Abstract
Cancer is the uncontrolled division and accumulation of cells in any part of the body. Surgery, radiotherapy, and systemic therapies are the main treatment strategies against cancers. However, systemic chemotherapy has various side effects, including nausea, vomiting, myelosuppression, cardiotoxicity (with anthracyclines), neurotoxicity (with mitotic spindle poisons), and nephrotoxicity (with platinum analogs). Although surgery can be curative in some cases, the main purposes of cancer treatments, especially in metastatic cancer patients, are the palliation of symptoms and increasing survival with better quality of life. Increasing the efficacy and decreasing the toxicity of chemotherapeutic agents are currently the main challenges in cancer treatment, for which substantial effort has been given for years. Melatonin is a hormone produced in the pineal gland from the essential amino acid tryptophan. It is one of the strongest antioxidants identified, with additional chemopreventive, oncostatic, and tumor inhibitory effects in a variety of in vitro and in vivo experimental cancer models. In addition to melatonin synthesis, tryptophan is involved in numerous metabolic activities in the human body, including the biosynthesis of serotonin, kynurenine, and nicotinamide, thereby regulating circadian rhythm, learning, memory, sleep, behavior, mood, appetite, aging, growth, reproduction, immune system, and cancer development. Therefore, tryptophan-related metabolic pathways and catabolites have gained considerable attention, especially in improving cancer treatment and predicting disease activity as well as patient survival. This chapter mainly focuses on the relationship between tryptophan metabolism and chemotherapy; the prognostic value of tryptophan catabolites as cancer biomarkers, tryptophan metabolism, and cancer-related fatigue; the association between melatonin and cancer therapy as well as chemotherapy side effects; and the significance of chronochemotherapy after an initial brief introduction about chemotherapeutic agents.
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References
Aldeghi R, Lissoni P, Barni S, Ardizzoia A, Tancini G, Piperno A et al (1994) Low-dose interleukin-2 subcutaneous immunotherapy in association with the pineal hormone melatonin as a first-line therapy in locally advanced or metastatic hepatocellular carcinoma. Eur J Cancer 30A(2):167–170. PubMed PMID: 8155391
Arendt J (2000) Melatonin, circadian rhythms, and sleep. N Engl J Med 343(15):1114–1116. PubMed PMID: 11027748
Baban B, Chandler PR, Sharma MD, Pihkala J, Koni PA, Munn DH et al (2009) IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol 183(4):2475–2483. PubMed PMID: 19635913. Pubmed Central PMCID: 3677163
Bardin AJ, Amon A (2001) Men and sin: what’s the difference? Nat Rev Mol Cell Biol 2(11):815–826. PubMed PMID: 11715048
Barni S, Lissoni P, Paolorossi F, Crispino S, Archili C, Tancini G (1990) A study of the pineal hormone melatonin as a second line therapy in metastatic colorectal cancer resistant to fluorouracil plus folates. Tumori 76(1):58–60. PubMed PMID: 2321275
Barni S, Lissoni P, Cazzaniga M, Ardizzoia A, Paolorossi F, Brivio F et al (1992) Neuroimmunotherapy with subcutaneous low-dose interleukin-2 and the pineal hormone melatonin as a second-line treatment in metastatic colorectal carcinoma. Tumori 78(6):383–387. PubMed PMID: 1297233
Barni S, Lissoni P, Cazzaniga M, Ardizzoia A, Meregalli S, Fossati V et al (1995) A randomized study of low-dose subcutaneous interleukin-2 plus melatonin versus supportive care alone in metastatic colorectal cancer patients progressing under 5-fluorouracil and folates. Oncology 52(3):243–245. PubMed PMID: 7715908
Barsevick A, Frost M, Zwinderman A, Hall P, Halyard M, Consortium G (2010) I’m so tired: biological and genetic mechanisms of cancer-related fatigue. Qual Life Res 19(10):1419–1427. PubMed PMID: 20953908. Pubmed Central PMCID: 3031957
Berthon C, Fontenay M, Corm S, Briche I, Allorge D, Hennart B et al (2013) Metabolites of tryptophan catabolism are elevated in sera of patients with myelodysplastic syndromes and inhibit hematopoietic progenitor amplification. Leuk Res 37(5):573–579. PubMed PMID: 23453284
Bharadwaj R, Yu H (2004) The spindle checkpoint, aneuploidy, and cancer. Oncogene 23(11):2016–2027. PubMed PMID: 15021889
Block KI, Koch AC, Mead MN, Tothy PK, Newman RA, Gyllenhaal C (2008) Impact of antioxidant supplementation on chemotherapeutic toxicity: a systematic review of the evidence from randomized controlled trials. Int J Cancer 123(6):1227–1239. PubMed PMID: 18623084
Boasso A, Herbeuval JP, Hardy AW, Anderson SA, Dolan MJ, Fuchs D et al (2007) HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells. Blood 109(8):3351–3359. PubMed PMID: 17158233. Pubmed Central PMCID: 1852248
Bonanno G, Mariotti A, Procoli A, Folgiero V, Natale D, De Rosa L et al (2012) Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma. J Transl Med 10:247. PubMed PMID: 23232072. Pubmed Central PMCID: 3543251
Brackowski R, Zubelewicz B, Romanowski W, Lissoni P, Barni S, Tancini G et al (1994) Preliminary study on modulation of the biological effects of tumor necrosis factor-alpha in advanced cancer patients by the pineal hormone melatonin. J Biol Regul Homeost Agents 8(3):77–80. PubMed PMID: 7754792
Braczkowski R, Zubelewicz B, Romanowski W, Lissoni P, Barni S (1995) Modulation of tumor necrosis factor-alpha (TNF-alpha) toxicity by the pineal hormone melatonin (MLT) in metastatic solid tumor patients. Ann N Y Acad Sci 768:334–336. PubMed PMID: 8526381
Bregani ER, Lissoni P, Rossini F, Barni S, Tancini G, Brivio F et al (1995) Prevention of interleukin-2-induced thrombocytopenia during the immunotherapy of cancer by a concomitant administration of the pineal hormone melatonin. Recenti Prog Med 86(6):231–233. PubMed PMID: 7624582
Brivio F, Lissoni P, Fumagalli L, Brivio O, Lavorato F, Rescaldani R et al (1995) Preoperative neuroimmunotherapy with subcutaneons low-dose interleukin-2 and melatonin in patients with gastrointestinal tumors – its efficacy in preventing surgery-induced lymphocytopenia. Oncol Rep 2(4):597–599. PubMed PMID: 21597783
