Novaković, Srdjan

Rudolf, Zvonimir

English

Digital repository of Slovenian research organizations

Radio! Oncol 1993; 27: 298-301. Serum interleukin-2 levels in malignant melanoma patients Zvonimir Rudolf and Srdjan Novakovic Institute of Oncology, Ljubljana, Slovenia In a majority of human neoplasms a mitogen mediated clecrease in the procluction of interleukin 2 (IL-2) in vitro can be observed. Poor resolution of the available tests cloes not enable the evaluation of spontaneous ancl in vivo IL-2 production in cancer patients. Using ELISA methocl (Genzyme), serum IL-2 concentrations were cleterminecl in malignant melanoma patients and healthy controls. The mean value (±SE) of serum IL-2 in 30 healthy donors was 269 Ulm! (269 ± 66).In patients with malignant melanoma this value was lower - 37 Ulm! (37 ± 16). The difference between mean values of both groups was significant (p < 0.05). The mean leve! of serum IL-2 in II patients treatecl with human leukocyte interferon was higher than the mean value of alf melanoma patients (53 Ulm!); the small number of patients ancl variability of the obtained results, however,render the clifference statistically insignificant. The results indicate that the clecreased in vitro procluction of IL-2 in malignant melanoma is associated with a decrease in in vivo IL-2 procluction in comparison with healthy persons. Key words: melanoma, interleukin-2 Introduction Solid malignant tumors are frequently accompa­nied by suppression of cell-mediated immunity and associated with that impaired survival. 1-3 The effects of specific antitumor responses, such as generation of cytotoxic T-cells, activated macrophages, and antitumor antibodies, are probably most relevant to immunologic control by the host. Besides the initial maturation ef­fects of thymic hormones,4 the most important is the so-called interleukin cascade which repre-Correspondence to: Prof. Zvonimir Rudolf, MD,PhD, Institute of Oncology, Zaloška 2, 61105 Ljubljana, Slovcnia, Tel. +386 61 1314225, Fax +386 61 1314180. UDC: 616-006.81-085:615.281.7 .015.45 sents a sequence of events involving the citoki­nes of monocyte lypmhoid origin helping to drive the cellular response to target antigens. Current studies focus on interleukin-2 (IL-2) which is a glycoprotein produced by activated T lymphocytes. According to the results of some studies5 it is known that most antitumor immune reac­tions, such as proliferation of T helper and cytotoxic cells, NK activity and generation of LAK cells, are IL-2 dependent. Acting on specific IL-2 celi surface receptors, expressed by activated though not resting immune cells, IL-2 stimulates immunity. Though activated T cells, B cells, and macrophages express IL-2 receptors, the most important source of serum IL-2 has stili not been clearly explained. Also, Serum interleukin-2 leve/s in malignant melanoma patients 299 the results of some studies6 suggest that serum IL-2 is involved in regulation of some IL-2-dependent immune functions. The central question is whether IL-2 function is abnormal in patients with solid tumors who commonly exhibit depression of cell-mediated immunity. Severa! studies have demonstrated a reduced in vitro IL-2 production after mitogenic stimu­lation in most patients with metastatic cancer. On account of too low sensitivity of previous assays, little data were available on IL-2 spon­taneous in vivo production in cancer patients until recently.7-9 The development of sensitiveELISA method enabled us to investigate serum IL-2 concentrations in patients with malignant melanoma. In vicw of the previously mentioned facts, serum Ievels of IL-2 were investigated in pa­tients with malignant melanoma in comparison with healthy persons. Patients and methods The study included 30 patients with malignant melanoma. There were 12 male and 13 female patients with the mean age 51.4 years (range 31-76 years). Thirty healthy persons (blooddonors) served as a control group; there were15 males and 15 females with the mean age 41years (range 25-57 years).In ali patients the tumor was histologically proven after surgical removal, and none of them was treated with exogenous recombinant