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Recombinant heregulin-Pseudomonas exotoxin fusion proteins: interactions with the heregulin receptors and antitumor activity in vivo.

Publication ,  Journal Article
Yang, D; Kuan, CT; Payne, J; Kihara, A; Murray, A; Wang, LM; Alimandi, M; Pierce, JH; Pastan, I; Lippman, ME
Published in: Clin Cancer Res
April 1998

Growth factor receptors provide unique opportunities for development of targeted anticancer therapy. Members of the type I receptor tyrosine kinase family, including epidermal growth factor (EGF) receptor (EGFR) and ErbB-2/neu, are often overexpressed in various human cancer cells, including breast. Recently, it has been shown that both ErbB-3 and ErbB-4 are receptors for heregulin (HRG)/Neu differentiation factor. Eight chimeric toxins composed of the extracellular and EGF-like domains of four different HRG isoforms and truncated Pseudomonas exotoxin (PE38KDEL) were constructed. The fusion proteins exhibited activity similar to the native HRG in inducing ErbB receptors phosphorylation. The EGF-like domain of HRG13 and HRGbeta2 fused to PE38KDEL showed the highest cytotoxic activity, with a IC50 of < or = 0.001 ng/ml. The alpha isoforms that were fused to PE38KDEL were 100-fold less active than the beta isoforms. The HRG-Pseudomonas exotoxin (PE) toxins show extremely high activity against cells expressing ErbB-4 receptor, alone or together with other members of the ErbB receptor family. Cells that do not express ErbB-4 but express ErbB-3 receptor, together with the ErbB-2 or EGFR, exhibited moderate sensitivity to HRG-PE toxins. HRG-PE toxins have little or no activity against cells expressing EGFR, ErbB-2, or ErbB-3 alone. More than an 80% tumor regression was achieved by intratumor injection of 1 microg of fusion proteins per day for 5 days. Continuous i.p. administration of EGF-like domain of HRGbeta1-PE38KDEL for 7 days via a miniosmotic pump at a dose of 40 microg/kg/day inhibited the growth of ErbB-4 receptor positive but not ErbB-4 receptor negative cell lines in athymic nude mice. We conclude that there is therapeutic potential of HRG-PE toxins in the therapy of cancers overexpressing the ErbB-4 or ErbB-2 plus ErbB-3 receptors.

Duke Scholars

Published In

Clin Cancer Res

ISSN

1078-0432

Publication Date

April 1998

Volume

4

Issue

4

Start / End Page

993 / 1004

Location

United States

Related Subject Headings

  • Tyrosine
  • Tumor Cells, Cultured
  • Stomach Neoplasms
  • Recombinant Fusion Proteins
  • Receptor, erbB-3
  • Receptor, ErbB-3
  • Proto-Oncogene Proteins
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Mice, Nude
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Yang, D., Kuan, C. T., Payne, J., Kihara, A., Murray, A., Wang, L. M., … Lippman, M. E. (1998). Recombinant heregulin-Pseudomonas exotoxin fusion proteins: interactions with the heregulin receptors and antitumor activity in vivo. Clin Cancer Res, 4(4), 993–1004.
Yang, D., C. T. Kuan, J. Payne, A. Kihara, A. Murray, L. M. Wang, M. Alimandi, J. H. Pierce, I. Pastan, and M. E. Lippman. “Recombinant heregulin-Pseudomonas exotoxin fusion proteins: interactions with the heregulin receptors and antitumor activity in vivo.Clin Cancer Res 4, no. 4 (April 1998): 993–1004.
Yang D, Kuan CT, Payne J, Kihara A, Murray A, Wang LM, et al. Recombinant heregulin-Pseudomonas exotoxin fusion proteins: interactions with the heregulin receptors and antitumor activity in vivo. Clin Cancer Res. 1998 Apr;4(4):993–1004.
Yang D, Kuan CT, Payne J, Kihara A, Murray A, Wang LM, Alimandi M, Pierce JH, Pastan I, Lippman ME. Recombinant heregulin-Pseudomonas exotoxin fusion proteins: interactions with the heregulin receptors and antitumor activity in vivo. Clin Cancer Res. 1998 Apr;4(4):993–1004.

Published In

Clin Cancer Res

ISSN

1078-0432

Publication Date

April 1998

Volume

4

Issue

4

Start / End Page

993 / 1004

Location

United States

Related Subject Headings

  • Tyrosine
  • Tumor Cells, Cultured
  • Stomach Neoplasms
  • Recombinant Fusion Proteins
  • Receptor, erbB-3
  • Receptor, ErbB-3
  • Proto-Oncogene Proteins
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Mice, Nude