doi:10.1006/cyto.2001.0899, available online at http://www.idealibrary.com on ROLE OF CYTOKINES IN CANCER CACHEXIA IN A MURINE MODEL OF INTRACEREBRAL INJECTION OF HUMAN TUMOURS Donatella R. M. Negri, 1 * Delia Mezzanzanica, 1 Silvano Sacco, 2 Massimo Gadina, 1 * Fabio Benigni, 2 Laura Cajola, 3 Gaetano Finocchiaro, 3 Pietro Ghezzi, 2 Silvana Canevari 1 To study the role of cytokines that are relevant in cancer cachexia syndrome due to intracerebral tumours, mice were injected with human A431 epidermoid carcinoma, OVCAR3 ovarian carcinoma and GBLF glioma cells comparing intracerebral (i.c.) and systemic (i.p. or s.c.) routes of implantation. Anorexia and weight loss developed within 7–10 days in mice injected i.c. with A431 or OVCAR3 cells well before a large tumour developed, while i.c.-injected GBLF cells did not induce cachexia until day 20, when the tumour was large. By contrast, mice injected i.p. or s.c. developed tumours without evidence of anorexia. Thus, intracerebrally-growing A431 and OVCAR3 resulted in cancer cachexia independent of tumour mass, and we investigated their cytokine pattern. Serum levels of murine and human cytokines are not predictive of cancer cachexia development. Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis revealed in the brain of i.c.-injected A431 tumour-bearing mice expression of human interleukin- (IL-)1, IL-1 and LIF in all samples and IL-6 in two of four samples while in i.c.-injected OVCAR3 tumour-bearing animals IL-6, and LIF were detected in all samples and tumour necrosis factor- (TNF) in two of four samples. Only LIF was expressed in brains of mice injected with GBLF cells. Murine IL-6 was increased only in the brains of A431-bearing mice. Only mice injected i.c. simultaneously with a monoclonal antibody (mAb) directed against the murine IL-6 receptor and OVCAR3 cells, but not those with mAb and A431 cells, showed a significant increase in survival time with a partial and temporary attenuation of cachexia symptoms. These results suggest that IL-6 in OVCAR3 model may be important cachectogenic factor when centrally released by even a limited number of tumour cells.  2001 Academic Press The cachexia syndrome is characterized by several homeostatic perturbations including depletion of muscle and fat tissue, hypoglycaemia and anaemia, accompanied by progressive wasting, weakness and anorexia. The cancer cachexia syndrome, which affects a large proportion of patients with solid tumours, is associated not only with decreasing quality of life but also with a shorter survival time and poor response to therapy. Cachexia is more common in children and elderly patients and becomes more pronounced as disease progresses, however the severity of cancer cachexia syndrome may be unrelated to tumour size since profound wasting has been observed in patients with tumour burdens of less than 1% body mass. 1,2 Although the pathophysiology of cancer cachexia syndrome is not well defined, several hypotheses have been explored including cytokines, circulating hor- mones, neuropeptides, neurotransmitters, and tumour- derived factors. 3,4 Studies in animal models have shown that several cytokines, including tumour necrosis factor- (TNF-), interleukin-(IL-)1, IL-6, interferon-(IFN-), LIF and TGF, can produce signs, symptoms and From the 1 Unit of Molecular Therapies, Department of Experimen- tal Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, 20133 Milano, Italy; 2 Laboratory of Neuroimmunology, Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’, Via Eritrea 62, Milano, Italy; 3 Unit of Neuro-Oncology and Gene Therapy, Istituto Neurologico ‘‘Besta’’, Via Celoria 11, Milano, Italy Correspondence to: Dr. Silvana Canevari, Unit of Molecular Therapies, Department of Experimental Oncology, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. E-mail, canevari@istitutotumori.mi.it *Present addresses: D.R.M. Negri, Istituto Superiore di Sanita’, Roma, Italy. M. Gadina, NIAMS, NIH, Bethesda, MD, USA Received 22 September 2000; received in revised form 9 April 2001; accepted for publication 18 May 2001  2001 Academic Press 1043–4666/01/130027+12 $35.00/0 KEY WORDS: Cancer anorexia-cachexia syndrome/intracerebral tumour growth/cytokines/animal model/Interleukin 6 CYTOKINE, Vol. 15, No. 1 (7 July), 2001: pp 27–38 27