interleukin-2. Disease activity was determined at the tiine when blood samples were collected. Eleven patients with malignant melanoma were treated intramuscularly with human leukocyte intereferon (2 X 106 U weekly for 30 weeks). The blood samples from those patients were collected throughout the duration of treatment. Serum interleukin-2 (serum IL-2) levels were measured by means of lnter Test 2 Human IL-2 ELISA test kit (Genzyme-Corporation, Boston, Massachusetts, USA) which is a solid phase enzyme immunoassay employing the multiple antibody sandwich principle. Results The mean value (±SE) of serum IL-2 in healthy donors was 269 U/ml (269±66, range 6.9 -1881 U/ml). In males the mean serum IL-2 value was 259 U/ml and in females 279 U/ml (Table 1). There was no significant sex- and age-related difference in the group of healthy persons. However, since there was a difference between mean age of healthy donors and mela­n01na patients, the control group was divided into two groups, i.e. persons over 40 and those under 40 years of age. The mean value in healthy donors over 40 years of age was 292 U/ ml, while in younger donors it was 249 U/ml; there was no significant impact of age on serum IL-2 levels. Table l. Serum interlcukin-2 levels in healthy donors according to the sex and age distribution. Group No AM* ± Malcs 15 259 Femalcs 15 279 Age: >40 14 292 <40 16 249 Ali 30 269 * AM arithmetic mcan ** SE standard error ± serum IL-2 Levels SE** Ra n g e  13.8 - 536.2 11.5 1881 13.8 1881 11.5 - 891 66 6.9 1881 In patients with malignant melanoma the mean value of serum IL-2 was 27 ±9 U/ml (Ta­ble 2); in female patients 28 U/ml and in male patients 26 U/ml. There were no sex-related differences noted in melanoma patients. In ol­der patients (over 51 years) mean serum IL-2 leve! was 27 U/ml, and in younger patients (under 51 years) this value was nearly the same - 27 U/ml.Table 2. Serum IL-2 levels in patients with malignant melanoma aceording to the sex and age distribution. Group No serum IL-2 Levels AM* ± SE** Ra n g e  Malcs 12 26.1 2 127 Females 13 28.4 2 - 200 Age: >51 II 27.3 2 127 <51 14 27.2 2 - 200Ali 25 27.3 ± 9.3 2 - 200 * AM - arithmetic mean ** SE - standard error 300 Rudolf Z. ancl Novakovic S. 2000 1800 1600· 1400 1200 1000 800· 600 400 200 o 200 180 160 140 120 I 100 80 60 40 20 o Figure l. Serum IL-2 levels in healthy donors and melanoma patients. Serum IL-2 Ievels in melanoma patients and healthy donors are presented in Figure l. The difference between mean values of serum IL-2 in melanoma patients and in healthy donors was significant (27±9 U/ml versus 269±66 U/ml, p<0.05). In 5 patients the disease was found to have recurred by the time of sample taking. In these patients with recurrence, the mean value was decreased (6.8 U/ml ). Despite of a Iow number of cases, it seems that the extent of disease ( or disease activity) influenced the serum IL-2 levels. IFN treatment melanoma patients Figure 2. Serum levels in all melanoma patients and 11 patients that were on adjuvant treatment with human Ieukoeyte interferon (2 x 106 units weekly, intramuscular application) after surgical removal of the primary tumor. At the time of sample taking 11 patients were on adjuvant treatment with human leukocyte interferon (2 X 106 units weekly, intramuscular application) after surgical removal of the pri­mary tumor. In these patients the mean value of serum IL-2 was 57U/ml (Figure 2), which was higher when compared with otherwise de­creased Ievels of serum IL-2 in melanoma pa­tients. Although, the difference in serum IL-2 levels between ali patients and patients treated with human leukocyte interferon was not signi­ficant. Also, the serum IL-2 levels were not in the range of the levels of controls employed in this study (i.e. 269 + 66 U/ml). However, according to our findings it can be postulated that the extent of the disease could influence the serum IL-2 levels since a decrease in serum IL-2 was found in the group of patients with recurrence when compared with the mean serum IL-2 value in ali patients (6.8 U/ml versus 27U/ml). Discussion The aim of this study was to assess the potential role of serum IL-2 in the diagnosis and predic­tion of recurrence in malignant melanoma pa­tients. Biological significance of altered Ievels of 11-2 is stili not clear; in particular, it is not yet clear whether the increased levels in the blood reflect possible activation of immune cells, or should be ascribed to immune dysfunction. Although the Iymphoproliferative response to mitogens or antigens is frequently depressed in cancer patients, their ability to produce fL-2 by lymphocyte stimulation with PHA appears relatively normal, as reported in literature. Ho­wever, subgroups with advanced disease did have depressed IL-2 prod uction. 