Brzezinski A (1997) Melatonin in humans. N Engl J Med 336(3):186–195. PubMed PMID: 8988899
Carlberg C (2000) Gene regulation by melatonin. Ann N Y Acad Sci 917:387–396. PubMed PMID: 11268365
Casciato DA (2009) Cancer chemotherapeutic agents. In: Casciato DA, Territo MC (eds) Manual of clinical oncology, 6th edn. Wolters Kluwer Health/Lippincott Williams & Wilkins, Philadelphia, pp 46–99
Catena-Dell’Osso M, Rotella F, Dell’Osso A, Fagiolini A, Marazziti D (2013) Inflammation, serotonin and major depression. Curr Drug Targets 14(5):571–577. PubMed PMID: 23531160
Cerea G, Vaghi M, Ardizzoia A, Villa S, Bucovec R, Mengo S et al (2003) Biomodulation of cancer chemotherapy for metastatic colorectal cancer: a randomized study of weekly low-dose irinotecan alone versus irinotecan plus the oncostatic pineal hormone melatonin in metastatic colorectal cancer patients progressing on 5-fluorouracil-containing combinations. Anticancer Res 23(2C):1951–1954. PubMed PMID: 12820485
Chang HM, Ling EA, Chen CF, Lue H, Wen CY, Shieh JY (2002) Melatonin attenuates the neuronal NADPH-d/NOS expression in the nodose ganglion of acute hypoxic rats. J Pineal Res 32(2):65–73. PubMed PMID: 12071470
Chava VK, Sirisha K (2012) Melatonin: a novel indolamine in oral health and disease. Int J Dent 2012:720185. PubMed PMID: 22899929. Pubmed Central PMCID: 3415143
Chen D, Cheng J, Yang K, Ma Y, Yang F (2013) Retrospective analysis of chronomodulated chemotherapy versus conventional chemotherapy with paclitaxel, carboplatin, and 5-fluorouracil in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. OncoTargets Ther 6:1507–1514. PubMed PMID: 24187501. Pubmed Central PMCID: 3810446
Chuang SC, Fanidi A, Ueland PM, Relton C, Midttun O, Vollset SE et al (2014) Circulating biomarkers of tryptophan and the kynurenine pathway and lung cancer risk. Cancer Epidemiol Biomarkers Prev. 23(3):461–468. PubMed PMID: 24357106
Claustrat B, Brun J, Chazot G (2005) The basic physiology and pathophysiology of melatonin. Sleep Med Rev 9(1):11–24. PubMed PMID: 15649735
Creelan BC, Antonia S, Bepler G, Garrett TJ, Simon GR, Soliman HH (2013) Indoleamine 2,3-dioxygenase activity and clinical outcome following induction chemotherapy and concurrent chemoradiation in Stage III non-small cell lung cancer. Oncoimmunology 2(3):e23428. PubMed PMID: 23802083. Pubmed Central PMCID: 3661168
Curti A, Aluigi M, Pandolfi S, Ferri E, Isidori A, Salvestrini V et al (2007a) Acute myeloid leukemia cells constitutively express the immunoregulatory enzyme indoleamine 2,3-dioxygenase. Leukemia 21(2):353–355. PubMed PMID: 17170728
Curti A, Pandolfi S, Valzasina B, Aluigi M, Isidori A, Ferri E et al (2007b) Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25+ T regulatory cells. Blood 109(7):2871–2877. PubMed PMID: 17164341
Cutando A, Gomez-Moreno G, Arana C, Acuna-Castroviejo D, Reiter RJ (2007) Melatonin: potential functions in the oral cavity. J Periodontol 78(6):1094–1102. PubMed PMID: 17539724
Cutando A, Aneiros-Fernandez J, Aneiros-Cachaza J, Arias-Santiago S (2011) Melatonin and cancer: current knowledge and its application to oral cavity tumours. J Oral Pathol Med 40(8):593–597. PubMed PMID: 21284745
Czesnikiewicz-Guzik M, Konturek SJ, Loster B, Wisniewska G, Majewski S (2007) Melatonin and its role in oxidative stress related diseases of oral cavity. J Physiol Pharmacol 58(Suppl 3):5–19. PubMed PMID: 17901579
de Jong WH, Smit R, Bakker SJ, de Vries EG, Kema IP (2009) Plasma tryptophan, kynurenine and 3-hydroxykynurenine measurement using automated on-line solid-phase extraction HPLC-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 877(7):603–609. PubMed PMID: 19196554
de Jong RA, Nijman HW, Boezen HM, Volmer M, Ten Hoor KA, Krijnen J et al (2011) Serum tryptophan and kynurenine concentrations as parameters for indoleamine 2,3-dioxygenase activity in patients with endometrial, ovarian, and vulvar cancer. Int J Gynecol Cancer 21(7):1320–1327. PubMed PMID: 21720257
Diaz-Moralli S, Tarrado-Castellarnau M, Miranda A, Cascante M (2013) Targeting cell cycle regulation in cancer therapy. Pharmacol Ther 138(2):255–271. PubMed PMID: 23356980
Divanovic S, Sawtell NM, Trompette A, Warning JI, Dias A, Cooper AM et al (2012) Opposing biological functions of tryptophan catabolizing enzymes during intracellular infection. J Infect Dis 205(1):152–161. PubMed PMID: 21990421. Pubmed Central PMCID: 3242739
Dolusic E, Larrieu P, Moineaux L, Stroobant V, Pilotte L, Colau D et al (2011) Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators. J Med Chem 54(15):5320–5334. PubMed PMID: 21726069
El Kholy NM, Sallam MM, Ahmed MB, Sallam RM, Asfour IA, Hammouda JA et al (2011) Expression of indoleamine 2,3-dioxygenase in acute myeloid leukemia and the effect of its inhibition on cultured leukemia blast cells. Med Oncol 28(1):270–278. PubMed PMID: 20300979
Focan C, Denis B, Kreutz F, Focan-Henrard D, Levi F (1995) Ambulatory chronotherapy with 5-fluorouracil, folinic acid, and carboplatin for advanced non-small cell lung cancer. A phase II feasibility trial. J Infus Chemother 5(3 Suppl 1):148–152. PubMed PMID: 8528976
Freter CE, Perry MC (2008) Systemic therapy. In: Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, Mc Kenna WG (eds) Abeloff’s clinical oncology, 4th edn. Churchill Livingstone/Elsevier, Philadelphia, PA, USA, pp 449–484
Fung SP, Wang H, Tomek P, Squire CJ, Flanagan JU, Palmer BD et al (2013) Discovery and characterisation of hydrazines as inhibitors of the immune suppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1). Bioorg Med Chem 21(24):7595–7603. PubMed PMID: 24262887
Garner E, Raj K (2008) Protective mechanisms of p53-p21-pRb proteins against DNA damage-induced cell death. Cell Cycle 7(3):277–282. PubMed PMID: 18235223
