolerability of intravenous (i.v.) iron in managing cancer-related anemia and iron deficiency has been clinically evaluated and reviewed recently. However, long-term data in cancer patients are not available; yet, long-term i.v. iron treatment in hemodialysis patients is not associated with increased cancer risk. This review summarizes epidemiological and nonclinical data on the role of iron in carcinogenesis. In humans, epidemiological data suggest correlations between certain cancers and increased iron exposure or iron overload. Nonclinical models that investigated whether iron can enhance carcinogenesis provide only limited evidence relevant for cancer patients since they were typically based on high iron doses as well as injection routes and iron formulations which are not used in the clinical setting. Nevertheless, in the absence of long-term outcome data from prospectively defined trials in i.v. iron-treated cancer patients, iron supplementation should be limited to periods of concomitant anti-tumor treatment.

Disciplines :

Hematology

Author, co-author :

Beguin, Yves ; Université de Liège - ULiège > GIGA-R : Hématologie

Aapro, Matti S.; Clinique de Genolier (Switzerland)

Ludwig, Heinrich P.

Mizzen, Lee

Osterborg, Anders C.

Language :

English

Title :

Epidemiological and nonclinical studies investigating effects of iron in carcinogenesis-A critical review

Publication date :

2014

Journal title :

Critical Reviews in Oncology/Hematology

ISSN :

1040-8428

eISSN :

1879-0461

Publisher :

Elsevier Scientific

Volume :

Pages :

