Summary
Models for hematogenous spread of human cancer to the central nervous system (CNS) were established by injecting human tumor cells into the internal carotid artery of nude rats. With 4 out of 10 cell lines, belonging to four different tumor types, metastases developed in all injected animals. Tumor growth manifested clinically as neurological symptoms which appeared after a median latency ranging from 19–87 days for the different tumors. The H-146 and DMS-273 small cell lung cancers and the LOX melanoma almost exclusively gave meningeal tumors, whereas with FEMX-I melanoma cells bone metastases in the skull dominated. For these tumor types a correlation was found between the capacity for experimental metastasis formation and the s.c. tumorigenicity. In agreement with clinical experience, none of the 2 sarcoma and 2 glioblastoma lines gave CNS metastases. With a modified microsurgical technique, allowing for repeated ipsilateral intracarotid injections, we analyzed the drug concentrations obtained in tumor and surrounding brain tissue after i.v. treatment with doxorubicin. The concentration in the LOX tumor reached therapeutic levels and was approximately 100 × higher than in normal brain tissue, both with and without intraarterial pretreatment with arabinose. In the same model, the tissue concentrations of 9.2.27-abrin immunotoxin 10 min after intracarotid injection were examined. Although the levels were low, a tumor to brain concentration ratio of up to 9 was achieved. The data demonstrate that clinically relevant tumor models can be established with the techniques described, and these models may successfully be used to evaluate the pharmacokinetics and effect of intravenous or intraarterial therapy.
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References
Gamache FWJR, Posner JB, Patterson RHJR: Metastatic brain tumors. In: Youmans JR (ed) Neurological surgery. Springer-Verlag, Philadelphia, 1982, pp 2872–2898
Zülch KJ: Metastatic tumors. In: Zülch KJ (ed) Brain Tumors: Their Biology and Pathology. Springer Verlag, Berlin, 1986, pp 490–498
Schackert G, Fidler IJ: Site-specific metastasis of mouse melanomas and a fibrosarcoma in the brain or meninges of syngeneic animals. Cancer Res 48: 3478–3484, 1988
Schackert G, Price JE, Zhang RD, Bucana CD, Itoh K, Fidler IJ: Regional growth of different human melanomas as metastases in the brain of nude mice. Am J Pathol 136: 95–102, 1990
KjØnniksen I, HØifØdt HK, Pihl A, Fodstad Ø: Different metastasis patterns of a human melanoma cell line in nude mice and rats: Influence of microenvironment. J Natl Cancer Inst 83: 1020–1024, 1991
Carney DN, Gazdar AF, Bepler G, Guccion JG, Marangos PJ, Moody TW, Zweig MH, Minna JD: Establishment and identification of small cell lung cancer cell lines having classic and variant features. Cancer Res 45: 2913–2923, 1985
Pettengill OS, Sorensen GD: Tissue culture andin vitro characteristics. In: Greco AF (ed) Small Cell Lung Cancer. Grune and Stratton, New York, 1981, pp 51–77
Myklebust AT, Beiske K, Pharo A, Davies CdeL, Aamdal S, Fodstad Ø: Selection of anti-SCLC antibodies for diagnosis of bone marrow metastasis. Br J Cancer (Suppl XII) 63: 49–53, 1991
Fodstad Ø, Aamdal S, McMenamin M, Nesland JM, Pihl A: A new experimental metastasis model in athymic nude mice, the human malignant melanoma LOX. Int J Cancer 41: 442–449, 1988
Fodstad Ø, KjØnniksen I, Aamdal S, Nesland JM, Boyd MR, Pihl A: Extrapulmonary, tissue-specific metastasis formation in nude mice injected with FEMX-I human melanoma cells. Cancer Res 48: 4382–4388, 1988
Helseth E, Unsgaard G, Dalen A, Vik R: The effects of type beta transforming growth factor on proliferation and epidermal growth factor receptor expression in a human glioblastoma cell line. J Neurooncol 6: 269–276, 1988
Fodstad Ø, BrØgger A, Bruland Ø, Solheim ØP, Nesland JM, Pihl A: Characteristics of a cell line established from a patient with multiple osteosarcoma, appearing 13 years after treatment for bilateral retinoblastoma. Int J Cancer 38: 33–40, 1986