Ghielmini M, Pagani O, de Jong J, Pampallona S, Conti A, Maestroni G et al (1999) Double-blind randomized study on the myeloprotective effect of melatonin in combination with carboplatin and etoposide in advanced lung cancer. Br J Cancer 80(7):1058–1061. PubMed PMID: 10362116. Pubmed Central PMCID: 2363039
Gonzalez R, Sanchez A, Ferguson JA, Balmer C, Daniel C, Cohn A et al (1991) Melatonin therapy of advanced human malignant melanoma. Melanoma Res 1(4):237–243. PubMed PMID: 1823632
Greenlee H, Hershman DL, Jacobson JS (2009) Use of antioxidant supplements during breast cancer treatment: a comprehensive review. Breast Cancer Res Treat 115(3):437–452. PubMed PMID: 18839308
Gu T, Rowswell-Turner RB, Kilinc MO, Egilmez NK (2010) Central role of IFNgamma-indoleamine 2,3-dioxygenase axis in regulation of interleukin-12-mediated antitumor immunity. Cancer Res 70(1):129–138. PubMed PMID: 20028855. Pubmed Central PMCID: 2805056
Haccard O, Jessus C (2006) Oocyte maturation, Mos and cyclins – a matter of synthesis: two functionally redundant ways to induce meiotic maturation. Cell Cycle 5(11):1152–1159. PubMed PMID: 16760654
Haynes NM, van der Most RG, Lake RA, Smyth MJ (2008) Immunogenic anti-cancer chemotherapy as an emerging concept. Curr Opin Immunol 20(5):545–557. PubMed PMID: 18573339
Hill SM, Frasch T, Xiang S, Yuan L, Duplessis T, Mao L (2009) Molecular mechanisms of melatonin anticancer effects. Integr Cancer Ther 8(4):337–346. PubMed PMID: 20050373
Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M et al (2007) Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res 67(2):792–801. PubMed PMID: 17234791
Hu S, Shen G, Yin S, Xu W, Hu B (2009) Melatonin and tryptophan circadian profiles in patients with advanced non-small cell lung cancer. Adv Ther 26(9):886–892. PubMed PMID: 19802530
Huang XL, Fu CJ, Bu RF (2011) Role of circadian clocks in the development and therapeutics of cancer. J Int Med Res 39(6):2061–2066. PubMed PMID: 22289520
Inaba T, Ino K, Kajiyama H, Yamamoto E, Shibata K, Nawa A et al (2009) Role of the immunosuppressive enzyme indoleamine 2,3-dioxygenase in the progression of ovarian carcinoma. Gynecol Oncol 115(2):185–192. PubMed PMID: 19665763
Inaba T, Ino K, Kajiyama H, Shibata K, Yamamoto E, Kondo S et al (2010) Indoleamine 2,3-dioxygenase expression predicts impaired survival of invasive cervical cancer patients treated with radical hysterectomy. Gynecol Oncol 117(3):423–428. PubMed PMID: 20350764
Ino K (2011) Indoleamine 2,3-dioxygenase and immune tolerance in ovarian cancer. Curr Opin Obstet Gynecol 23(1):13–18. PubMed PMID: 20930628
Ino K, Yamamoto E, Shibata K, Kajiyama H, Yoshida N, Terauchi M et al (2008) Inverse correlation between tumoral indoleamine 2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: its association with disease progression and survival. Clin Cancer Res 14(8):2310–2317. PubMed PMID: 18413819
Italian Study Group for the Di Bella Multitherapy Trials (1999) Evaluation of an unconventional cancer treatment (the Di Bella multitherapy): results of phase II trials in Italy. Italian Study Group for the Di Bella Multitherapy Trails. BMJ 318(7178):224–228. PubMed PMID: 9915729. Pubmed Central PMCID: 27702
Ito H, Hoshi M, Ohtaki H, Taguchi A, Ando K, Ishikawa T et al (2010) Ability of IDO to attenuate liver injury in alpha-galactosylceramide-induced hepatitis model. J Immunol 185(8):4554–4560. PubMed PMID: 20844202
Jackman KA, Brait VH, Wang Y, Maghzal GJ, Ball HJ, McKenzie G et al (2011) Vascular expression, activity and function of indoleamine 2,3-dioxygenase-1 following cerebral ischaemia-reperfusion in mice. Naunyn Schmiedebergs Arch Pharmacol 383(5):471–481. PubMed PMID: 21359968
Jia L, Schweikart K, Tomaszewski J, Page JG, Noker PE, Buhrow SA et al (2008) Toxicology and pharmacokinetics of 1-methyl-d-tryptophan: absence of toxicity due to saturating absorption. Food Chem Toxicol 46(1):203–211. PubMed PMID: 17868966. Pubmed Central PMCID: 2744343
Johnson TS, Munn DH (2012) Host indoleamine 2,3-dioxygenase: contribution to systemic acquired tumor tolerance. Immunol Invest 41(6–7):765–797. PubMed PMID: 23017145
Jung B, Ahmad N (2006) Melatonin in cancer management: progress and promise. Cancer Res 66(20):9789–9793. PubMed PMID: 17047036
Kelleher FC, Rao A, Maguire A (2014) Circadian molecular clocks and cancer. Cancer Lett 342(1):9–18. PubMed PMID: 24099911
Kim HP, Kim TY, Lee MS, Jong HS, Kim TY, Lee JW et al (2005) TGF-beta1-mediated activations of c-Src and Rac1 modulate levels of cyclins and p27(Kip1) CDK inhibitor in hepatoma cells replated on fibronectin. Biochim Biophys Acta 1743(1–2):151–161. PubMed PMID: 15777850
Koblish HK, Hansbury MJ, Bowman KJ, Yang G, Neilan CL, Haley PJ et al (2010) Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors. Mol Cancer Ther 9(2):489–498. PubMed PMID: 20124451
Kumar V, Fausto N (2005) Chapter 7: Neoplasia. In: Kumar V, Abbas AK, Fausto N, Robbins SL, Cotran RS (eds) Robbins and Cotran pathologic basis of disease, 7th edn. Elsevier Saunders, Michigan, pp 269–342
Kwidzinski E, Bunse J, Aktas O, Richter D, Mutlu L, Zipp F et al (2005) Indolamine 2,3-dioxygenase is expressed in the CNS and down-regulates autoimmune inflammation. FASEB J 19(10):1347–1349. PubMed PMID: 15939737
Lee CO (2006) Complementary and alternative medicines patients are talking about: melatonin. Clin J Oncol Nurs 10(1):105–107. PubMed PMID: 16482735
Levi F (1997) Chronopharmacology of anticancer agents. In: Andreotti F, Redfern PH, Lemmer B (eds) Physiology and pharmacology of biological rhythms, vol 125, Handbook of experimental pharmacology. Springer, Berlin, pp 299–331
Levi F, Benavides M, Chevelle C, Le Saunier F, Bailleul F, Misset JL et al (1990) Chemotherapy of advanced ovarian cancer with 4′-O-tetrahydropyranyl doxorubicin and cisplatin: a randomized phase II trial with an evaluation of circadian timing and dose-intensity. J Clin Oncol 8(4):705–714. PubMed PMID: 2179481
Levi F, Zidani R, Misset JL (1997) Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. Int Organ Cancer Chronother Lancet 350(9079):681–686. PubMed PMID: 9291901
Levi F, Focan C, Karaboue A, de la Valette V, Focan-Henrard D, Baron B et al (2007) Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Adv Drug Deliv Rev 59(9–10):1015–1035. PubMed PMID: 17692427
Levi F, Okyar A, Dulong S, Innominato PF, Clairambault J (2010) Circadian timing in cancer treatments. Annu Rev Pharmacol Toxicol 50:377–421. PubMed PMID: 20055686
Li Y, Xu J, Zou H, Wang C (2010) 1-MT enhances potency of tumor cell lysate-pulsed dendritic cells against pancreatic adenocarcinoma by downregulating the percentage of Tregs. J Huazhong Univ Sci Technol Med Sci = Hua zhong ke ji da xue xue bao Yi xue Ying De wen ban = Huazhong keji daxue xuebao Yixue Yingdewen ban 30(3):344–348
Liao C, Li J, Bin Q, Cao Y, Gao F (2010) Chronomodulated chemotherapy versus conventional chemotherapy for advanced colorectal cancer: a meta-analysis of five randomized controlled trials. Int J Colorectal Dis 25(3):343–350. PubMed PMID: 19936767
Lim S, Kaldis P (2013) Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development 140(15):3079–3093. PubMed PMID: 23861057
Lissoni P (2002) Is there a role for melatonin in supportive care? Support Care Cancer 10(2):110–116. PubMed PMID: 11862501
Lissoni P, Viviani S, Bajetta E, Buzzoni R, Barreca A, Mauri R et al (1986) A clinical study of the pineal gland activity in oncologic patients. Cancer 57(4):837–842. PubMed PMID: 3943015
Lissoni P, Barni S, Tancini G, Crispino S, Paolorossi F, Lucini V et al (1987) Clinical study of melatonin in untreatable advanced cancer patients. Tumori 73(5):475–480. PubMed PMID: 3686681
Lissoni P, Barni S, Crispino S, Tancini G, Fraschini F (1989) Endocrine and immune effects of melatonin therapy in metastatic cancer patients. Eur J Cancer Clin Oncol 25(5):789–795. PubMed PMID: 2525469
Lissoni P, Brivio F, Barni S, Tancini G, Cattaneo G, Archili C et al (1990) Neuroimmunotherapy of human cancer with interleukin-2 and the neurohormone melatonin: its efficacy in preventing hypotension. Anticancer Res 10(6):1759–1761. PubMed PMID: 2285255
Lissoni P, Barni S, Cattaneo G, Tancini G, Esposti G, Esposti D et al (1991) Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies. Oncology 48(6):448–450. PubMed PMID: 1749579
Lissoni P, Barni S, Ardizzoia A, Paolorossi F, Crispino S, Tancini G et al (1992a) Randomized study with the pineal hormone melatonin versus supportive care alone in advanced nonsmall cell lung cancer resistant to a first-line chemotherapy containing cisplatin. Oncology 49(5):336–339. PubMed PMID: 1382256
Lissoni P, Tisi E, Barni S, Ardizzoia A, Rovelli F, Rescaldani R et al (1992b) Biological and clinical results of a neuroimmunotherapy with interleukin-2 and the pineal hormone melatonin as a first line treatment in advanced non-small cell lung cancer. Br J Cancer 66(1):155–158. PubMed PMID: 1322155. Pubmed Central PMCID: 1977913
Lissoni P, Barni S, Ardizzoia A, Olivini G, Brivio F, Tisi E et al (1993a) Cancer immunotherapy with low-dose interleukin-2 subcutaneous administration: potential efficacy in most solid tumor histotypes by a concomitant treatment with the pineal hormone melatonin. J Biol Regul Homeost Agents 7(4):121–125. PubMed PMID: 8023699
Lissoni P, Barni S, Rovelli F, Brivio F, Ardizzoia A, Tancini G et al (1993b) Neuroimmunotherapy of advanced solid neoplasms with single evening subcutaneous injection of low-dose interleukin-2 and melatonin: preliminary results. Eur J Cancer 29A(2):185–189. PubMed PMID: 8422280
Lissoni P, Brivio F, Ardizzoia A, Tancini G, Barni S (1993c) Subcutaneous therapy with low-dose interleukin-2 plus the neurohormone melatonin in metastatic gastric cancer patients with low performance status. Tumori 79(6):401–404. PubMed PMID: 8171739
Lissoni P, Barni S, Tancini G, Ardizzoia A, Rovelli F, Cazzaniga M et al (1993d) Immunotherapy with subcutaneous low-dose interleukin-2 and the pineal indole melatonin as a new effective therapy in advanced cancers of the digestive tract. Br J Cancer 67(6):1404–1407. PubMed PMID: 8512825. Pubmed Central PMCID: 1968531
Lissoni P, Meregalli S, Fossati V, Paolorossi F, Barni S, Tancini G et al (1994a) A randomized study of immunotherapy with low-dose subcutaneous interleukin-2 plus melatonin vs chemotherapy with cisplatin and etoposide as first-line therapy for advanced non-small cell lung cancer. Tumori 80(6):464–467. PubMed PMID: 7900237
Lissoni P, Barni S, Ardizzoia A, Tancini G, Conti A, Maestroni G (1994b) A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer 73(3):699–701. PubMed PMID: 8299092
Lissoni P, Barni S, Tancini G, Ardizzoia A, Ricci G, Aldeghi R et al (1994c) A randomised study with subcutaneous low-dose interleukin 2 alone vs interleukin 2 plus the pineal neurohormone melatonin in advanced solid neoplasms other than renal cancer and melanoma. Br J Cancer 69(1):196–199. PubMed PMID: 8286206. Pubmed Central PMCID: 1968792
Lissoni P, Barni S, Cazzaniga M, Ardizzoia A, Rovelli F, Brivio F et al (1994d) Efficacy of the concomitant administration of the pineal hormone melatonin in cancer immunotherapy with low-dose IL-2 in patients with advanced solid tumors who had progressed on IL-2 alone. Oncology 51(4):344–347. PubMed PMID: 8208518
Lissoni P, Barni S, Tancini G, Brivio F, Tisi E, Zubelewicz B et al (1994e) Role of the pineal gland in the control of macrophage functions and its possible implication in cancer: a study of interactions between tumor necrosis factor-alpha and the pineal hormone melatonin. J Biol Regul Homeost Agents 8(4):126–129. PubMed PMID: 7660855
Lissoni P, Barni S, Meregalli S, Fossati V, Cazzaniga M, Esposti D et al (1995a) Modulation of cancer endocrine therapy by melatonin: a phase II study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone. Br J Cancer 71(4):854–856. PubMed PMID: 7710954. Pubmed Central PMCID: 2033724
Lissoni P, Ardizzoia A, Barni S, Paolorossi F, Tancini G, Meregalli S et al (1995b) A randomized study of tamoxifen alone versus tamoxifen plus melatonin in estrogen receptor-negative heavily pretreated metastatic breast-cancer patients. Oncol Rep 2(5):871–873. PubMed PMID: 21597833
