Abstract
Biotherapy including interleukin-2 (IL-2) treatment seems to be more effective outside the central nervous system when compared to the effects obtained when the same tumour is located intracerebrally. Recently published studies suggest that reduced activity of NK cells in tumour tissue can be increased by histamine. The present study was designed to determine whether IL-2 and histamine, alone or in combination, can induce anti-tumour effects in an orthotopic rat glioma model. One group of rats was treated with histamine alone (4 mg kg–1s.c. as daily injections from day 6 after intracranial tumour implantation), another group with IL-2 alone as a continuous subcutaneous infusion and a third group with both histamine and IL-2. The animals were sacrificed at day 24 after tumour implantation. IL-2 and histamine in combination significantly reduced tumour growth. The microvessel density was significantly reduced, an effect mainly affecting the small vessels. No obvious alteration in the pattern of VEGF mRNA expression was evident and no significant changes in apoptosis were observed. Neither IL-2 nor histamine alone caused any detectable effects on tumour growth. Histamine caused an early and pronounced decline in tumour blood flow compared to normal brain. The results indicate that the novel combination of IL-2 and histamine can be of value in reducing intracerebral tumour growth and, thus, it might be of interest to re-evaluate the therapeutic potential of biotherapy in malignant glioma. © 2000 Cancer Research Campaign
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Alexander JT, Saris SC and Oldfield EH (1989) The effect of interleukin-2 on the blood–brain barrier in the 9L gliosarcoma rat model. J Neurosurg 70: 92–96
Asea A, Hermodsson S and Hellstrand K (1996) Histaminergic regulation of natural killer cell-mediated clearance of tumour cells in mice. Scand J Immunol 43: 9–15
Barba D, Saris SC, Holder C, Rosenberg SA and Oldfield EH 1989a) Intratumoral LAK cell and interleukin-2 therapy of human gliomas. J Neurosurg 70: 175–182
Barba D, Saris SC, Holder C, Rosenberg SA and Oldfield EH 1989b) Intratumoral LAK cell and interleukin-2 therapy of human gliomas. J Neurosurg 70: 175–182
Bergenheim AT, Elfversson J, Gunnarsson P-O, Edman K, Hartman M and Henriksson R (1994) Cytotoxic effect and uptake of estramustine in a rat glioma model. Int J Oncol 5: 293–299
Bruce JN, Criscuolo GR, Merrill MJ, Moquin RR, Blacklock JB and Oldfield EH (1987) Vascular permeability induced by protein product of malignant brain tumors: inhibition by dexamethasone. J Neurosurg 67: 880–884
Burtin C, Scheinmann P, Salomon JC, Lespinats G and Canu P (1982) Decrease in tumour growth by injections of histamine or serotonin in fibrosarcoma-bearing mice: influence of H1 and H2 histamine receptors. Br J Cancer 45: 54–60
Caligiuri MA, Murray C, Robertson MJ, Wang E, Cochran K, Cameron C, Schow P, Ross ME, Klumpp TR, Soiffer RJ, Smith KA and Ritz J (1993) Selective modulation of human natural killer cells in vivo after prolonged infusion of low dose recombinant interleukin 2. J Clin Invest 91: 123–132
Danaila L, Ghyka G and Ursaciuc C (1993) Interleukin-2 (IL-2) in the treatment of malignant brain tumors (glioblastomas). Rom J Neurol Psychiatry 31: 195–206
Dijkstra CD, Dopp EA, Joling P and Kraal G (1985) The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology 54: 589–599
Fathallah Shaykh HM, Gao W, Cho M and Herrera MA (1998) Priming in the brain, an immunologically privileged organ, elicits anti-tumor immunity. Int J Cancer 75: 266–276
Fleshner M, Watkins LR, Redd JM, Kruse CA and Bellgrau D (1992) A 9L gliosarcoma transplantation model for studying adoptive immunotherapy into the brains of conscious rats. Cell Transplant 1: 307–312
Fontana A, Hengartner H, de Tribolet N and Weber E (1984) Glioblastoma cells release interleukin 1 and factors inhibiting interleukin 2-mediated effects. J Immunol 132: 1837–1844
Glick RP, Lichtor T, Mogharbel A, Taylor CA and Cohen EP (1997) Intracerebral versus subcutaneous immunization with allogeneic fibroblasts genetically engineered to secrete interleukin-2 in the treatment of central nervous system glioma and melanoma. Neurosurgery 41: 898–906
Hayes RL, Koslow M, Hiesiger EM, Hymes KB, Hochster HS, Moore EJ, Pierz DM, Chen DK, Budzilovich GN and Ransohoff J (1995) Improved long term survival after intracavitary interleukin-2 and lymphokine-activated killer cells for adults with recurrent malignant glioma. Cancer 76: 840–852
Heiss JD, Papavassiliou E, Merrill MJ, Nieman L, Knightly JJ, Walbridge S, Edwards NA and Oldfield EH (1996) Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor. J Clin Invest 98: 1400–1408
Hellstrand K and Hermodsson S (1990) Synergistic activation of human natural killer cell cytotoxicity by histamine and interleukin-2. Int Arch Allergy Appl Immunol 92: 379–389