Morgan ACJr, Galloway DR, Reisfeld RA: Production and characterization of monoclonal antibody to a melanoma specific glycoprotein. Hybridoma 1: 27–38, 1981
Olsnes S: Toxic and nontoxic lectins from Abrus precatorius. In: Ginsburg V (ed) Complex carbohydrates. Academic Press, New York, 1978, pp 323–331
Godal A, Fodstad Ø, Morgan AC, Pihl A: Human melanoma cell lines showing striking inherent differences in sensitivity to immunotoxins containing holotoxins. J Natl Cancer Inst 77: 1247–1253, 1986
Fraker PJ, Speck JCJr: Protein and cell membrane iodinations with a sparingly soluble chloramide, 1,3,4,6-tetrachloro-3a,6a-diphenyl-glycouril. Biochem Biophys Res Commun 80: 849–857, 1978
Auerbach R, Lu WC, Pardon E, Gumkowski F, Kaminska G, Kaminski M: Specificity of adhesion between murine tumor cells and capillary endothelium: anin vitro correlation of preferential metastasisin vivo. Cancer Res 47: 1492–1496, 1987
Fodstad Ø, Aass N, Pihl A: Assessment of tumor growth and of human melanomas in athymic, nude mice. Br J Cancer (Suppl IV) 41: 146–149, 1980
Rapoport SI, Fredericks WR, Ohno K, Pettigrew KD: Quantitative aspects of reversible osmotic opening of the blood-brain barrier. Am J Physiol 238: R421-R423, 1980
Aronson M, Garcia JH, Aronson BE: Metastatic neoplasms of the brain: their frequency in relation to age. Cancer 17: 558–563, 1964
Abrams J, Doyle LA, Aisner J: Staging, prognostic factors, and special considerations in small cell lung cancer. Semin Oncol 15: 261–277, 1988
Neuwelt EA, Frenkel EP, D'Agostino AN, Carney DN, Minna JD, Barnett PA, McCormick CI: Growth of human lung tumor in the brain of the nude rat as a model to evaluate antitumor agent delivery across the blood-brain barrier. Cancer Res 45: 2827–2833, 1985
Johnson VG, Wrobel C, Wilson D, Zovickian J, Greenfield L, Oldfield EH, Youle R: Improved tumor-specific immunotoxins in the treatment of CNS and leptomeningeal neoplasia. J Neurosurg 70: 240–248, 1989
Myklebust AT, Godal A, Fodstad Ø: Targeted therapy with immunotoxins in a nude rat model for leptomeningeal growth of human small cell lung cancer. Cancer Res 54: 2146–2150, 1994
Fidler IJ: Rationale and methods for the use of nude mice to study the biology and therapy of human cancer metastasis. Cancer Metastasis Rev 5: 29–49, 1986
Fodstad Ø: Transplantability of human tumors in nude mice. In: Boven E, Winograd B (eds) The Nude Mouse in Oncology Research. CRC Press, Amsterdam, 1991, pp 65–80
Shapiro WR, Basler GA, Chernik NL, Posner JB: Human brain tumor transplantation into nude mice. J Natl Cancer Inst 62: 447–452, 1979
Schrappe M, Klier FG, Spiro RC, Waltz TA, Reisfeld RA, Gladson CL: Correlation of chondroitin sulfate proteoglycan expression on proliferating brain capillary endothelial cells with the malignant phenotype of astroglial cells. Cancer Res 51: 4986–4993, 1991
Liotta LA, Rao CN, Wewer UM: Biochemical interactions of tumor cells with the basement membrane. Annu Rev Biochem 55: 1037–1057, 1986
Liotta LA, Stetler-Stevenson W: Metalloproteinases and malignant conversion: does correlation imply causality? J Natl Cancer Inst 81: 556–557, 1989
Nicolson GL: Organ specificity of tumor metastases; role of preferential adhesion, invasion and growth of malignant cells at specific secondary sites. Cancer Metastasis Rev 7: 143–188, 1988
KjØnniksen I, Storeng R, Pihl A, McLemore TL, Fodstad Ø: A human tumor lung metastasis model in athymic nude rats. Cancer Res 49: 5148–5152, 1989
Shoemaker RH, Dykes DJ, Plowman J, Harrison SD, Griswold DPJr, Abbott BJ, Mayo JG, Fodstad O, Boyd MR: Practical spontaneous metastasis model forin vivo therapeutic studies using a human melanoma. Cancer Res 51: 2837–2841, 1991
Schackert G, Price JE, Bucana CD, Fidler IJ: Unique patterns of brain metastasis produced by different human carcinomas in athymic nude mice. Int J Cancer 44: 892–897, 1989
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Myklebust, A.T., Helseth, A., Breistøl, K. et al. Nude rat models for human tumor metastasis to CNS. J Neuro-Oncol 21, 215–224 (1994). https://doi.org/10.1007/BF01063770
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DOI: https://doi.org/10.1007/BF01063770