WALTER A. HALL:  FRIDAY 31 MARCH 2006, 16:55

Anti-Angiogenic Targeted Toxins against Malignant Gliomas

Walter Hall*, Edward Rustamzadeh*, Daniel Vallera*
Neurosurgery, University of Minnesota, 55403 Minneapolis, USA
* These authors contributed equally to this work

A recombinant hybrid fusion protein DTAT was created using a mutated diphtheria toxin (DT) linked to the amino terminal (AT) fragment of human urokinase-type plasminogen activator (uPA). DTAT has the advantage over other fusion proteins of targeting malignant glioma cells and the neovasculature that supplies the tumor. The toxicity, specificity and efficacy of DTAT were evaluated in an intracranial model of human GBM. The maximum tolerated dose (MTD) of DTAT was determined for three consecutive injections administered every-other-day and by convection enhanced delivery (CED). Intratumoral injection of 0.15 µg every other day for 3 doses was performed in a murine intracranial U87MG GBM model. Convection enhanced delivery of DTAT on an every-other-day basis in nude mice with established U87MG brain tumors resulted in significant reductions in tumor volume and prolongation of survival in treated animals compared to controls (P < 0.0001). Magnetic resonance (MR) imaging was performed to evaluate the brain for neurotoxicity and the tumor for a therapeutic response. The total MTD for DTAT was 0.45 µg and the total MTD using CED was 5 µg. Toxicity was manifest as weight loss and cerebral infarction. MR imaging demonstrated a marked decrease in tumor burden and no evidence of intracranial hemorrhage or vascular leak syndrome. DTAT is an active agent against intracranial GBM without demonstrating evidence of hemorrhage on MR imaging or neurotoxicity on histologic examination. These results support the further development of DTAT for future clinical trials in patients with GBM.

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