The Early Cancer Anorexia Paradigm: Changes in Plasma Free Tryptophan and Feeding Indexes

Abstract

Tumor growth is accompanied by an anorexia mediated by humoral factors that appear to influence appetitive mechanisms in the brain. Because tumor resection is followed by resumption of normal food intake, the circulating anorexigenic substance(s) are produced either by the neoplastic tissue or by the host in response to the tumor. Increased levels of plasma free tryptophan and plasma ammonia have been proposed to mediate cancer anorexia. With animal models, it is often difficult to ascertain whether changes in food intake depend upon metabolic changes or the progressively increasing tumor mass per se. The feeding patterns and biochemical changes that occur during tumor growth were evaluated in 96 male Fischer rats that were inoculated with 10(6) methylcholanthrene sarcoma cells or saline (controls). Rats were placed into metabolic cages equipped with an Automated Computerized Rat Eater Meter to continuously determine meal size and meal number. Plasma free tryptophan and ammonia were evaluated 6, 10, 16, 18, 22, and 26 days after tumor inoculation. Anorexia developed by day 17-18, when food intake started to decrease via a decrease in meal size but not meal number and reached 60% of control by day 26. However, long before anorexia developed, free tryptophan was significantly higher 6 days after tumor inoculation, and the greatest increase occurred after 18 days. Ammonia did not differ from control at any time. Data confirm tumor-associated increases in plasma free tryptophan that occurred before the manifestation of anorexia and support a possible role of brain serotonin in cancer anorexia.

Hypothalamic integration of immune function and metabolism

“…Other peripheral mechanisms of cytokines may be the enhancement of the availability of tryptophan (the 5-HT precursor) to maintain an elevated 5-HT turnover (Dunn, 1992) given that brain 5-HT synthesis depends on the brain availability of this amino acid (Schaechter and Wurtman, 1990) which is positively correlated to plasma-free tryptophan concentration (Fernstrom and Wurtman, 1972). In different anorexia animal models (Kurzer et al, 1988;Meguid et al, 1992;Muscaritoli et al, 1996;Laviano et al, 1999) and anorectic patients with different diseases (Cangiano et al, 1994;Laviano et al, 1997;Aguilera et al, 2000) an increase in plasma and brain free tryptophan concentrations and brain serotoninergic activity has been reported suggesting a connection between anorexia disease, circulating tryptophan, brain serotoninergic activity and cytokines. Moreover, in anorectic tumorbearing rats, enhanced free tryptophan circulating levels decrease to normal levels after tumor removal thereby improving food intake (Cangiano et al, 1994).…”

Components of the anorexia–cachexia syndrome: gastrointestinal symptom correlates of cancer anorexia

“…The mechanism is unknown [15,37]. It reduces food intake and predicts shorter survival [18,34]. Early satiety can occur without anorexia, but it is experienced by most with moderate to severe anorexia [14,18,20,31,43].…”

Optimal management of cancer anorexia–cachexia syndrome

“…In addition, data from the authors’ own laboratory show that BCAAs (in particular leucine) act by decreasing skeletal muscle protein degradation, mainly by inhibiting the activation of the ubiquitin proteolytic system 73. Free tryptophan (the precursor of brain serotonin) is increased during cancer and BCAA may act by competing for the same transport system as tryptophan across the blood–brain barrier 74,75. This hypothesis has been tested in anorectic cancer patients receiving an oral supplementation of BCAA with encouraging results, as the treatment decreased the severity of the anorexia in the treated patients 73…”