Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1998 Aug;78(4):486–494. doi: 10.1038/bjc.1998.520

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

J H Turner 1, A H Rose 1, R J Glancy 1, W J Penhale 1
PMCID: PMC2063083  PMID: 9716032

Abstract

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.

Full text

PDF
486

Images in this article

488Figure 1
on p.488
490Figure 2
on p.490
491Figure 3
on p.491

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Begent R. H., Ledermann J. A., Green A. J., Bagshawe K. D., Riggs S. J., Searle F., Keep P. A., Adam T., Dale R. G., Glaser M. G. Antibody distribution and dosimetry in patients receiving radiolabelled antibody therapy for colorectal cancer. Br J Cancer. 1989 Sep;60(3):406–412. doi: 10.1038/bjc.1989.295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Begent R. H., Pedley R. B. Antibody targeted therapy in cancer: comparison of murine and clinical studies. Cancer Treat Rev. 1990 Sep;17(2-3):373–378. doi: 10.1016/0305-7372(90)90071-m. [DOI] [PubMed] [Google Scholar]
  3. Blumenthal R. D., Sharkey R. M., Haywood L., Natale A. M., Wong G. Y., Siegel J. A., Kennel S. J., Goldenberg D. M. Targeted therapy of athymic mice bearing GW-39 human colonic cancer micrometastases with 131I-labeled monoclonal antibodies. Cancer Res. 1992 Nov 1;52(21):6036–6044. [PubMed] [Google Scholar]
  4. DeNardo G. L., Kroger L. A., DeNardo S. J., Miers L. A., Salako Q., Kukis D. L., Fand I., Shen S., Renn O., Meares C. F. Comparative toxicity studies of yttrium-90 MX-DTPA and 2-IT-BAD conjugated monoclonal antibody (BrE-3). Cancer. 1994 Feb 1;73(3 Suppl):1012–1022. doi: 10.1002/1097-0142(19940201)73:3+<1012::aid-cncr2820731340>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
  5. Dykes P. W., Bradwell A. R., Chapman C. E., Vaughan A. T. Radioimmunotherapy of cancer: clinical studies and limiting factors. Cancer Treat Rev. 1987 Jun;14(2):87–106. doi: 10.1016/0305-7372(87)90042-9. [DOI] [PubMed] [Google Scholar]
  6. Fidler I. J. Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res. 1990 Oct 1;50(19):6130–6138. [PubMed] [Google Scholar]
  7. Fridman R., Kibbey M. C., Royce L. S., Zain M., Sweeney M., Jicha D. L., Yannelli J. R., Martin G. R., Kleinman H. K. Enhanced tumor growth of both primary and established human and murine tumor cells in athymic mice after coinjection with Matrigel. J Natl Cancer Inst. 1991 Jun 5;83(11):769–774. doi: 10.1093/jnci/83.11.769. [DOI] [PubMed] [Google Scholar]
  8. Fu X. Y., Besterman J. M., Monosov A., Hoffman R. M. Models of human metastatic colon cancer in nude mice orthotopically constructed by using histologically intact patient specimens. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9345–9349. doi: 10.1073/pnas.88.20.9345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kallinowski F., Schlenger K. H., Runkel S., Kloes M., Stohrer M., Okunieff P., Vaupel P. Blood flow, metabolism, cellular microenvironment, and growth rate of human tumor xenografts. Cancer Res. 1989 Jul 15;49(14):3759–3764. [PubMed] [Google Scholar]
  10. Kubota T. Metastatic models of human cancer xenografted in the nude mouse: the importance of orthotopic transplantation. J Cell Biochem. 1994 Sep;56(1):4–8. doi: 10.1002/jcb.240560103. [DOI] [PubMed] [Google Scholar]
