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Development of a Large-Animal Human Brain Tumor Xenograft Model in Immunosuppressed Cats¹

Division of Neurosurgery, Department of Surgery [B. W. K., M. A. F.-J., J. D. M., B. K. W., K. C. P.], and Division of Neuropathology, Department of Pathology [B. M.], University of Alberta, Edmonton, Alberta T6G 2G3, Canada

A large-animal model was developed to facilitate the noninvasive investigation of the effect on the human glioma-derived D-54 MG (glioblastoma multiforme) continuous cell line of a variety of therapeutic regimens. Twenty random-bred male cats were inoculated intracerebrally with 1 x 10⁷ D-54 MG tumor cells after being initiated on one of three preparatory regimens of cyclosporin A p.o. Reproducible success of D-54 MG xenotransplantation (100%, 6 of 6 cats) was achieved only after pretreatment with 120 mg cyclosporin A p.o. (24–30 mg/kg) daily for 10 days prior to tumor implantation. High-performance liquid chromatography-derived whole blood cyclosporin A 12-h trough levels of 640 ng/ml were seen in successful implants. Lesions ranging from 2 to 20 mm in diameter were seen in cats sacrificed 27–44 days after implantation with no growth seen in control animals.

Histopathological examination revealed the tumors to be well-circumscribed anaplastic intracerebral tumors with some invasion into surrounding host parenchyma. Perivascular lymphocytic cuffing was observed, but intratumoral lymphocytic infiltration was minimal. Gadolinium-EDTA-enhanced nuclear magnetic resonance imaging provided accurate tumor localization in T₁-weighted images (T_E 26 ms; T_R 600 ms). Biochemical tests of kidney, liver, and hematological function were within normal limits, although 10% (2 of 20) of the animals developed gingival hyperplasia, and 5% (1 of 20) developed intussusception.

The reproducible growth of the D-54 MG human glioblastoma cell line in a large-animal model eliminates many of the limitations associated with the standard nude mouse/rat model, thereby providing a novel test bed for a variety of imaging modalities as well as for drug immunoconjugate localization and toxicity studies.

¹ Supported by Alberta Cancer Board Grant RIP 18 and the Alberta Heritage Foundation for Medical Research (B. W. K.)

² To whom requests for reprints should be addressed, at Department of Surgery, Division of Neurosurgery, University of Alberta Hospitals, 2D1.02 Walter Mackenzie Health Sciences Centre, 8840-112 St., Edmonton, Alberta T6G 2G3, Canada.

Received 10/ 5/90. Accepted 2/15/91.