Lissoni P, Barni S, Brivio F, Rossini F, Fumagalli L, Ardizzoia A et al (1995c) A biological study on the efficacy of low-dose subcutaneous interleukin-2 plus melatonin in the treatment of cancer-related thrombocytopenia. Oncology 52(5):360–362. PubMed PMID: 7637951
Lissoni P, Barni S, Fossati V, Ardizzoia A, Cazzaniga M, Tancini G et al (1995d) A randomized study of neuroimmunotherapy with low-dose subcutaneous interleukin-2 plus melatonin compared to supportive care alone in patients with untreatable metastatic solid tumour. Support Care Cancer 3(3):194–197. PubMed PMID: 7655780
Lissoni P, Brivio F, Brivio O, Fumagalli L, Gramazio F, Rossi M et al (1995e) Immune effects of preoperative immunotherapy with high-dose subcutaneous interleukin-2 versus neuroimmunotherapy with low-dose interleukin-2 plus the neurohormone melatonin in gastrointestinal tract tumor patients. J Biol Regul Homeost Agents 9(1):31–33. PubMed PMID: 8553906
Lissoni P, Barni S, Tancini G, Mainini E, Piglia F, Maestroni GJ et al (1995f) Immunoendocrine therapy with low-dose subcutaneous interleukin-2 plus melatonin of locally advanced or metastatic endocrine tumors. Oncology 52(2):163–166. PubMed PMID: 7854778
Lissoni P, Paolorossi F, Tancini G, Ardizzoia A, Barni S, Brivio F et al (1996a) A phase II study of tamoxifen plus melatonin in metastatic solid tumour patients. Br J Cancer 74(9):1466–1468. PubMed PMID: 8912546. Pubmed Central PMCID: 2074765
Lissoni P, Meregalli S, Nosetto L, Barni S, Tancini G, Fossati V et al (1996b) Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology 53(1):43–46. PubMed PMID: 8570130
Lissoni P, Brivio O, Brivio F, Barni S, Tancini G, Crippa D et al (1996c) Adjuvant therapy with the pineal hormone melatonin in patients with lymph node relapse due to malignant melanoma. J Pineal Res 21(4):239–242. PubMed PMID: 8989723
Lissoni P, Paolorossi F, Tancini G, Barni S, Ardizzoia A, Brivio F et al (1996d) Is there a role for melatonin in the treatment of neoplastic cachexia? Eur J Cancer 32A(8):1340–1343. PubMed PMID: 8869096
Lissoni P, Paolorossi F, Ardizzoia A, Barni S, Chilelli M, Mancuso M et al (1997a) A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin as a first-line treatment of advanced non-small cell lung cancer patients in a poor clinical state. J Pineal Res 23(1):15–19. PubMed PMID: 9379341
Lissoni P, Cazzaniga M, Tancini G, Scardino E, Musci R, Barni S et al (1997b) Reversal of clinical resistance to LHRH analogue in metastatic prostate cancer by the pineal hormone melatonin: efficacy of LHRH analogue plus melatonin in patients progressing on LHRH analogue alone. Eur Urol 31(2):178–181. PubMed PMID: 9076462
Lissoni P, Barni S, Ardizzoia A, Tancini G (1997c) Immunotherapy with low-dose interleukin-2 in association with melatonin as salvage therapy for metastatic soft tissue sarcomas. Oncol Rep 4(1):157–159. PubMed PMID: 21590033
Lissoni P, Fumagalli L, Paolorossi F, Rovelli F, Roselli MG, Maestroni GJ (1997d) Anticancer neuroimmunomodulation by pineal hormones other than melatonin: preliminary phase II study of the pineal indole 5-methoxytryptophol in association with low-dose IL-2 and melatonin. J Biol Regul Homeost Agents 11(3):119–122. PubMed PMID: 9498162
Lissoni P, Tancini G, Barni S, Paolorossi F, Ardizzoia A, Conti A et al (1997e) Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin. Support Care Cancer 5(2):126–129. PubMed PMID: 9069612
Lissoni P, Giani L, Zerbini S, Trabattoni P, Rovelli F (1998) Biotherapy with the pineal immunomodulating hormone melatonin versus melatonin plus aloe vera in untreatable advanced solid neoplasms. Nat Immun 16(1):27–33. PubMed PMID: 9789122
Lissoni P, Tancini G, Paolorossi F, Mandala M, Ardizzoia A, Malugani F et al (1999a) Chemoneuroendocrine therapy of metastatic breast cancer with persistent thrombocytopenia with weekly low-dose epirubicin plus melatonin: a phase II study. J Pineal Res 26(3):169–173. PubMed PMID: 10231730
Lissoni P, Barni S, Mandala M, Ardizzoia A, Paolorossi F, Vaghi M et al (1999b) Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. Eur J Cancer 35(12):1688–1692. PubMed PMID: 10674014
Lissoni P, Bucovec R, Bonfanti A, Giani L, Mandelli A, Roselli MG et al (2001) Thrombopoietic properties of 5-methoxytryptamine plus melatonin versus melatonin alone in the treatment of cancer-related thrombocytopenia. J Pineal Res 30(2):123–126. PubMed PMID: 11270479
Lissoni P, Vaghi M, Ardizzoia A, Malugani F, Fumagalli E, Bordin V et al (2002) A phase II study of chemoneuroimmunotherapy with platinum, subcutaneous low-dose interleukin-2 and the pineal neurohormone melatonin (P.I.M.) as a second-line therapy in metastatic melanoma patients progressing on dacarbazine plus interferon-alpha. In Vivo 16(2):93–96. PubMed PMID: 12073777
Lissoni P, Chilelli M, Villa S, Cerizza L, Tancini G (2003) Five years survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial. J Pineal Res 35(1):12–15. PubMed PMID: 12823608
Liu X, Shin N, Koblish HK, Yang G, Wang Q, Wang K et al (2010) Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood 115(17):3520–3530. PubMed PMID: 20197554
Lo BK, Jalili RB, Zloty D, Ghahary A, Cowan B, Dutz JP et al (2011) CXCR3 ligands promote expression of functional indoleamine 2,3-dioxygenase in basal cell carcinoma keratinocytes. Br J Dermatol 165(5):1030–1036. PubMed PMID: 21711334
Lob S, Konigsrainer A, Zieker D, Brucher BL, Rammensee HG, Opelz G et al (2009) IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism. Cancer Immunol Immunother 58(1):153–157. PubMed PMID: 18418598
Lyon DE, Walter JM, Starkweather AR, Schubert CM, McCain NL (2011) Tryptophan degradation in women with breast cancer: a pilot study. BMC Res Notes 4:156. PubMed PMID: 21615916. Pubmed Central PMCID: 3117722
Ma Y, Kepp O, Ghiringhelli F, Apetoh L, Aymeric L, Locher C et al (2010) Chemotherapy and radiotherapy: cryptic anticancer vaccines. Semin Immunol 22(3):113–124. PubMed PMID: 20403709
Maddika S, Ande SR, Panigrahi S, Paranjothy T, Weglarczyk K, Zuse A et al (2007) Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy. Drug Resist Updat 10(1–2):13–29. PubMed PMID: 17303468
