Orthotopic xenografts of human melanoma and colonic and ovarian carcinoma in sheep to evaluate radioimmunotherapy

• Published in: British journal of cancer Vol. 78; no. 4; pp. 486 - 494
• Main Authors: TURNER, J. H, ROSE, A. H, GLANCY, R. J, PENHALE, W. J
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.08.1998; Nature Publishing Group|1
• Subjects: Adenocarcinoma - therapy; Animal tumors. Experimental tumors; Animals; Antibodies, Monoclonal - therapeutic use; Biological and medical sciences; Carcinoembryonic Antigen - immunology; Colonic Neoplasms - pathology; Colonic Neoplasms - therapy; Combined treatment; Cystadenocarcinoma - therapy; Experimental tumors, general aspects; Female; Humans; Immunosuppression; Iodine Radioisotopes - metabolism; Iodine Radioisotopes - therapeutic use; Medical sciences; Melanoma - pathology; Melanoma - therapy; Neoplasm Transplantation; Ovarian Neoplasms - pathology; Ovarian Neoplasms - therapy; Radioimmunotherapy; Sheep; Transplantation, Heterologous; Treatment. General aspects; Tumor Cells, Cultured; Tumors; Evaluation; Animal model; Melanoma; Malignant tumor; Heterograft; Female genital diseases; Colonic disease; Ovarian diseases; Ovary; Vertebrata; Mammalia; Animal; Immunoradiotherapy; Digestive diseases; Intestinal disease; Tumor; Sheep; Artiodactyla; Colon; Ungulata
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.1998.520

Extrapolation to humans from experimental radioimmunotherapy in nude mouse xenograft models is confounded by large relative tumour size and small volume of distribution in mice allowing tumour uptake of radiolabelled antibodies unattainable in patients. Our large animal model of human tumours in cyclosporin-immunosuppressed sheep demonstrated tumour uptake of targeted radiolabelled monoclonal antibodies comparable with uptakes reported in clinical trials. Sheep immunosuppression with daily intravenous cyclosporin augmented by oral ketoconazole maintained trough blood levels of cyclosporin within the range 1000-1500 ng ml(-1). Human tumour cells were transplanted orthotopically by inoculation of 10(7) cells: SKMEL melanoma subcutaneously; LS174T and HT29 colon carcinoma into bowel, peritoneum and liver; and JAM ovarian carcinoma into ovary and peritoneum. Tumour xenografts grew at all sites within 3 weeks of inoculation, preserving characteristic morphology without evidence of necrosis or host rejection. Lymphatic metastasis was demonstrated in regional nodes draining xenografts of melanoma and ovarian carcinoma. Colonic LS1 74T xenografts produced mucin and carcinoembryonic antigen (CEA). The anti-CEA IgG1 monoclonal antibody A5B7 was radiolabelled with iodine-131 and administered intravenously to sheep. Peak uptake at 5 days in orthotopic human tumour transplants in gut was 0.027% DI g(-1) (percentage of injected dose per gram) and 0.034% DI g(-1) in hepatic metastases with tumour to blood ratios of 2-2.5. Non-specific tumour uptake in melanoma was 0.003% DI g(-1). Uptake of radiolabelled monoclonal antibody in human tumours in our large animal model is comparable with that observed in patients and may be more realistic than nude mice xenografts for prediction of clinical efficacy of radioimmunotherapy.