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Intracerebral infusion of the bispecific targeted toxin DTATEGF in a mouse xenograft model of a human metastatic non-small cell lung cancer

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Abstract

The aim of this study is to investigate the anti-cancer effect of the bispecific diphtheria toxin (DT) based immunotoxin DTATEGF, which targets both the epidermal growth factor (EGF) receptor (EGFR) and the urokinase-type plasminogen activator (uPA) receptor (uPAR) in vitro and in vivo when delivered by convection-enhanced delivery (CED) via an osmotic minipump in a human metastatic non-small cell lung cancer (NSCLC) brain tumor mouse xenograft model. The effects of the bispecific immunotoxin DTATEGF, and monospecific DTAT, DTEGF and control DT at various concentrations were tested for their ability to inhibit the proliferation of human metastatic NSCLC PC9-BrM3 cells in vitro by MTT assay. A xenograft model of human metastatic NSCLC intracranial model was established in nude mice using the human NSCLC PC9-BrM3 cell line genetically marked with a firefly luciferase reporter gene. One microgram of DTATEGF in the treatment group or control DT in the control group was delivered intracranially by CED via an osmotic minipump. The bioluminescent imaging (BLI) was performed at day 7, 14, 1 month, 2 months, and 3 months. Kaplan–Meier survival curves for the two groups were generated. The brain tissue samples were stained by hematoxylin and eosin for histopathological assessment. In vitro, DTATEGF could selectively kill PC9-BrM3 cells and showed an IC50 less than 0.001 nM, representing a more than 100- to 1000-fold increase in activity as compared to monospecific DTAT and DTEGF. In vivo, mice with tumors were treated intracranially with drug via CED where the results showed the treatment was successful in providing a survival benefit with the median survival of mice treated with DTATEGF being significantly prolonged relative to controls (87 vs. 63 days, P = 0.006). The results of these experiments indicate that DTATEGF kills the NSCLC PC9-BrM3 cell line in vitro, and when it is delivered via CED intracranially, it is highly efficacious against metastatic NSCLC brain tumors. DTATEGF is a safe and effective drug where further preclinical and clinical development is warranted for the management of metastatic brain tumors.

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Abbreviations

CED:

Convection-enhanced delivery

NSCLC:

Non-small cell lung cancer

EGF:

Epidermal growth factor

EGFR:

EGF receptor

uPAR:

Urokinase plasminogen activator receptor

BLI:

Bioluminescent imaging

IC50:

Half maximal inhibitory concentration

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Authors and Affiliations

  1. Department of Neurosurgery, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA

    Jun Huang, Yan Michael Li & Walter A. Hall

  2. Department of Neurosurgery, Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China

    Jun Huang

  3. Cancer Biology and Genetics Program, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Joan Massague

  4. Department of Therapeutic Radiology, University of Minnesota Medical School, Minneapolis, MN, USA

    Andy Sicheneder & Daniel A. Vallera

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  1. Jun Huang
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  2. Yan Michael Li
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  3. Joan Massague
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  5. Daniel A. Vallera
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Correspondence to Walter A. Hall.

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Huang, J., Li, Y.M., Massague, J. et al. Intracerebral infusion of the bispecific targeted toxin DTATEGF in a mouse xenograft model of a human metastatic non-small cell lung cancer. J Neurooncol 109, 229–238 (2012). https://doi.org/10.1007/s11060-012-0904-6

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  • DOI: https://doi.org/10.1007/s11060-012-0904-6

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