Unconjugated pteridines and the activation of macrophages by interferon gamma

ancer hemotherapyand harmacology Cancer Chemother Pharmacol (1990) 25:308 - 309 9 Springer-Verlag 1990 Letter to the Editors Unconjugated pteridines and the activation of macrophages by interferon gamma Gilbert Reibnegger, Dietmar Fuchs, Arno Hausen, Ernst R. Werner, Gabriele Werner-Felmayer, and Helmut Wachter Institute for Medical Chemistry and Biochemistry, University of Innsbruck, Fritz Pregl Str. 3, A-6020 Innsbruck, Austria Sirs, W e b b e r and Nazarbaghi [12] are to be c o m m e n d e d for their studies on the transport o f unconjugated pteridines in C C R F - C E M h u m a n lymphoblastic cells. However, the discussion relating to the occurrence of certain pteridines during the activation of i m m u n e response mechanisms deserves some comments. It is now well recognized that among the several pterins excreted, e.g., in human urine, only the concentration o f D-erythro-neopterin is associated with activated human macrophages, because these cells produce large quantities of neopterin u p o n induction by interferon gamma, derived from activated T cells [111. A multitude of clinically oriented investigations by a multitude of research groups have shown that measuring neopterin in human b o d y fluids enables sensitive monitoring of a variety o f diseases, all being characterized by the involvement of m a c r o p h a g e activation. These issues have recently been reviewed [11]. Importantly, studies conducted on neopterin and biopterin levels in diseases involving macrophage activation have failed to demonstrate a similar association of biopterin with the i m m u n e response [21. In contrast, measurements of biopterin derivatives are essential in the rare group of metabolic diseases caused by failure to synthesize tetrahydrobiopterin, the well-known cofactor of certain monooxygenases, notably, in the differential diagnosis of the variants of atypical phenylketonuria [3]. It has previously been claimed that 6-hydroxymethylpterin was excreted in raised amounts by t u m o r cells in culture and was thus suited for clinically relevant discrimination between cancer patients and healthy subjects [8]. Doubts have been raised against this statement, and the original authors themselves corrected their finding a few years later, reporting that urinary concentrations of 6-hydroxymethylpterin in cancer patients were not different from those in healthy individuals [9]. Rather, the authors noted raised neopterin concentrations in urine from cancer patients, in agreement with previous observations of our group [101. Meanwhile, there is agreement that among the pteridines found in h u m a n b o d y fluids, neopterin is most consistently raised in certain tumor types [11]. Furthermore, several i n d e p e n d e n t studies [1, 4 - 7 ] have demonstrated that high neopterin concentrations in the urine and serum of cancer patients are significantly associated with a p o o r prognosis. The suppressed immune responsiveness o f can- cer patients that can be measured by, e. g., skin test anergy or a reduced in vitro proliferative response of T cells, does not exclude the presence of circulating cytokines in these patients. This seems to indicate that a persistent macrophage activation can be found in malignant disease. Little is known at present concerning the function of immune response-associated neopterin production by human m o n o c y t e s / m a c r o p h a g e s . The notion of an efficient interferon g a m m a - i n d u c e d degradation o f t r y p t o p h a n via the kynurenine pathway [13] by induction of i n d o l e a m i n e 2,3-dioxygenase may be helpful for further research on this unresolved question. References 1. Abate G, Comella P, Marfella A, Santelli G, Nitsch F, Fiore M, Perna M (1989) Prognostic relevance of urinary neopterin in non-Hodgkin's lymphomas. Cancer 63:484 2. Abita JP, Cost H, Milstien S, Kaufman S, Saimot G (1985) Urinary neopterin and biopterin levels in patients with AIDS and AIDS related complex. Lancet II: 51 3. Kaufman S (1963) The structure of phenylalanine hydroxylation cofactor. Proc Natl Acad Sci USA 50:1085 4. Kawasaki K, Watanabe H, Yamada S, Watanabe K, Suyama A (1988) Prognostic significance of urinary neopterin levels in patients with hepatocellular carcinoma. Tohoku J Exp Med 155:311 5. Lewenhaupt A, Ekman P, Eneroth P, Eriksson A, Nilsson B, Nordstr6m L (1986) Serum levels of neopterin as related to the prognosis of human prostatic carcinoma. Eur Urol 12: 422 6. Reibnegger G J, Bichler AH, Dapunt O, Fuchs DN, Fuith LC, Hausen A, Hetzel H, Lutz H, Werner ER, Wachter H (1986) Neopterin as a prognostic indicator in patients with carcinoma of the uterine cervix. Cancer Res 46:950 7. Reibnegger G, Hetzel H, Fuchs D, Fuith LC, Hausen A, Werner ER, Wachter H (1987) Clinical significance of neopterin for prognosis and follow-up in ovarian cancer. Cancer Res 47:4977 8. Stea B, Backlund PS, Berkey PB, Cho A, Halpern BC, Halpern RM, Smith RA (1978) Folate and pterin metabolism by cancer cells in culture. Cancer Res 38:2378 9. Stea B, Halpern RM, Halpern BC, Smith RA (1981) Urinary excretion levels of unconjugated pterins in cancer patients and normal individuals. Clin Chim Acta 113:231 10. Wachter H, Hausen A, Grassmayr K (1979) Erh6hte Ausscheidung von Neopterin im Ham yon Patienten mit malighen Tumoren und mit Viruserkrankungen. Hoppe Seylers Z Physiol Chem 360:1957 309 1l. Wachter H, Fuchs D, Hausen A, Reibnegger G, Werner ER (1989) Neopterin as marker for activation of cellular immunity: immunologic basis and clinical application. Adv Clin Chem 27:81 12. Webber S, Nazarbaghi R (1989) The transport of pteridines in CCRF-CEM human lymphoblastic cells. Cancer Chemother Pharmacol 23:283 13. Werner ER, Bitterlich G, Fuchs D, Hausen A, Reibnegger G, Szabo G, Dierich MP, Wachter H (1987) Human macrophages degrade tryptophan upon induction by interferon gamma. Life Sci 41 : 273 Received 15 May 1989/Accepted 19 July 1989