1-15

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 27 January 2014

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Bibliography

Toyokuni S. Role of iron in carcinogenesis: cancer as a ferrotoxic disease. Cancer Sci 2009, 100(1):9-16.
Hentze M.W., Muckenthaler M.U., Galy B., Camaschella C. Two to tango: regulation of Mammalian iron metabolism. Cell 2010, 142(1):24-38.
Chua A.C., Graham R.M., Trinder D., Olynyk J.K. The regulation of cellular iron metabolism. Crit Rev Clin Lab Sci 2007, 44(5-6):413-459.
Galaris D., Skiada V., Barbouti A. Redox signaling and cancer: the role of labile iron. Cancer Lett 2008, 266(1):21-29.
Weiss G., Goodnough L.T. Anemia of chronic disease. N Engl J Med 2005, 352(10):1011-1023.
Krause A., Neitz S., Magert H.J., et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett 2000, 480(2-3):147-150.
Chung B., Chaston T., Marks J., Srai S.K., Sharp P.A. Hepcidin decreases iron transporter expression in vivo in mouse duodenum and spleen and in vitro in THP-1 macrophages and intestinal Caco-2 cells. J Nutr 2009, 139(8):1457-1462.
Caro J.J., Salas M., Ward A., Goss G. Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer 2001, 91(12):2214-2221.
Auerbach M., Ballard H., Trout J.R., et al. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial. J Clin Oncol 2004, 22(7):1301-1307.
Crawford J., Cella D., Cleeland C.S., et al. Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer 2002, 95(4):888-895.
Aapro M., Osterborg A., Gascon P., Ludwig H., Beguin Y. Prevalence and management of cancer-related anaemia, iron deficiency and the specific role of i.v. iron. Ann Oncol 2012, 23(8):1954-1962.
Auerbach M., Silberstein P.T., Webb R.T., et al. Darbepoetin alfa 300 or 500μg once every 3 weeks with or without intravenous Iron in patients with chemotherapy-induced anemia. Am J Hematol 2010, 85(9):655-663.
Bastit L., Vandebroek A., Altintas S., et al. Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. J Clin Oncol 2008, 26(10):1611-1618.
Hedenus M., Birgegard G., Nasman P., et al. Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study. Leukemia 2007, 21(4):627-632.
Henry D.H., Dahl N.V., Auerbach M., Tchekmedyian S., Laufman L.R. Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist 2007, 12(2):231-242.
Pedrazzoli P., Farris A., Del P.S., et al. Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alpha. J Clin Oncol 2008, 26(10):1619-1625.
Adamson J.W. Iron, erythropoietic stimulating agents, and anemia in cancer. Crit Rev Oncog 2013, 18(5):471-483.
National Comprehensive Cancer Network Inc. NCCN practice guidelines in oncology; cancer and chemotherapy-induced anemia - v.2 2014, http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf [last accessed 01.09.13].
Rizzo J.D., Brouwers M., Hurley P., et al. American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. Blood 2010, 116(20):4045-4059.
Auerbach M., Glaspy J. What is the right balance between iron and erythropoiesis stimulating agents in chemotherapy induced anemia. Eur J Clin Med Oncol 2009, 1:7-12.
Beguin Y., Maertens J., De Prijck B., et al. Darbepoetin-alfa and I.V. iron administration after autologous hematopoietic stem cell transplantation: a prospective randomized multicenter trial. Blood 2008, 112:54.
Okada S. Iron and carcinogenesis in laboratory animals and humans: a mechanistic consideration and a review of literature. Int J Clin Oncol 1998, 3:191-203.
Weinberg E.D. The role of iron in cancer. Eur J Cancer Prev 1996, 5(1):19-36.
Torti S.V., Torti F.M. Iron and cancer: more ore to be mined. Nat Rev Cancer 2013, 13(5):342-355.
Bacon B.R., Adams P.C., Kowdley K.V., Powell L.W., Tavill A.S. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011, 54(1):328-343.
Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. Gastroenterology 2010, 139(2):393-408. 408.
Ellervik C., Birgens H., Tybjaerg-Hansen A., Nordestgaard B.G. Hemochromatosis genotypes and risk of 31 disease endpoints: meta-analyses including 66,000 cases and 226,000 controls. Hepatology 2007, 46(4):1071-1080.
Kowdley K.V. Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 2004, 127(5 Suppl 1):S79-S86.
Rivers C.A., Barton J.C., Gordeuk V.R., et al. Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African Americans in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Blood Cells Mol Dis 2007, 38(3):247-252.
Barton J.C., Acton R.T., Lee P.L., West C. SLC40A1 Q248H allele frequencies and Q248H-associated risk of non-HFE iron overload in persons of sub-Saharan African descent. Blood Cells Mol Dis 2007, 39(2):206-211.
Corley D.A., Kubo A., Levin T.R., et al. Hemochromatosis gene status as a risk factor for Barrett's esophagus. Dig Dis Sci 2008, 53(12):3095-3102.
Hsing A.W., McLaughlin J.K., Olsen J.H., Mellemkjar L., Wacholder S., Fraumeni J.F. Cancer risk following primary hemochromatosis: a population-based cohort study in Denmark. Int J Cancer 1995, 60(2):160-162.
Kallianpur A.R., Hall L.D., Yadav M., et al. Increased prevalence of the HFE C282Y hemochromatosis allele in women with breast cancer. Cancer Epidemiol Biomarkers Prev 2004, 13(2):205-212.
Nelson R.L., Davis F.G., Persky V., Becker E. Risk of neoplastic and other diseases among people with heterozygosity for hereditary hemochromatosis. Cancer 1995, 76(5):875-879.
Niederau C., Fischer R., Sonnenberg A., Stremmel W., Trampisch H.J., Strohmeyer G. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 1985, 313(20):1256-1262.
Shaheen N.J., Silverman L.M., Keku T., et al. Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer. J Natl Cancer Inst 2003, 95(2):154-159.
Simonart T. Iron: a target for the management of Kaposi's sarcomaα. BMC Cancer 2004, 4:1.
Chua A.C., Klopcic B., Lawrance I.C., Olynyk J.K., Trinder D. Iron: an emerging factor in colorectal carcinogenesis. World J Gastroenterol 2010, 16(6):663-672.
Pra D., Rech Franke S.I., Pegas Henriques J.A., Fenech M. A possible link between iron deficiency and gastrointestinal carcinogenesis. Nutr Cancer 2009, 61(4):415-426.
Chao A., Thun M.J., Connell C.J., et al. Meat consumption and risk of colorectal cancer. J Am Med Assoc 2005, 293(2):172-182.
Nelson R.L. Iron and colorectal cancer risk: human studies. Nutr Rev 2001, 59(5):140-148.
Norat T., Bingham S., Ferrari P., et al. Meat, fish, and colorectal cancer risk: the European Prospective Investigation into cancer and nutrition. J Natl Cancer Inst 2005, 97(12):906-916.
Kabat G.C., Miller A.B., Jain M., Rohan T.E. A cohort study of dietary iron and heme iron intake and risk of colorectal cancer in women. Br J Cancer 2007, 97(1):118-122.
Kato I., Dnistrian A.M., Schwartz M., et al. Iron intake, body iron stores and colorectal cancer risk in women: a nested case-control study. Int J Cancer 1999, 80(5):693-698.
Noto J.M., Gaddy J.A., Lee J.Y., et al. Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans. J Clin Invest 2013, 123(1):479-492.
Cross A.J., Pollock J.R., Bingham S.A. Haem, not protein or inorganic iron, is responsible for endogenous intestinal N-nitrosation arising from red meat. Cancer Res 2003, 63(10):2358-2360.
Kabat G.C., Miller A.B., Jain M., Rohan T.E. Dietary iron and heme iron intake and risk of breast cancer: a prospective cohort study. Cancer Epidemiol Biomarkers Prev 2007, 16(6):1306-1308.
Moore A.B., Shannon J., Chen C., et al. Dietary and stored iron as predictors of breast cancer risk: A nested case-control study in Shanghai. Int J Cancer 2009, 125(5):1110-1117.
Kallianpur A.R., Lee S.A., Gao Y.T., et al. Dietary animal-derived iron and fat intake and breast cancer risk in the Shanghai Breast Cancer Study. Breast Cancer Res Treat 2008, 107(1):123-132.
Kabat G.C., Miller A.B., Jain M., Rohan T.E. Dietary iron and haem iron intake and risk of endometrial cancer: a prospective cohort study. Br J Cancer 2008, 98(1):194-198.
Michaud D.S., Spiegelman D., Clinton S.K., Rimm E.B., Willett W.C., Giovannucci E. Prospective study of dietary supplements, macronutrients, micronutrients, and risk of bladder cancer in US men. Am J Epidemiol 2000, 152(12):1145-1153.
Mainous A.G., Wells B.J., Koopman R.J., Everett C.J., Gill J.M. Iron, lipids, and risk of cancer in the Framingham Offspring cohort. Am J Epidemiol 2005, 161(12):1115-1122.
Mainous A.G., Gill J.M., Everett C.J. Transferrin saturation, dietary iron intake, and risk of cancer. Ann Fam Med 2005, 3(2):131-137.
Stevens R.G., Jones D.Y., Micozzi M.S., Taylor P.R. Body iron stores and the risk of cancer. N Engl J Med 1988, 319(16):1047-1052.
Stevens R.G., Graubard B.I., Micozzi M.S., Neriishi K., Blumberg B.S. Moderate elevation of body iron level and increased risk of cancer occurrence and death. Int J Cancer 1994, 56(3):364-369.
Wells B.J., Mainous A.G., Everett C.J., Gill J.M. Iron, cholesterol, and the risk of cancer in an 18-year cohort. Asian Pac J Cancer Prev 2005, 6(4):505-509.
Wu T., Sempos C.T., Freudenheim J.L., Muti P., Smit E. Serum iron, copper and zinc concentrations and risk of cancer mortality in US adults. Ann Epidemiol 2004, 14(3):195-201.
Gaur A., Collins H., Wulaningsih W., et al. Iron metabolism and risk of cancer in the Swedish AMORIS study. Cancer Causes Control 2013, 24(7):1393-1402.
Hercberg S., Estaquio C., Czernichow S., et al. Iron status and risk of cancers in the SU.VI.MAX cohort. J Nutr 2005, 135(11):2664-2668.
Edgren G., Reilly M., Hjalgrim H., et al. Donation frequency, iron loss, and risk of cancer among blood donors. J Natl Cancer Inst 2008, 100(8):572-579.
Zacharski L.R., Chow B.K., Howes P.S., et al. Decreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trial. J Natl Cancer Inst 2008, 100(14):996-1002.
Kato J., Miyanishi K., Kobune M., et al. Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C. J Gastroenterol 2007, 42(10):830-836.
Barrett J.C. Mechanisms of multistep carcinogenesis and carcinogen risk assessment. Environ Health Perspect 1993, 100:9-20.
HADDOW A., HORNING E.S. On the carcinogenicity of an iron-dextran complex. J Natl Cancer Inst 1960, 24:109-147.
Richmond H.G. Induction of sarcoma in the rat by iron-dextran complex. Br Med J 1959, 1(5127):947-949.
Baker S.B., Golberg L., Martin L.E., Smith J.P. Tissue changes following injection of iron-dextran complex. J Path Bact 1961, 82:453-470.
Carter R.L., Percival W.H., ROE F.J. The effects of iron-dextran on squirrel monkeys (Saimiri sciurea). Br J Cancer 1968, 22(1):116-121.
Haddow A., Roe F.J., Mitchley B.C. Induction of Sarcomata in rabbits by intramuscular injection of iron-dextran (IMFERON). Br Med J 1964, 1(5398):1593-1594.
Roe F.J., Haddow A., Dukes C.E., Mitchley B.C. Iron-dextran carcinogenesis in rats: effect of distributing injected material between one, two, four, or six sites. Br J Cancer 1964, 18:801-808.
Steensma D.P., Sloan J.A., Dakhil S.R., et al. Phase III, randomized study of the effects of parenteral iron, oral iron, or no iron supplementation on the erythropoietic response to darbepoetin alfa for patients with chemotherapy-associated anemia. J Clin Oncol 2011, 29(1):97-105.
Ebina Y., Okada S., Hamazaki S., Ogino F., Li J.L., Midorikawa O. Nephrotoxicity and renal cell carcinoma after use of iron- and aluminum-nitrilotriacetate complexes in rats. J Natl Cancer Inst 1986, 76(1):107-113.
Li J.L., Okada S., Hamazaki S., Ebina Y., Midorikawa O. Subacute nephrotoxicity and induction of renal cell carcinoma in mice treated with ferric nitrilotriacetate. Cancer Res 1987, 47(7):1867-1869.
