Pegylated interferon-α2b treatment in melanoma patients: influence on amino acids, 5-hydroxyindolacetic acid and pteridine plasma concentrations

Abstract

Our objective was to study the influence of pegylated interferon-alpha2b (PEG-IFN-alpha) on the metabolism of amino acids and pteridines. We used an exploratory study into plasma concentrations of large neutral amino acids, 5-hydroxyindolacetic acid (5-HIAA), total biopterin (BIOP) and neopterin (NEOP) in 40 high-risk melanoma patients. Patients were randomized to treatment with PEG-IFN-alpha once a week in a dose of 6 microg/kg/week s.c. during 8 weeks, followed by a maintenance treatment of 3 microg/kg/week s.c. or to observation only. We found that treatment with PEG-IFN-alpha decreases tryptophan (TRP) concentrations in the first 3 months of treatment to a maximum of 25.3% compared to controls [95% confidence interval (CI): 14.9 to 34.4]. The TRP:LNAA ratio, an index for the availability of TRP to the central nervous system (CNS), decreases during 6 months with 18.8% (95% CI: 11.9 to 25.2). Concentrations of NEOP rose; however, concentrations of BIOP, the sum of tetrahydrobiopterin [BH4] and its oxidative products, did not decrease. The ratio of phenylalanine to tyrosine was increased with 11.7% (95% CI: 1.0 to 23.5) during 6 months. We conclude that, like conventional IFN-alpha, PEG-IFN-alpha lowers TRP concentrations and decreases the availability of TRP to the CNS. PEG-IFN-alpha has a similar influence on pteridine metabolism as standard IFN-alpha. If a lowered availability of TRP and a consequent decrease of serotonergic neurotransmission are indeed a mechanism underlying neuropsychiatric side-effects of IFN-alpha, patients on PEG-IFN-alpha are not at a lower risk of developing neuropsychiatric side-effects as patients on conventional IFN-alpha.

Interferon-α Influences Tryptophan Metabolism without Inducing Psychiatric Side Effects

“…The results of this prospective study confirmed earlier findings of our own previous retrospective studies and studies of others on the relation between IFN-␣ treatment and the TRP metabolism [5,[10][11][12] . Clearly, treatment with (PEG) IFN-␣ decreased TRP concentrations at all time points and TRP/LNAA ratios at 2 out of 3 time points, as a consequence of which diminished TRP availability to the CNS and consequent decrease in 5-HT synthesis in the short and in the long term can be expected.…”

“…As TRP competes with the other large neutral amino acids (LNAA) to the CNS, the TRP/LNAA ratio is a parameter considered to reflect the availability of TRP to the CNS. Accordingly, the TRP/ LNAA ratio has previously been found to be lowered in some studies in patients treated with IFN-␣ [8, 10,11] . The hypothesis that altered TRP metabolism is involved in IFN-␣ -induced depression is further supported by the observation that several studies performed in patients treated with IFN-␣ found significant correlations between measures for depression and a decrease in TRP concentrations [5,8,12] .…”

“…The hypothesis that altered TRP metabolism is involved in IFN-␣ -induced depression is further supported by the observation that several studies performed in patients treated with IFN-␣ found significant correlations between measures for depression and a decrease in TRP concentrations [5,8,12] . An additional mechanism potentially underlying IFN-␣ -mediated effects on the synthesis of TRP into 5-HT is through a change in pterin metabolism affecting the synthesis of tetrahydrobiopterin (BH 4 ), thereby hampering the synthesis of 5-HT [10,11] .…”

“…However, relatively few studies have been performed so far, yielding conflicting results. The aim of this exploratory study was to investigate whether the above-mentioned alterations in TRP metabolism, which in part were elucidated by our former retrospective studies [10,11] , indeed occur in a prospective trial during IFN-␣ treatment in oncology patients, and if so, whether these changes are associated with emerging psychiatric symptoms and syndromes using regular psychiatric assessments combining clinical judgment, standardized diagnosis, observer-based rating scales and self-report questionnaires. Since there are two types of IFN-␣ , conventional and pegylated (PEG) IFN-␣ , that are both widely used, alter TRP metabolism equally and can lead to a comparable extent and frequency of depressive symptoms [10,11,14,15] , patients treated with either one of these types of IFN-␣ were allowed to be accrued.…”

Serum Neopterin in Patients with Malignant Melanoma

“…Neopterin determination has been used to monitor systemic effects of cytokine therapy in melanoma patients. Neopterin concentrations increased significantly after the administration of interferon-alpha or interleukin-2 alone or in combination with chemotherapy (17)(18)(19)(20). In some of these studies, the increase in neopterin concentrations was accompanied by decreased tryptophan or increased kynurenine that reflect the activity of another IFN-γ-induced enzyme, indoleamine (2,3)-dioxygenase (17)(18)(19).…”