Targeted toxins approaches against glioblastoma were under investigation in phase I and II clinical trials with several immunotoxins (IT)/ligand toxins such as IL4-Pseudomonas aeruginosa exotoxin A (IL4-PE, NBI-3001), tumour growth factor fused to PE38, a shorter PE variant, (TGF)alpha-TP-38, IL13-PE38, and a transferrin-C diphtheriae toxin mutant (Tf-CRM107).
Antisense oligonucleotides (oligos) against transforming growth factor-alpha (TGF-alpha) (MR1) and its binding site, the epidermal growth factor receptor (EGFR) (MR2), are efficacious against the UACC 897 breast, PC-3 and LNCaP prostate, and T98G glioblastoma tumor lines in both in vitro and in vivo studies.
Treatment of the T98G glioblastoma cell line with antisense oligonucleotides directed toward mRNA encoding transforming growth factor-alpha and the epidermal growth factor receptor.
To identify genes that may be critical in mediating TGF-alpha impact on the malignant progression of astrocytomas, we have used cDNA arrays to investigate TGF-alpha effects on the gene expression profile of U-373 MG glioblastoma cells.
Amplification of epidermal growth factor receptor, transforming growth factor alpha and N-myc which have been described previously in glioblastoma were not observed in T3095.
The specificity of the elevated transcription of TGF-alpha, TGF-beta, bFGF and flg in glioblastoma cell lines is further suggested by the fact that the transcription of the proto-oncogene c-erbB2, which is overproduced in breast tumor cell lines, was not elevated in glioblastoma cell lines.
Preliminary histochemical observations showed that intracellular levels of transforming growth factor alpha, a putative biochemical link between these two oncogenes, were significantly higher in glioblastoma cells than in controls.