Crichton R., Danielson B.G., Geisser P. Iron therapy with special emphasis on intravenous administration 2008, Uni-Med, Bremen. 4th ed.
Mizote A., Hida A.I., Hosako M., Fujisawa M., Kamekawa M., Okada S. Effects of phlebotomy on the growth of ferric nitrilotriacetate-induced renal cell carcinoma. Acta Med Okayama 2002, 56(4):199-204.
Goyer R.A., Falk H.L., Hogan M., Feldman D.D., Richter W. Renal tumors in rats given trisodium nitrilotriacetic acid in drinking water for 2 years. J Natl Cancer Inst 1981, 66(5):869-880.
Jiang L., Zhong Y., Akatsuka S., et al. Deletion and single nucleotide substitution at G:C in the kidney of gpt delta transgenic mice after ferric nitrilotriacetate treatment. Cancer Sci 2006, 97(11):1159-1167.
Hiasa Y., Kitahori Y., Konishi N., Shimoyama T. Dose-related effect of trisodium nitrilotriacetate monohydrate on renal tumorigenesis initiated with N-ethyl-N-hydroxyethylnitrosamine in rats. Carcinogenesis 1985, 6(6):907-910.
Smith A.G., Cabral J.R., Carthew P., Francis J.E., Manson M.M. Carcinogenicity of iron in conjunction with a chlorinated environmental chemical, hexachlorobenzene, in C57BL/10ScSn mice. Int J Cancer 1989, 43(3):492-496.
Smith A.G., Francis J.E. Genetic variation of iron-induced uroporphyria in mice. Biochem J 1993, 291(Pt 1):29-35.
Smith A.G., Francis J.E., Carthew P. Iron as a synergist for hepatocellular carcinoma induced by polychlorinated biphenyls in Ah-responsive C57BL/10ScSn mice. Carcinogenesis 1990, 11(3):437-444.
Carthew P., Nolan B.M., Smith A.G., Edwards R.E. Iron promotes DEN initiated GST-P foci in rat liver. Carcinogenesis 1997, 18(3):599-603.
Rezazadeh H., Athar M. Evidence that iron-overload promotes 7,12-dimethylbenz(a)anthracene- induced skin tumorigenesis in mice. Redox Rep 1997, 3(5-6):303-309.
Rezazadeh H., Athar M. Effect of iron overload on the benzoyl peroxide-mediated tumor promotion in mouse skin. Cancer Lett 1998, 126(2):135-142.
Rezazadeh H., Nayebi A.R., Athar M. Role of iron-dextran on 7,12-dimethylbenz(a) anthracene-initiated and croton oil-promoted cutaneous tumorigenesis in normal and pregnant mice. Hum Exp Toxicol 2001, 20(9):471-476.
Bhasin G., Kauser H., Athar M. Free radical generating agents lead to the rapid progression of benign skin tumors to carcinoma in iron-overloaded mice. Arch Toxicol 2004, 78(3):139-146.
Bhasin G., Kauser H., Athar M. Low iron state is associated with reduced tumor promotion in a two-stage mouse skin carcinogenesis model. Food Chem Toxicol 2002, 40(8):1105-1111.
Rezazadeh H., Nayebi A.R., Garjani A., Sheikhulislami A., Babaei H. Evidence that iron overload plus croton oil induce skin tumours in mice. Hum Exp Toxicol 2005, 24(8):409-413.
Chen X., Yang G., Ding W.Y., Bondoc F., Curtis S.K., Yang C.S. An esophagogastroduodenal anastomosis model for esophageal adenocarcinogenesis in rats and enhancement by iron overload. Carcinogenesis 1999, 20(9):1801-1808.
Seril D.N., Liao J., Ho K.L., Warsi A., Yang C.S., Yang G.Y. Dietary iron supplementation enhances DSS-induced colitis and associated colorectal carcinoma development in mice. Dig Dis Sci 2002, 47(6):1266-1278.
Seril D.N., Liao J., Yang C.S., Yang G.Y. Systemic iron supplementation replenishes iron stores without enhancing colon carcinogenesis in murine models of ulcerative colitis: comparison with iron-enriched diet. Dig Dis Sci 2005, 50(4):696-707.
Ilsley J.N., Belinsky G.S., Guda K., et al. Dietary iron promotes azoxymethane-induced colon tumors in mice. Nutr Cancer 2004, 49(2):162-169.
Nelson R.L., Yoo S.J., Tanure J.C., Andrianopoulos G., Misumi A. The effect of iron on experimental colorectal carcinogenesis. Anticancer Res 1989, 9(6):1477-1482.
Jagadeesan V., Rao N.J., Sesikeran B. Effect of iron deficiency on DMH-induced gastrointestinal tract tumors and occurrence of hepatocyte abnormalities in Fischer rats. Nutr Cancer 1994, 22(3):285-291.
Hann H.W., Stahlhut M.W., Menduke H. Iron enhances tumor growth. Observation on spontaneous mammary tumors in mice. Cancer 1991, 68(11):2407-2410.
Spear A.T., Sherman A.R. Iron deficiency alters DMBA-induced tumor burden and natural killer cell cytotoxicity in rats. J Nutr 1992, 122(1):46-55.
Thompson H.J., Kennedy K., Witt M., Juzefyk J. Effect of dietary iron deficiency or excess on the induction of mammary carcinogenesis by 1-methyl-1-nitrosourea. Carcinogenesis 1991, 12(1):111-114.
Wyllie S., Liehr J.G. Enhancement of estrogen-induced renal tumorigenesis in hamsters by dietary iron. Carcinogenesis 1998, 19(7):1285-1290.
Liehr J.G., Jones J.S. Role of iron in estrogen-induced cancer. Curr Med Chem 2001, 8(7):839-849.
Vyhlidal C., Li X., Safe S. Estrogen regulation of transferrin gene expression in MCF-7 human breast cancer cells. J Mol Endocrinol 2002, 29(3):305-317.
Prime S.S., MacDonald D.G., Rennie J.S. The effect of iron deficiency on experimental oral carcinogenesis in the rat. Br J Cancer 1983, 47(3):413-418.
Omara F.O., Blakley B.R. Influence of low dietary iron and iron overload on urethan-induced lung tumors in mice. Can J Vet Res 1993, 57(3):209-211.
Bergeron R.J., Streiff R.R., Elliott G.T. Influence of iron on in vivo proliferation and lethality of L1210 cells. J Nutr 1985, 115(3):369-374.
Brookes M.J., Hughes S., Turner F.E., et al. Modulation of iron transport proteins in human colorectal carcinogenesis. Gut 2006, 55(10):1449-1460.
Boult J., Roberts K., Brookes M.J., et al. Overexpression of cellular iron import proteins is associated with malignant progression of esophageal adenocarcinoma. Clin Cancer Res 2008, 14(2):379-387.
Hann H.W., Stahlhut M.W., Blumberg B.S. Iron nutrition and tumor growth: decreased tumor growth in iron-deficient mice. Cancer Res 1988, 48(15):4168-4170.
Richardson D.R., Kalinowski D.S., Lau S., Jansson P.J., Lovejoy D.B. Cancer cell iron metabolism and the development of potent iron chelators as anti-tumour agents. Biochim Biophys Acta 2009, 1790(7):702-717.
Richardson A., Kovacevic Z., Richardson D.R. Iron chelation: inhibition of key signaling pathways in the induction of the epithelial mesenchymal transition in pancreatic cancer and other tumors. Crit Rev Oncog 2013, 18(5):409-434.
Kalinowski D.S., Richardson D.R. The evolution of iron chelators for the treatment of iron overload disease and cancer. Pharmacol Rev 2005, 57(4):547-583.
Yu Y., Kovacevic Z., Richardson D.R. Tuning cell cycle regulation with an iron key. Cell Cycle 2007, 6(16):1982-1994.
Buss J.L., Greene B.T., Turner J., Torti F.M., Torti S.V. Iron chelators in cancer chemotherapy. Curr Top Med Chem 2004, 4(15):1623-1635.
Hann H.W., Stahlhut M.W., Rubin R., Maddrey W.C. Antitumor effect of deferoxamine on human hepatocellular carcinoma growing in athymic nude mice. Cancer 1992, 70(8):2051-2056.
Wang F., Elliott R.L., Head J.F. Inhibitory effect of deferoxamine mesylate and low iron diet on the 13762NF rat mammary adenocarcinoma. Anticancer Res 1999, 19(1A):445-450.
Sakaida I., Hironaka K., Uchida K., Okita K. Iron chelator deferoxamine reduces preneoplastic lesions in liver induced by choline-deficient l-amino acid-defined diet in rats. Dig Dis Sci 1999, 44(3):560-569.
Selig R.A., White L., Gramacho C., Sterling-Levis K., Fraser I.W., Naidoo D. Failure of iron chelators to reduce tumor growth in human neuroblastoma xenografts. Cancer Res 1998, 58(3):473-478.
Simonart T., Boelaert J.R., Andrei G., Clercq E.D., Snoeck R. Iron withdrawal strategies fail to prevent the growth of SiHa-induced tumors in mice. Gynecol Oncol 2003, 90(1):91-95.