Hellstrand K, Asea A and Hermodsson S (1990) Role of histamine in natural killer cell-mediated resistance against tumor cells. J Immunol 145: 4365–70
Hellstrand K, Asea A, Dahlgren C and Hermodsson S 1994a) Histaminergic regulation of NK cells. Role of monocyte-derived reactive oxygen metabolites. J Immunol 153: 4940–4947
Hellstrand K, Naredi P, Lindner P, Lundholm K, Rudenstam CM, Hermodsson S, Asztely M and Hafstrom L 1994b) Histamine in immunotherapy of advanced melanoma: a pilot study. Cancer Immunol Immunother 39: 416–419
Henriksson R, Widmark A, Bergh A and Damber JE (1992) Interleukin-2-induced growth inhibition of prostatic adenocarcinoma (Dunning R3327) in rats. Urol Res 20: 189–191
Henriksson R, Nilsson S, Colleen S, Wersall P, Helsing M, Zimmerman R and Engman K (1998) Survival in renal cell carcinoma – a randomized evaluation of tamoxifen vs interleukin 2, alpha-interferon (leucocyte) and tamoxifen. Br J Cancer 77: 1311–1317
Holladay FP, Lopez G, De M, Morantz RA and Wood GW (1992) Generation of cytotoxic immune responses against a rat glioma by in vivo priming and secondary in vitro stimulation with tumor cells. Neurosurgery 30: 499–504
Johansson M, Bergenheim AT, Henriksson R, Koskinen LO, Vallbo C and Widmark A (1997) Tumor blood flow and the cytotoxic effects of estramustine and its constituents in a rat glioma model. Neurosurgery 41: 237–243
Johansson S, Landstrom M, Hellstrand K and Henriksson R (1998) The response of Dunning R3327 prostatic adenocarcinoma to IL-2, histamine and radiation. Br J Cancer 77: 1213–1219
Joseph IB and Isaacs JT (1998) Macrophage role in the anti-prostate cancer response to one class of antiangiogenic agents [see comments]. J Natl Cancer Inst 90: 1648–1653
Kruse CA, Cepeda L, Owens B, Johnson SD, Stears J and Lillehei KO (1997) Treatment of recurrent glioma with intracavitary alloreactive cytotoxic T lymphocytes and interleukin-2. Cancer Immunol Immunother 45: 77–87
Lillehei KO, Mitchell DH, Johnson SD, McCleary EL and Kruse CA (1991) Long-term follow-up of patients with recurrent malignant gliomas treated with adjuvant adoptive immunotherapy. Neurosurgery 28: 16–23
Lindgren M, Johansson M, Sandstrom J, Jonsson Y, Bergenheim AT and Henriksson R (1997) VEGF and tPA co-expressed in malignant glioma. Acta Oncol 36: 615–618
Ljungberg B and Henriksson R (1997) Immunotherapy of metastatic renal cell carcinoma. Curr Opin Urol 7: 252–258
Melder RJ, Koenig GC, Witwer BP, Safabakhsh N, Munn LL and Jain RK (1996) During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium [see comments]. Nat Med 2: 992–997
Nomura T, Ikezaki K, Matsukado K and Fukui M (1994) Effect of histamine on the blood-tumor barrier in transplanted rat brain tumors. Acta Neurochir (Wien) 60: 400–402
Saris SC, Spiess P, Lieberman DM, Lin S, Walbridge S and Oldfield EH (1992) Treatment of murine primary brain tumors with systemic interleukin-2 and tumor-infiltrating lymphocytes. J Neurosurg 76: 513–519
Takai N, Tanaka R, Yoshida S, Hara N and Saito T (1988) In vivo and in vitro effect of adoptive immunotherapy of experimental murine brain tumors using lymphokine-activated killer cells. Cancer Res 48: 2047–2052
Tzeng JJ, Barth RF, Clendenon NR and Gordon WA (1990) Adoptive immunotherapy of a rat glioma using lymphokine-activated killer cells and interleukin 2. Cancer Res 50: 4338–4343
Weber F, List J, Rommel T, Menzel J, Symas J, Pohl U, Mohr H, Schmitz R and Amue B (1989) Influence of interleukin II on xenotransplanted grade 3 to 4 glioma in nude mice. Strahlenther Onkol 165: 556–558
Weidner N (1993) Tumor angiogenesis: review of current applications in tumour prognostication. Semin Diagn Pathol 10: 302–313
Wijsman JH, RJonker R, Keijzer R, DeVelde DJH, Cornel-Issue CJ and erendonck JHV (1993) A new method to detect apoptosis in paraffin sections: In situ end-labelling of fragmented DNA. J Histochem Cytochem 41: 7–12
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Johansson, M., Henriksson, R., Bergenheim, A. et al. Interleukin-2 and histamine in combination inhibit tumour growth and angiogenesis in malignant glioma. Br J Cancer 83, 826–832 (2000). https://doi.org/10.1054/bjoc.2000.1354
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2000.1354
Keywords
This article is cited by
-
Anti-Vascular Endothelial Growth Factor Therapy Abolishes Glioma-Associated Endothelial Cell-Induced Tumor Invasion
Journal of Molecular Neuroscience (2023)
-
Effects of the VEGFR inhibitor ZD6474 in combination with radiotherapy and temozolomide in an orthotopic glioma model
Journal of Neuro-Oncology (2008)
-
Protein expression in experimental malignant glioma varies over time and is altered by radiotherapy treatment
British Journal of Cancer (2006)
-
Disrupting tumour blood vessels
Nature Reviews Cancer (2005)
-
The tyrosine kinase inhibitor ZD6474 inhibits tumour growth in an intracerebral rat glioma model
British Journal of Cancer (2004)