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Diphtheria toxin-epidermal growth factor fusion protein DAB389EGF for the treatment of bladder cancer.

Publication ,  Journal Article
Yang, X; Kessler, E; Su, L-J; Thorburn, A; Frankel, AE; Li, Y; La Rosa, FG; Shen, J; Li, C-Y; Varella-Garcia, M; Glodé, LM; Flaig, TW
Published in: Clin Cancer Res
January 1, 2013

PURPOSE: The novel fusion protein, DAB(389)EGF, is composed of both the catalytic and the translocation domains of diphtheria toxin that are fused to the human EGF, providing a targeting and a toxicity component. We tested DAB(389)EGF for antitumor activity in both in vitro and in vivo urinary bladder cancer models. EXPERIMENTAL DESIGN: Human bladder cancer lines were treated with DAB(389)EGF and assessed for growth inhibition and clonogenic suppression. Using 6- to 8-week-old female athymic nude mice implanted orthotopically with HTB9 cells, DAB(389)EGF was administered intravesically twice weekly for 2 weeks. The response of the luciferase-expressing HTB9 cells was monitored via bioluminescence as the primary endpoint. RESULTS: Treatment response with DAB(389)EGF was specific and robust, with an IC(50) ranging from 0.5 to 15 ng/mL in eight tested bladder cancer cell lines, but greater than 50 ng/mL in the EGF receptor (EGFR)-negative H520 control cell line. Simulating short-duration intravesical therapy used clinically, a 2-hour treatment exposure of DAB(389)EGF (10 ng/mL) produced clonogenic suppression in three selected bladder cancer cell lines. In vivo, luciferase activity was suppressed in five of six mice treated with DAB(389)EGF [70 μL (1 ng/μL) per mouse], as compared with only one of six mice treated with a control diphtheria toxin (DT) fusion protein. Histologic assessment of tumor clearance correlated with the bioluminescent changes observed with DAB(389)EGF treatment. Immunocompetent mice treated with intravesical DAB(389)EGF did not show any nonspecific systemic toxicity. CONCLUSIONS: The intravesical delivery of targeted toxin fusion proteins is a novel treatment approach for non-muscle-invasive urinary bladder cancer. With appropriate targeting, the treatments are effective and well-tolerated in vivo.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

January 1, 2013

Volume

19

Issue

1

Start / End Page

148 / 157

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Urinary Bladder Neoplasms
  • Tumor Stem Cell Assay
  • Recombinant Fusion Proteins
  • Oncology & Carcinogenesis
  • Mice
  • Humans
  • Female
  • ErbB Receptors
  • Dose-Response Relationship, Drug
 

Citation

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Yang, X., Kessler, E., Su, L.-J., Thorburn, A., Frankel, A. E., Li, Y., … Flaig, T. W. (2013). Diphtheria toxin-epidermal growth factor fusion protein DAB389EGF for the treatment of bladder cancer. Clin Cancer Res, 19(1), 148–157. https://doi.org/10.1158/1078-0432.CCR-12-1258
Yang, Xiaoping, Elizabeth Kessler, Lih-Jen Su, Andrew Thorburn, Arthur E. Frankel, Yuan Li, Francisco G. La Rosa, et al. “Diphtheria toxin-epidermal growth factor fusion protein DAB389EGF for the treatment of bladder cancer.Clin Cancer Res 19, no. 1 (January 1, 2013): 148–57. https://doi.org/10.1158/1078-0432.CCR-12-1258.
Yang X, Kessler E, Su L-J, Thorburn A, Frankel AE, Li Y, et al. Diphtheria toxin-epidermal growth factor fusion protein DAB389EGF for the treatment of bladder cancer. Clin Cancer Res. 2013 Jan 1;19(1):148–57.
Yang, Xiaoping, et al. “Diphtheria toxin-epidermal growth factor fusion protein DAB389EGF for the treatment of bladder cancer.Clin Cancer Res, vol. 19, no. 1, Jan. 2013, pp. 148–57. Pubmed, doi:10.1158/1078-0432.CCR-12-1258.
Yang X, Kessler E, Su L-J, Thorburn A, Frankel AE, Li Y, La Rosa FG, Shen J, Li C-Y, Varella-Garcia M, Glodé LM, Flaig TW. Diphtheria toxin-epidermal growth factor fusion protein DAB389EGF for the treatment of bladder cancer. Clin Cancer Res. 2013 Jan 1;19(1):148–157.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

January 1, 2013

Volume

19

Issue

1

Start / End Page

148 / 157

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Urinary Bladder Neoplasms
  • Tumor Stem Cell Assay
  • Recombinant Fusion Proteins
  • Oncology & Carcinogenesis
  • Mice
  • Humans
  • Female
  • ErbB Receptors
  • Dose-Response Relationship, Drug