  11. Lane D. M., Eagle K. F., Begent R. H., Hope-Stone L. D., Green A. J., Casey J. L., Keep P. A., Kelly A. M., Ledermann J. A., Glaser M. G. Radioimmunotherapy of metastatic colorectal tumours with iodine-131-labelled antibody to carcinoembryonic antigen: phase I/II study with comparative biodistribution of intact and F(ab')2 antibodies. Br J Cancer. 1994 Sep;70(3):521–525. doi: 10.1038/bjc.1994.338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Ledermann J. A., Begent R. H., Massof C., Kelly A. M., Adam T., Bagshawe K. D. A phase-I study of repeated therapy with radiolabelled antibody to carcinoembryonic antigen using intermittent or continuous administration of cyclosporin A to suppress the immune response. Int J Cancer. 1991 Mar 12;47(5):659–664. doi: 10.1002/ijc.2910470505. [DOI] [PubMed] [Google Scholar]
  13. Manzotti C., Audisio R. A., Pratesi G. Importance of orthotopic implantation for human tumors as model systems: relevance to metastasis and invasion. Clin Exp Metastasis. 1993 Jan;11(1):5–14. doi: 10.1007/BF00880061. [DOI] [PubMed] [Google Scholar]
  14. O'Donoghue H. L., Penhale W. J., Manning L. S., Reynoldson J. A., Turner J. H. Cyclosporine a immunosuppression in sheep with response enhancement by concomitant ketoconazole. Clin Exp Pharmacol Physiol. 1996 Sep;23(9):797–803. doi: 10.1111/j.1440-1681.1996.tb01182.x. [DOI] [PubMed] [Google Scholar]
  15. Pedley R. B., Boden J. A., Boden R., Dale R., Begent R. H. Comparative radioimmunotherapy using intact or F(ab')2 fragments of 131I anti-CEA antibody in a colonic xenograft model. Br J Cancer. 1993 Jul;68(1):69–73. doi: 10.1038/bjc.1993.288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Pedley R. B., Boden J., Keep P. A., Harwood P. J., Green A. J., Rogers G. T. Relationship between tumour size and uptake of radiolabelled anti-CEA in a colon tumour xenograft. Eur J Nucl Med. 1987;13(4):197–202. doi: 10.1007/BF00256491. [DOI] [PubMed] [Google Scholar]
  17. Rygaard J., Povlsen C. O. Heterotransplantation of a human malignant tumour to "Nude" mice. Acta Pathol Microbiol Scand. 1969;77(4):758–760. doi: 10.1111/j.1699-0463.1969.tb04520.x. [DOI] [PubMed] [Google Scholar]
  18. Schroeder T. J., Melvin D. B., Clardy C. W., Wadhwa N. K., Myre S. A., Reising J. M., Wolf R. K., Collins J. A., Pesce A. J., First M. R. Use of cyclosporine and ketoconazole without nephrotoxicity in two heart transplant recipients. J Heart Transplant. 1987 Mar-Apr;6(2):84–89. [PubMed] [Google Scholar]
  19. Senekowitsch R., Reidel G., Möllenstädt S., Kriegel H., Pabst H. W. Curative radioimmunotherapy of human mammary carcinoma xenografts with iodine-131-labeled monoclonal antibodies. J Nucl Med. 1989 Apr;30(4):531–537. [PubMed] [Google Scholar]
  20. Sgouros G. Radioimmunotherapy of micrometastases: sidestepping the solid-tumor hurdle. J Nucl Med. 1995 Oct;36(10):1910–1912. [PubMed] [Google Scholar]
  21. Siler K., Eggensperger D., Hand P. H., Milenic D. E., Miller L. S., Houchens D. P., Hinkle G., Schlom J. Therapeutic efficacy of a high-affinity anticarcinoembryonic antigen monoclonal antibody (COL-1). Biotechnol Ther. 1993;4(3-4):163–181. [PubMed] [Google Scholar]
  22. Wahl R. L. Experimental radioimmunotherapy. A brief overview. Cancer. 1994 Feb 1;73(3 Suppl):989–992. doi: 10.1002/1097-0142(19940201)73:3+<989::aid-cncr2820731336>3.0.co;2-u. [DOI] [PubMed] [Google Scholar]
  23. Ward B. G., Wallace K., Shepherd J. H., Balkwill F. R. Intraperitoneal xenografts of human epithelial ovarian cancer in nude mice. Cancer Res. 1987 May 15;47(10):2662–2667. [PubMed] [Google Scholar]
  24. Yu B., Carrasquillo J., Milenic D., Chung Y., Perentesis P., Feuerestein I., Eggensperger D., Qi C. F., Paik C., Reynolds J. Phase I trial of iodine 131-labeled COL-1 in patients with gastrointestinal malignancies: influence of serum carcinoembryonic antigen and tumor bulk on pharmacokinetics. J Clin Oncol. 1996 Jun;14(6):1798–1809. doi: 10.1200/JCO.1996.14.6.1798. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES