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Journal of Clinical Oncology, Vol 23, No 9 (March 20), 2005: pp. 2112 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.299
In Reply:Cleveland Clinic Taussig Cancer Center, Cleveland, OH We appreciate Drs Laviano, Meguid, and Fanelli's comments and observations. They are correct to point out the well-documented circumstantial evidence surrounding tryptophan and cancer anorexia that they and others have published. This evidence suggests that elevated plasma and CNS tryptophan levels are associated with anorexia in cancer cirrhosis, uremia, and sepsis. However, there are also several lines of evidence which conflict with this hypothesis. Tryptophan injections alone do not alter rodent food intake; neither does a combination of subcutaneous tumor necrosis factor alpha and tryptophan.1,2 The combination of interleukin 1 and tryptophan does diminish food intake in rodents. Others have demonstrated that it is stress rather than tryptophan alone which induces hypothalamic serotonin levels.3 Anorexia induced by experimental colitis in rodents does not appear to be related to tryptophan, but rather elevated hypothalamic paraventricular serotonin or reduced hypothalamic ventromedial dopamine.4,5 Counter-wise food restriction reduces hypothalamic serotonin levels but not hypothalamic tryptophan.6 It seems, at least in rodents, that anorexia is caused by signals from the anterior periformis cortex that activates the hypothalamic serotonin system, and is related to deficiencies in branched-chain amino acids in the periformis cortex rather than elevated CNS tryptophan.7,8 In particular animal cancer models (MCG 101 tumor model, for example) food intake (and body weight) does not correlate with either increased serotonin availability, reduced serotonin levels, or serotonin receptor activity.9 Capuron et al10 found that anorexia in cancer patients who were administered interleukin 2 have low rather than elevated plasma tryptophan levels. In addition, cancer patients treated with either serotonin blocker cyproheptadine or ondansetron have only minor appetite response in clinical trials. Serotonin blockers have not found clinical favor in anorexia associated with advanced cancer.11,12 In summary, there is a significant body of experimental and clinical data suggesting that serum and hypothalamic tryptophan levels do not correlate with anorexia. Hypothalamic serotonin levels and anorexia appear to be caused by stress or proinflammatory cytokines, and not tryptophan. Hypothalamic serotonin levels may be related to reduced branched-chain amino acids and altered signals from the anterior periforms cortex rather than elevated CNS tryptophan. There is conflicting evidence regarding tryptophan levels and anorexia. Finally, in humans, serotonin receptor antagonists have little effect on appetite in advanced cancer suggesting that other neurotransmitters and their receptors may be more important. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES 1. Sato T, Laviano A, Meguid MM, et al: Involvement of plasma leptin, insulin and free tryptophan in cytokine-induced anorexia. Clin Nutr 22:139-146, 2003[Medline] 2. Sato T, Lacviano A, Meguid MM, et al: Plasma leptin, insulin and free tryptophan contribute to cytokine-induced anorexia. Adv Exp Med Biol 527:233-239, 2003[Medline] 3. Haleem DJ, Jabeen B, Parveen T: Inhibition of resistant-induced anorexia by injected tryptophan. Life Sci 63:PL205-212, 1998[Medline] 4. Ballinger A, El-Haj T, Perrett D, et al: The role of medial hypothalamic serotonin in the suppression of feeding in a rat model of colitis. Gastroenterology 118:544-553, 2000[CrossRef][Medline] 5. Torelli GF, Meguid MM, Miyata G, et al: VMN hypothalamic dopamine and serotonin in anorectic septic rats. Shock 13:204-208, 2000[Medline] 6. Haleem DJ, Haider S: Food restriction decreases serotonin and its synthesis rate in the hypothalamus. Neuroreport 7:1153-1156, 1996[Medline]
7. Gietzen DW, Magrum LJ: Molecular mechanisms in the brain involved in the anorexia of branched-chain amino acid deficiency. J Nutr 131:851S-855S, 2001 (suppl) 8. Blevins JE, The PS, Wang CX, et al: Effects of amino acid deficiency on monoamines in the lateral hypothalamus (LH) in rats. Nutr Neurosci 6:291-299, 2003[Medline] 9. Wang W, Danielson A, Svanberg E, et al: Lack of effects by tricyclic antidepressant and serotonin inhibitors on anorexia in MCG 101 tumor-bearing mice with eicosanoid-related cachexia. Nutrition 19:47-53, 2003[Medline] 10. Capuron L, Ravaud A, Neveu PJ, et al: Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 7:468-473, 2002[CrossRef][Medline] 11. Kardinal CG, Loprinzi CL, Schaid DJ, et al: A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia. Cancer 65:2657-2662, 1990[CrossRef][Medline] 12. Edelman MJ, Gandara DR, Meyers FJ, et al: Serotonergic blockade in the treatment of cancer anorexia-cachexia syndrome. Cancer 86:684-688, 1999[Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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