Simonart T., Boelaert J.R., Andrei G., et al. Desferrioxamine enhances AIDS-associated Kaposi's sarcoma tumor development in a xenograft model. Int J Cancer 2002, 100(2):140-143.
Jiang X.P., Wang F., Yang D.C., Elliott R.L., Head J.F. Induction of apoptosis by iron depletion in the human breast cancer MCF-7 cell line and the 13762NF rat mammary adenocarcinoma in vivo. Anticancer Res 2002, 22(5):2685-2692.
Yuan J., Lovejoy D.B., Richardson D.R. Novel di-2-pyridyl-derived iron chelators with marked and selective antitumor activity: in vitro and in vivo assessment. Blood 2004, 104(5):1450-1458.
Whitnall M., Howard J., Ponka P., Richardson D.R. A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc Natl Acad Sci U S A 2006, 103(40):14901-14906.
Becker E.M., Lovejoy D.B., Greer J.M., Watts R., Richardson D.R. Identification of the di-pyridyl ketone isonicotinoyl hydrazone (PKIH) analogues as potent iron chelators and anti-tumour agents. Br J Pharmacol 2003, 138(5):819-830.
Chaston T.B., Watts R.N., Yuan J., Richardson D.R. Potent antitumor activity of novel iron chelators derived from di-2-pyridylketone isonicotinoyl hydrazone involves fenton-derived free radical generation. Clin Cancer Res 2004, 10(21):7365-7374.
Roth M., Will B., Simkin G., et al. Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation. Blood 2012, 120(2):386-394.
Kohgo Y., Ikuta K., Ohtake T., Torimoto Y., Kato J. Body iron metabolism and pathophysiology of iron overload. Int J Hematol 2008, 88(1):7-15.
Kruszewski M. Labile iron pool: the main determinant of cellular response to oxidative stress. Mutat Res 2003, 531(1-2):81-92.
Park E., Glei M., Knobel Y., Pool-Zobel B.L. Blood mononucleocytes are sensitive to the DNA damaging effects of iron overload - in vitro and ex vivo results with human and rat cells. Mutat Res 2007, 619(1-2):59-67.
Knobel Y., Glei M., Osswald K., Pool-Zobel B.L. Ferric iron increases ROS formation, modulates cell growth and enhances genotoxic damage by 4-hydroxynonenal in human colon tumor cells. Toxicol In Vitro 2006, 20(6):793-800.
Knobel Y., Weise A., Glei M., Sendt W., Claussen U., Pool-Zobel B.L. Ferric iron is genotoxic in non-transformed and preneoplastic human colon cells. Food Chem Toxicol 2007, 45(5):804-811.
Klenow S., Pool-Zobel B.L., Glei M. Influence of inorganic and organic iron compounds on parameters of cell growth and survival in human colon cells. Toxicol In Vitro 2009, 23(3):400-407.
Messner D.J., Kowdley K.V. Neoplastic transformation of rat liver epithelial cells is enhanced by non-transferrin-bound iron. BMC Gastroenterol 2008, 8:2.
Jiang X.P., Elliott R.L., Head J.F. Manipulation of iron transporter genes results in the suppression of human and mouse mammary adenocarcinomas. Anticancer Res 2010, 30(3):759-765.
Pinnix Z.K., Miller L.D., Wang W., et al. Ferroportin and iron regulation in breast cancer progression and prognosis. Sci Transl Med 2010, 2(43):43ra56.
Zhang F., Wang W., Tsuji Y., Torti S.V., Torti F.M. Post-transcriptional modulation of iron homeostasis during p53-dependent growth arrest. J Biol Chem 2008, 283(49):33911-33918.
Weiss G. Iron metabolism in the anemia of chronic disease. Biochim Biophys Acta 2009, 1790(7):682-693.
Weizer-Stern O., Adamsky K., Margalit O., et al. Hepcidin, a key regulator of iron metabolism, is transcriptionally activated by p53. Br J Haematol 2007, 138(2):253-262.
Brookes M.J., Boult J., Roberts K., et al. A role for iron in Wnt signalling. Oncogene 2008, 27(7):966-975.
Radulescu S., Brookes M.J., Salgueiro P., et al. Luminal iron levels govern intestinal tumorigenesis after Apc loss in vivo. Cell Rep 2012, 2(2):270-282.
Habel M.E., Lemieux R., Jung D. Iron specific growth inhibition of Burkitt's lymphoma cells in vitro, associated with a decrease in translocated c-myc expression. J Cell Physiol 2005, 203(1):277-285.