Maestroni GJ, Conti A, Lissoni P (1994) Colony-stimulating activity and hematopoietic rescue from cancer chemotherapy compounds are induced by melatonin via endogenous interleukin 4. Cancer Res 54(17):4740–4743. PubMed PMID: 7914829
Mansfield AS, Heikkila PS, Vaara AT, von Smitten KA, Vakkila JM, Leidenius MH (2009) Simultaneous Foxp3 and IDO expression is associated with sentinel lymph node metastases in breast cancer. BMC Cancer 9:231. PubMed PMID: 19604349. Pubmed Central PMCID: 2723126
Mantovani G, Maccio A, Massa E, Madeddu C (2001) Managing cancer-related anorexia/cachexia. Drugs 61(4):499–514. PubMed PMID: 11324680
Mediavilla MD, Sanchez-Barcelo EJ, Tan DX, Manchester L, Reiter RJ (2010) Basic mechanisms involved in the anti-cancer effects of melatonin. Curr Med Chem 17(36):4462–4481. PubMed PMID: 21062257
Mellor AL, Chandler P, Baban B, Hansen AM, Marshall B, Pihkala J et al (2004) Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase. Int Immunol 16(10):1391–1401. PubMed PMID: 15351783
Metz R, Duhadaway JB, Kamasani U, Laury-Kleintop L, Muller AJ, Prendergast GC (2007) Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan. Cancer Res 67(15):7082–7087. PubMed PMID: 17671174
Mills E, Wu P, Seely D, Guyatt G (2005) Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res 39(4):360–366. PubMed PMID: 16207291
Miyazaki T, Moritake K, Yamada K, Hara N, Osago H, Shibata T et al (2009) Indoleamine 2,3-dioxygenase as a new target for malignant glioma therapy. Lab Investig J Neurosurg 111(2):230–237. PubMed PMID: 19199463
Mohib K, Wang S, Guan Q, Mellor AL, Sun H, Du C et al (2008) Indoleamine 2,3-dioxygenase expression promotes renal ischemia-reperfusion injury. Am J Physiol Renal Physiol 295(1):F226–F234. PubMed PMID: 18480171. Pubmed Central PMCID: 2494522
Moretti S, Menicali E, Voce P, Morelli S, Cantarelli S, Sponziello M et al (2014) Indoleamine 2,3-dioxygenase 1 (Ido1) is upregulated in thyroid carcinoma and drives the development of an immunosuppressant tumor microenvironment. J Clin Endocrinol Metab 11:jc20133351. PubMed PMID: 24517146
Mormont MC, Levi F (1997) Circadian-system alterations during cancer processes: a review. Int J Cancer 70(2):241–247. PubMed PMID: 9009166
Muller AJ, Prendergast GC (2005) Marrying immunotherapy with chemotherapy: why say IDO? Cancer Res 65(18):8065–8068. PubMed PMID: 16166276
Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC (2005) Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med 11(3):312–319. PubMed PMID: 15711557
Muller AJ, Sharma MD, Chandler PR, Duhadaway JB, Everhart ME, Johnson BA 3rd et al (2008) Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase. Proc Natl Acad Sci U S A 105(44):17073–17078. PubMed PMID: 18952840. Pubmed Central PMCID: 2579380
Muller AJ, DuHadaway JB, Jaller D, Curtis P, Metz R, Prendergast GC (2010) Immunotherapeutic suppression of indoleamine 2,3-dioxygenase and tumor growth with ethyl pyruvate. Cancer Res 70(5):1845–1853. PubMed PMID: 20160032. Pubmed Central PMCID: 3176890
Munn DH, Sharma MD, Hou D, Baban B, Lee JR, Antonia SJ et al (2004) Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest 114(2):280–290. PubMed PMID: 15254595. Pubmed Central PMCID: 449750
Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D et al (2005) GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22(5):633–642. PubMed PMID: 15894280
Nahleh Z, Pruemer J, Lafollette J, Sweany S (2010) Melatonin, a promising role in taxane-related neuropathy. Clin Med Insights Oncol 4:35–41. PubMed PMID: 20567633. Pubmed Central PMCID: 2883241
Nakano S, Takai K, Isaka Y, Takahashi S, Unno Y, Ogo N et al (2012) Identification of novel kynurenine production-inhibiting benzenesulfonamide derivatives in cancer cells. Biochem Biophys Res Commun 419(3):556–561. PubMed PMID: 22369947
Neri B, Fiorelli C, Moroni F, Nicita G, Paoletti MC, Ponchietti R et al (1994) Modulation of human lymphoblastoid interferon activity by melatonin in metastatic renal cell carcinoma. A phase II study. Cancer 73(12):3015–3019. PubMed PMID: 8199998
Ninomiya S, Hara T, Tsurumi H, Hoshi M, Kanemura N, Goto N et al (2011) Indoleamine 2,3-dioxygenase in tumor tissue indicates prognosis in patients with diffuse large B-cell lymphoma treated with R-CHOP. Ann Hematol 90(4):409–416. PubMed PMID: 20938662
Ogawa K, Hara T, Shimizu M, Ninomiya S, Nagano J, Sakai H et al (2012) Suppression of azoxymethane-induced colonic preneoplastic lesions in rats by 1-methyltryptophan, an inhibitor of indoleamine 2,3-dioxygenase. Cancer Sci 103(5):951–958. PubMed PMID: 22320717
Okamoto A, Nikaido T, Ochiai K, Takakura S, Saito M, Aoki Y et al (2005) Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin Cancer Res 11(16):6030–6039. PubMed PMID: 16115948
Okamoto T, Tone S, Kanouchi H, Miyawaki C, Ono S, Minatogawa Y (2007) Transcriptional regulation of indoleamine 2,3-dioxygenase (IDO) by tryptophan and its analogue: down-regulation of the indoleamine 2,3-dioxygenase (IDO) transcription by tryptophan and its analogue. Cytotechnology 54(2):107–113. PubMed PMID: 19003025. Pubmed Central PMCID: 2267499
Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S et al (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478(7368):197–203. PubMed PMID: 21976023
Ozenne P, Eymin B, Brambilla E, Gazzeri S (2010) The ARF tumor suppressor: structure, functions and status in cancer. Int J Cancer 127(10):2239–2247. PubMed PMID: 20549699
Pilotte L, Larrieu P, Stroobant V, Colau D, Dolusic E, Frederick R et al (2012) Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc Natl Acad Sci U S A 109(7):2497–2502. PubMed PMID: 22308364. Pubmed Central PMCID: 3289319
Platten M, Wick W, Van den Eynde BJ (2012) Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res 72(21):5435–5440. PubMed PMID: 23090118
Potula R, Poluektova L, Knipe B, Chrastil J, Heilman D, Dou H et al (2005) Inhibition of indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in an animal model of HIV-1 encephalitis. Blood 106(7):2382–2390. PubMed PMID: 15961516. Pubmed Central PMCID: 1895260
