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Interstitial Diphtheria Toxin-Epidermal Growth Factor Fusion Protein Therapy Produces Regressions of Subcutaneous Human Glioblastoma Multiforme Tumors in Athymic Nude Mice

¹ Department of Medicine, Pathology, and Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina ² Department of Pharmaceutical Sciences, Medical University Of South Carolina, Charleston, South Carolina, USA

Requests for reprints: Arthur E. Frankel, Wake Forest University School of Medicine, Hanes 5045, Medical Center Boulevard, Winston-Salem, NC 27157. Phone: 336-716-3313; Fax: 336-716-9113; E-mail: afrankel{at}wfubmc.edu.

Purpose: The novel fusion protein, DAB₃₈₉EGF, composed of the catalytic and translocation domains of diphtheria toxin (DAB₃₈₉) fused with a His-Ala linker to human epidermal growth factor (EGF) was tested for antiglioma efficacy in an in vivo model of human glioma.

Experimental Design: Female athymic nude mice (ages 4-6 weeks) were inoculated s.c. with 10 million U87MG human glioma cells in the right flank. When tumor volumes reached 100 mm³ (6-8 days), i.t. injections of saline, DAB₃₈₉IL2, or DAB₃₈₉EGF 1, 3, 5 or 10 µg in 50 µL were given every other day for three to six doses. Animals were monitored twice daily and tumor measurements were made by calipers.

Results: The maximal tolerated dose (MTD) of DAB₃₈₉EGF was 3 µg every other day. Above the MTD, animals experienced loss of activity, reduced oral intake, and dehydration. Blood chemistries confirmed elevated blood urea nitrogen, creatinine, aspartate transaminase, and alanine transaminase. Histopathology revealed renal tubular necrosis. At the MTD, tumor regression was seen in all animals. Relapses occurred in 4 of 16 (25%) of animals after 1 month. These tumors contained EGF receptor, were sensitive in vitro to DAB₃₈₉EGF, and responded to a second course of i.t. DAB₃₈₉EGF.

Conclusions: DAB₃₈₉EGF fusion protein shows in vivo antiglioma efficacy in a s.c. tumor model and warrants further preclinical testing in an i.c. tumor model for eventual treatment of patients with recurrent or refractory EGF receptor–positive glioblastoma multiforme.

Key Words: glioblastoma multiforme • diphtheria toxin • epidermal growth factor receptor • fusion protein

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