Habel M.E., Jung D. Free radicals act as effectors in the growth inhibition and apoptosis of iron-treated Burkitt's lymphoma cells. Free Radic Res 2006, 40(8):789-797.
Ganz T. Iron in innate immunity: starve the invaders. Curr Opin Immunol 2009, 21(1):63-67.
Porto G., De S.M. Iron overload and immunity. World J Gastroenterol 2007, 13(35):4707-4715.
Kumar V., Choudhry V.P. Iron deficiency and infection. Indian J Pediatr 2010, 77(7):789-793.
Ahluwalia N., Sun J., Krause D., Mastro A., Handte G. Immune function is impaired in iron-deficient, homebound, older women. Am J Clin Nutr 2004, 79(3):516-521.
Regis G., Bosticardo M., Conti L., et al. Iron regulates T-lymphocyte sensitivity to the IFN-gamma/STAT1 signaling pathway in vitro and in vivo. Blood 2005, 105(8):3214-3221.
Weiss G., Iron immunity: a double-edged sword. Eur J Clin Invest 2002, 32(Suppl 1):70-78.
Oexle H., Kaser A., Most J., et al. Pathways for the regulation of interferon-gamma-inducible genes by iron in human monocytic cells. J Leukoc Biol 2003, 74(2):287-294.
Konig C., Kleber M., Ihorst G., et al. Prevalence of iron overload vs iron deficiency in multiple myeloma: resembling or different from MDS-and stem cell transplant (SCT)-patientsα. Clin Lymphoma Myeloma Leuk 2013, [Epub ahead of print]. 10.1016/j.clml.2013.06.001.
Edgren G., Nyren O., Melbye M. Cancer as a ferrotoxic disease: are we getting hard stainless evidenceα. J Natl Cancer Inst 2008, 100(14):976-977.
Beshara S., Sorensen J., Lubberink M., et al. Pharmacokinetics and red cell utilization of 52Fe/59Fe-labelled iron polymaltose in anaemic patients using positron emission tomography. Br J Haematol 2003, 120(5):853-859.
Danielson B.G. Structure, chemistry, and pharmacokinetics of intravenous iron agents. J Am Soc Nephrol 2004, 15(Suppl 2):S93-S98.
Van Wyck D.B. Labile iron: manifestations and clinical implications. J Am Soc Nephrol 2004, 15(Suppl 2):S107-S111.
Toblli J.E., Cao G., Olivieri L., Angerosa M. Comparison of the renal, cardiovascular and hepatic toxicity data of original intravenous iron compounds. Nephrol Dial Transplant 2010, 25(11):3631-3640.
Funk F., Ryle P., Canclini C., Neiser S., Geisser P. The new generation of intravenous iron: chemistry, pharmacology, and toxicology of ferric carboxymaltose. Arzneimittelforschung 2010, 60(6a):345-353.
Geisser P., Baer M., Schaub E. Structure/histotoxicity relationship of parenteral iron preparations. Arzneimittelforschung 1992, 42(12):1439-1452.
Geisser P. The pharmacology and safety profile of ferric carboxymaltose (Ferinject®): structure/reactivity relationships of iron preparations. Port J Nephrol Hypert 2009, 23(1):11-16.
Toblli J.E., Cao G., Oliveri L., Angerosa M. Differences between the original iron sucrose complex Venofer® and the iron sucrose similar Generis®, and potential implications. Port J Nephrol Hypert 2009, 23(1):53-63.
Edgren G., Bagnardi V., Bellocco R., et al. Pattern of declining hemoglobin concentration before cancer diagnosis. Int J Cancer 2010, 127(6):1429-1436.
Okada S., Hamazaki S., Toyokuni S., Midorikawa O. Induction of mesothelioma by intraperitoneal injections of ferric saccharate in male Wistar rats. Br J Cancer 1989, 60(5):708-711.
Hu Q., Akatsuka S., Yamashita Y., et al. Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma. Lab Invest 2010, 90(3):360-373.
Kato J., Kobune M., Kohgo Y., et al. Hepatic iron deprivation prevents spontaneous development of fulminant hepatitis and liver cancer in Long-Evans Cinnamon rats. J Clin Invest 1996, 98(4):923-929.
Bhasin G., Kausar H., Sarwar A.M., Athar M. Progressive iron overload enhances chemically mediated tumor promotion in murine skin. Arch Biochem Biophys 2003, 409(2):262-273.