Prendergast GC, Chang MY, Mandik-Nayak L, Metz R, Muller AJ (2011) Indoleamine 2,3-dioxygenase as a modifier of pathogenic inflammation in cancer and other inflammation-associated diseases. Curr Med Chem 18(15):2257–2262. PubMed PMID: 21517753
Qian F, Villella J, Wallace PK, Mhawech-Fauceglia P, Tario JD Jr, Andrews C et al (2009) Efficacy of levo-1-methyl tryptophan and dextro-1-methyl tryptophan in reversing indoleamine-2,3-dioxygenase-mediated arrest of T-cell proliferation in human epithelial ovarian cancer. Cancer Res 69(13):5498–5504. PubMed PMID: 19491279
Qian F, Liao J, Villella J, Edwards R, Kalinski P, Lele S et al (2012) Effects of 1-methyltryptophan stereoisomers on IDO2 enzyme activity and IDO2-mediated arrest of human T cell proliferation. Cancer Immunol Immunother 61(11):2013–2020. PubMed PMID: 22527253
Ravishankar B, Liu H, Shinde R, Chandler P, Baban B, Tanaka M et al (2012) Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase. Proc Natl Acad Sci U S A 109(10):3909–3914. PubMed PMID: 22355111. Pubmed Central PMCID: 3309765
Regelson W, Pierpaoli W (1987) Melatonin: a rediscovered antitumor hormone? Its relation to surface receptors; sex steroid metabolism, immunologic response, and chronobiologic factors in tumor growth and therapy. Cancer Invest 5(4):379–385. PubMed PMID: 3311315
Reiter RJ, Paredes SD, Manchester LC, Tan DX (2009) Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin. Crit Rev Biochem Mol Biol 44(4):175–200. PubMed PMID: 19635037
Rogerio F, Teixeira SA, de Rezende AC, de Sa RC, de Souza QL, De Nucci G et al (2005) Superoxide dismutase isoforms 1 and 2 in lumbar spinal cord of neonatal rats after sciatic nerve transection and melatonin treatment. Brain Res Dev Brain Res 154(2):217–225. PubMed PMID: 15707675
Ryan JL, Carroll JK, Ryan EP, Mustian KM, Fiscella K, Morrow GR (2007) Mechanisms of cancer-related fatigue. Oncologist 12(Suppl 1):22–34. PubMed PMID: 17573453
Sagan D, Kocki T, Kocki J, Szumilo J (2012) Serum kynurenic acid: possible association with invasiveness of non-small cell lung cancer. Asian Pac J Cancer Prev 13(9):4241–4244. PubMed PMID: 23167321
Sakurai K, Enomoto K, Kitajima A, Tani M, Amano S, Shiono M (2008) Indoleamine 2,3-dioxygenase expression in breast cancer patients during chemotherapy. Gan to kagaku ryoho Cancer Chemother 35(12):2265–2267. PubMed PMID: 19106591
Sakurai K, Matsuo S, Enomoto K, Tani M, Kitajima A, Amano S (2009) Indoleamine 2,3-dioxygenase activity during chemotherapy in patients with breast cancer. Gan to kagaku ryoho Cancer Chemother 36(12):1991–1993. PubMed PMID: 20037301
Sakurai K, Enomoto K, Amano S (2010) Indoleamine 2,3-dioxygenase activity during chemotherapy or hormone therapy in patients with breast cancer. Gan to kagaku ryoho Cancer Chemother 37(12):2252–2254. PubMed PMID: 21224538
Sakurai K, Fujisaki S, Nagashima S, Shibata M, Maeda T, Ueda Y et al (2011) Long-term follow-up study: indolemamine 2,3-dioxygenase activity during chemotherapy or hormone therapy in patients with breast cancer. Gan to kagaku ryoho Cancer Chemother 38(12):1930–1932. PubMed PMID: 22202242
Sakurai K, Fujisaki S, Nagashima S, Maeda T, Shibata M, Gonda K et al (2012) Indoleamine 2, 3-dioxygenase activity during chemotherapy or trastuzumab therapy in patients with breast cancer. Gan to kagaku ryoho Cancer Chemother 39(12):1791–1793. PubMed PMID: 23267888
Sanchez-Barcelo EJ, Cos S, Fernandez R, Mediavilla MD (2003) Melatonin and mammary cancer: a short review. Endocr Relat Cancer 10(2):153–159. PubMed PMID: 12790777
Sanchez-Barcelo EJ, Mediavilla MD, Alonso-Gonzalez C, Reiter RJ (2012) Melatonin uses in oncology: breast cancer prevention and reduction of the side effects of chemotherapy and radiation. Expert Opin Investig Drugs 21(6):819–831. PubMed PMID: 22500582
Saporita AJ, Maggi LB Jr, Apicelli AJ, Weber JD (2007) Therapeutic targets in the ARF tumor suppressor pathway. Curr Med Chem 14(17):1815–1827. PubMed PMID: 17627519. Pubmed Central PMCID: 2859726
Schmidt SK, Siepmann S, Kuhlmann K, Meyer HE, Metzger S, Pudelko S et al (2012) Influence of tryptophan contained in 1-Methyl-Tryptophan on antimicrobial and immunoregulatory functions of indoleamine 2,3-dioxygenase. PLoS One 7(9):e44797. PubMed PMID: 23028625. Pubmed Central PMCID: 3441469
Sclafani RA, Holzen TM (2007) Cell cycle regulation of DNA replication. Annu Rev Genet 41:237–280. PubMed PMID: 17630848. Pubmed Central PMCID: 2292467
Seely D, Wu P, Fritz H, Kennedy DA, Tsui T, Seely AJ et al (2012) Melatonin as adjuvant cancer care with and without chemotherapy: a systematic review and meta-analysis of randomized trials. Integr Cancer Ther 11(4):293–303. PubMed PMID: 22019490
Sharma MD, Hou DY, Liu Y, Koni PA, Metz R, Chandler P et al (2009) Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood 113(24):6102–6111. PubMed PMID: 19366986. Pubmed Central PMCID: 2699232
Skeel RT (2011) Biologic and pharmacologic basis of cancer chemotherapy. In: Skeel RT, Khleif SN (eds) Handbook of cancer chemotherapy. Lippincott Williams & Wilkins, Philadelphia, pp 1–15
Soliman H, Rawal B, Fulp J, Lee JH, Lopez A, Bui MM et al (2013) Analysis of indoleamine 2-3 dioxygenase (IDO1) expression in breast cancer tissue by immunohistochemistry. Cancer Immunol Immunother 62(5):829–837. PubMed PMID: 23344392
Sperka T, Wang J, Rudolph KL (2012) DNA damage checkpoints in stem cells, ageing and cancer. Nat Rev Mol Cell Biol 13(9):579–590. PubMed PMID: 22914294
Starr KW (1969) Hormonal imbalance and the sarcomata. Aust N Z J Surg 39(2):142–150. PubMed PMID: 4313733
Stone TW, Darlington LG (2002) Endogenous kynurenines as targets for drug discovery and development. Nat Rev Drug Discov 1(8):609–620. PubMed PMID: 12402501
Stone TW, Stoy N, Darlington LG (2013) An expanding range of targets for kynurenine metabolites of tryptophan. Trends Pharmacol Sci 34(2):136–143. PubMed PMID: 23123095
