Recombinant toxin DAB389EGF produces regressions of human glioma xenografts in nude mice

Abstract

3101 Background: DAB389EGF, composed of the catalytic and translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal growth factor is selectively toxic to epidermal growth factor receptor (EGFR) overexpressing human glioma cells (Curr Pharm Biotech, 4, 39, 2003; Cancer Res, 63, 1834, 2003; J Neurooncol, 65, 77, 2003; Bioconj Chem, 14, 1167, 2003). Based on this in vitro activity and the high frequency of EGFR expression in human gliomas (Mol Cancer Ther, 2, 783, 2003), we examined the in vivo anti-glioma activity of DAB389EGF. Methods: Groups of five 8 wk old female athymic nu/nu mice were inoculated with 10 million U87MG human glioma cells subcutaneously. After tumors grew to at least 100 mm3, intra-tumor injections were given in 50 microliter volume every other day of saline or DAB389EGF (1, 5, or 10 μg). Tumor size and animal weights were recorded. After one month, animals were euthanized, and tumor samples were examined by routine histology, immuno-reactivity with anti-EGFR antibody, and sensitivity to DAB389EGF in tissue culture. Results: Tumor regressions and inhibition of growth were observed at all dose levels of DAB389EGF as shown in the table below. At the highest dose levels (10 μg), histology showed only a few residual tumor cells. At the lower dose levels (1 and 5 μg), residual tumor was observed and retained EGFR positivity and DAB389EGF sensitivity. The growth inhibition was significant for all dose levels analyzed by the Student's t test (one-sided) p=0.01, 0.005, and <0.0001 for DAB389EGF 1ug, 5ug and 10ug, respectively. Conclusions: DAB389EGF is an excellent candidate agent for interstitial therapy of high-grade gliomas. No significant financial relationships to disclose.