1 • 8 Furthermo­re, in some studies the presence of soluble form of IL-2 receptors was evaluated; increased va­lues were found in patients with small-cell lung carcinoma . Additionally, in breast cancer pa­tients serum IL-2R levels after surgery were significantly higher than those before surgery. 10 The values were found to correlate with the extent of disease.11 Serum interleukin-2 leve/s in malignant melanoma patients 30[ Decreased serum IL-2 levels in our study are consistent with some other reports, and so is also the finding that further decrease in serum IL-2 levels in our melanoma patients was asso­ciated with recurrence of the disease. The in­fluence of human leukocyte interferon could be ascribed to various reasons though it is possible that, with respect to a small number of cases studied, interferon could influence the produc­tion of IL-2 in vivo. The increased serum JL-2 levels in patients treated with human leukocyte interferon could also be ascribed to crude ex­tract of interferon containing minor quantities of IL-2. Acknowledgements Research work was supported by the Ministry of Science and Teclmology of Slovenia, Grant No. C3-0563-302/27-40/B. Refereneces l. Wancbo 1-IJ, Pacc R, I-largctt S, Katz D, Sando J. Production of and rcsponsc to intcrlcukin-2 in pcriphcral blood lymphocytcs of canccr paticnts. Cancer 1986; 57: 656-62.2. Rudolf Z, Scrša G, Krošl G. In vitro monocytcmaturation in paticnts with malignant melanomaancl colorcctal canccr- clinical significancc. Neo­plasma 1986; 33: 71-8.3. Djcu JY, Kasahara T, Balow JE, Tsokos GC.Dccrcascd intcrlcukin-2 inhibitor in sera of pa­ticnts with autoimmunc disordcrs. Ciin Exp Jmmu­nol 1986; 65: 279-84. 4. Low TLK, Goldstein AL. Thymosins - isolation, structural studics and biologic activitics. In: Stoll B, cel. Relation of immune testing to prognosis.New York, Plenum Prcss, 1988: 21-35.5. Farrar JJ, cnjamin WR, I-lilfikcr ML, 1-loward M.Farrar WL Fullcr-Farrar J. Thc biochcmistry,biology, and role of intcrlcukin-2 in thc incluction of cytotoxic T-ccll and antibody-forming B-ccll rcsponscs. Jmmunol Rev 1989; 63: 129-36. 6. Thompson .TA, Lee DJ, Cox WW, Lindgrc CG,Collins C, Ncraas KA, Dcnnin RA, Fcfcr A. Rccombinant intcrlcukin-2 toxicity ,pharmacoki­nctcs, ancl immuno-modulatory cffccts in a phasc 1 tria!. Cancer Res 1987; 47: 4202-7. 7. Cadcras JM. Human intcrlcukin-2: quantitationby a scnsitivc radioimmunoassay . .! lmmwwl 1986; 89: 181-6.8. Lissoni P, Viviani S, Santoro A, Barni S, TanciniG. Serum lcvcls of intcrlcukin-2 in canccr paticnts­prcliminary consiclcrations. lnt .! Biol Markers1989; 4: 203-6. 9. Yamaguchi K, Nishimura Y, Kiyokawa T, Matsu­zaki 1-1, Ishii T, Kubota K, Kawahara M. Elcvatcdserum lcvcls of solublc intcrlcukin-2 rcccptors in small ccll lung carcinoma . .! Lab Ciin Med 1990;116: 457-61.IO. Brivio F, Lissoni P, Mancini D, Tisi E, Tancini G, Barni S, Nociti V. Effcct of antitumor surgcry on solublc intcrlcukin-2 receptor serum lcvcls. Am .! Surg 1991; 161: 466-9. 1 l .  Sharma S, Saha K, Shingal RN. Maluk GB. Serum solublc intcrlcukin-2 (IL-2) receptor lcvcls in womcn with brcast carcinoma and its corrcla­tion with IL-2 receptor cxprcssion on bloocl lym­phocytcs and lymphocytic infiltration within thc tumor. Cancer lmmunol fmmunotlzer 1991; 33: 198-202. 

Serum interleukin-2 levels in malignant melanoma patients

https://dirros.openscience.si/Dokument.php?id=24081&dn=

Serum interleukin-2 levels in malignant melanoma patients

Abstract

Similar works

Full text

Available Versions

Digital repository of Slovenian research organizations