Sun T, Chen XH, Tang ZD, Cai J, Wang XY, Wang SC et al (2010) Novel 1-alkyl-tryptophan derivatives downregulate IDO1 and IDO2 mRNA expression induced by interferon-gamma in dendritic cells. Mol Cell Biochem 342(1–2):29–34. PubMed PMID: 20424892
Temml V, Kuehnl S, Schuster D, Schwaiger S, Stuppner H, Fuchs D (2013) Interaction of Carthamus tinctorius lignan arctigenin with the binding site of tryptophan-degrading enzyme indoleamine 2,3-dioxygenase. FEBS Open Bio 3:450–452. PubMed PMID: 24251110. Pubmed Central PMCID: 3829989
Thaker AI, Rao MS, Bishnupuri KS, Kerr TA, Foster L, Marinshaw JM et al (2013) IDO1 metabolites activate beta-catenin signaling to promote cancer cell proliferation and colon tumorigenesis in mice. Gastroenterology 145(2):416–425 e1–4. PubMed PMID: 23669411. Pubmed Central PMCID: 3722304
Todisco M, Casaccia P, Rossi N (2001) Cyclophosphamide plus somatostatin, bromocriptin, retinoids, melatonin and ACTH in the treatment of low-grade non-Hodgkin’s lymphomas at advanced stage: results of a phase II trial. Cancer Biother Radiopharm 16(2):171–177. PubMed PMID: 11385964
Topal T, Oter S, Korkmaz A, Sadir S, Metinyurt G, Korkmazhan ET et al (2004) Exogenously administered and endogenously produced melatonin reduce hyperbaric oxygen-induced oxidative stress in rat lung. Life Sci 75(4):461–467. PubMed PMID: 15147832
Tu Y, Chen C, Pan J, Xu J, Zhou ZG, Wang CY (2012) The Ubiquitin Proteasome Pathway (UPP) in the regulation of cell cycle control and DNA damage repair and its implication in tumorigenesis. Int J Clin Exp Pathol 5(8):726–738. PubMed PMID: 23071855. Pubmed Central PMCID: 3466981
Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N et al (2003) Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 9(10):1269–1274. PubMed PMID: 14502282
Vasilyeva ED, Kaledin V, Nikolin VP, Popova NA, Kirilyuk IA, Grigor’ev IA (2012) Accelerated rejection of the second transplants of immunogenic tumor in mice under inhibition of indoleamine 2,3-dioxygenase activity by ethyl pyruvate. Exp Oncol 34(1):66–68. PubMed PMID: 22453153
Viviani S, Negretti E, Orazi A, Sozzi G, Santoro A, Lissoni P et al (1990) Preliminary studies on melatonin in the treatment of myelodysplastic syndromes following cancer chemotherapy. J Pineal Res 8(4):347–354. PubMed PMID: 2395074
Wang XS (2008) Pathophysiology of cancer-related fatigue. Clin J Oncol Nurs 12(5 Suppl):11–20. PubMed PMID: 18842520. Pubmed Central PMCID: 3281752
Wang WZ, Fang XH, Stephenson LL, Baynosa RC, Khiabani KT, Zamboni WA (2005) Microcirculatory effects of melatonin in rat skeletal muscle after prolonged ischemia. J Pineal Res 39(1):57–65. PubMed PMID: 15978058
Wang YM, Jin BZ, Ai F, Duan CH, Lu YZ, Dong TF et al (2012) The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemother Pharmacol 69(5):1213–1220. PubMed PMID: 22271210
Williams KM, Hakim FT, Gress RE (2007) T cell immune reconstitution following lymphodepletion. Semin Immunol 19(5):318–330. PubMed PMID: 18023361. Pubmed Central PMCID: 2180244
Wu G (2010) Functional amino acids in growth, reproduction, and health. Adv Nutr 1(1):31–37. PubMed PMID: 22043449. Pubmed Central PMCID: 3042786
Yan JJ, Shen F, Wang K, Wu MC (2002) Patients with advanced primary hepatocellular carcinoma treated by melatonin and transcatheter arterial chemoembolization: a prospective study. Hepatobiliary Pancreat Dis Int 1(2):183–186. PubMed PMID: 14607735
Yao K, Fang J, Yin YL, Feng ZM, Tang ZR, Wu G (2011) Tryptophan metabolism in animals: important roles in nutrition and health. Front Biosci 3:286–297. PubMed PMID: 21196377
Yi YM, Zhang G, Zeng J, Huang SC, Li LL, Fang R et al (2011) A new tumor vaccine: FAPtau-MT elicits effective antitumor response by targeting indolamine2,3-dioxygenase in antigen presenting cells. Cancer Biol Ther 11(10):866–873. PubMed PMID: 21372637
Yoshida N, Ino K, Ishida Y, Kajiyama H, Yamamoto E, Shibata K et al (2008) Overexpression of indoleamine 2,3-dioxygenase in human endometrial carcinoma cells induces rapid tumor growth in a mouse xenograft model. Clin Cancer Res Off J Am Assoc Cancer Res 14(22):7251–7259. PubMed PMID: 19010841
Yoshikawa T, Hara T, Tsurumi H, Goto N, Hoshi M, Kitagawa J et al (2010) Serum concentration of L-kynurenine predicts the clinical outcome of patients with diffuse large B-cell lymphoma treated with R-CHOP. Eur J Haematol 84(4):304–309. PubMed PMID: 19995374
Yue EW, Douty B, Wayland B, Bower M, Liu X, Leffet L et al (2009) Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model. J Med Chem 52(23):7364–7367. PubMed PMID: 19507862
Zhang R, Li H, Yu J, Zhao J, Wang X, Wang G et al (2011) Immunoactivative role of indoleamine 2,3dioxygenase in gastric cancer cells in vitro. Mol Med Reports 4(1):169–173. PubMed PMID: 21461581
Zhang Y, Li L, Xiang C, Ma Z, Ma T, Zhu S (2013) Protective effect of melatonin against Adriamycin-induced cardiotoxicity. Exp Ther Med 5(5):1496–1500. PubMed PMID: 23737906. Pubmed Central PMCID: 3671825
Zhu CB, Blakely RD, Hewlett WA (2006) The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology 31(10):2121–2131. PubMed PMID: 16452991
Zhu CB, Lindler KM, Owens AW, Daws LC, Blakely RD, Hewlett WA (2010) Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters. Neuropsychopharmacology 35(13):2510–2520. PubMed PMID: 20827273. Pubmed Central PMCID: 3055584
Zitvogel L, Apetoh L, Ghiringhelli F, Andre F, Tesniere A, Kroemer G (2008a) The anticancer immune response: indispensable for therapeutic success? J Clin Invest 118(6):1991–2001. PubMed PMID: 18523649. Pubmed Central PMCID: 2396905
Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G (2008b) Immunological aspects of cancer chemotherapy. Nat Rev Immunol 8(1):59–73. PubMed PMID: 18097448
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Kesikli, S.A., Guler, N. (2015). Chemotherapeutic Agents in Cancer Treatment and Tryptophan Metabolism. In: Engin, A., Engin, A. (eds) Tryptophan Metabolism: Implications for Biological Processes, Health and Disease. Molecular and Integrative Toxicology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-15630-9_13
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