Diphtheria Toxin-Epidermal Growth Factor Fusion Protein and Pseudomonas Exotoxin-Interleukin 13 Fusion protein Exert synergistic Toxicity against human Glioblastoma multiforme cells

摘要

The cytotoxicity of combinations of a diphtheria toxin-human epidermal growth factor fusion protein (DAB_389EGF)and a Pseudomonas exotoxin-human interleukin 13 fusion protein (IL13PE38QQR)was tested against 14 human glioma cell lines.After cells were cultured for 48 h with various concentrations of the fusion proteins,the percentage reductions in thymidine incorporation were determined.Seven of fourteen cell lines were highly sensitive to DAB_389EGF alone,and six cell lines were highly sensitive to IL13PE38QQR alone with IC_90's<100 pM.When combined,synergistic cel killing was observed for seven of hte cell lines based upon concave isobolograms and combination indices (CI's)of 0.2 to 0.7.Supraadditive cytotoxicitky was confirmed by measurements of induction of apoptosis.Receptor expression was assessed by flow cytometry ad confocal microscopy.Marked heterogeneity may contribute to incomplete cell lilling with the individual fusion proteins and synergistic cell kill with the combination.These results suggest that both fusion proteins may yield antitumor effects in partients with recurrent gliomas and that combinatin fusion protein intracranial therapy of malignant gliomas may yield an improved therapeutic index.