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Activity of a recombinant transforming growth factor-α-Pseudomonas exotoxin hybrid protein against primary human tumor colony-forming units

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Summary

Transforming growth factor-α-Pseudomonas exotoxin-40 (TP40) is a recombinant fusion protein. TP40 consists of the entire human transforming growth factor-α (TGFα) protein fused to a 40,000 Da. segment of thePseudomonas exotoxin A protein. TP40 is a bifunctional molecule that possesses the epidermal growth factor (EGF) receptor binding properties of TGFα and the cell killing properties ofPseudomonas exotoxin A. These properties make TP40 a selective cytotoxic agent that kills EGF receptor bearing cells. TP40 has been shown to effectively kill human tumor cell lines that possess EGF receptorsin vitro and in nude mice. In the present study, TP40 was tested against tumors taken directly from patients and grown in a soft agar human tumor cloning system. A total of 107 patients' tumors (taken from patients with tumors refractory to chemotherapy) were tested with a continuous exposure to 0.5–50 nM concentrations of the agent. TP40 exhibited a clear dose response effect against a wide variety of human solid tumor colony-forming units with ≥ 84% of evaluable tumors responding at a drug concentration ≥ 24 nM. When used as a continuous exposure, concentrations of TP40 as low as 5 nM demonstrated substantialin vitro activity. This activity included cytotoxicity against breast, colorectal, endometrial, head and neck, non small-cell lung, gastric, sarcoma, and pancreatic cancer tumor colony-forming units. Additionalin vivo testing of this compound is warranted.

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Abbreviations

TP40:

recombinant transforming growth factor-α-PE40 toxin hybrid protein

HTCA:

human tumor cloning assay

TFG-α :

transforming growth factor-α

EGF:

epidermal growth factor

PBS:

phosphate buffered saline

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Authors and Affiliations

  1. Cancer Therapy and Research Center of South Texas, 4450 Medical Drive, 78229, San Antonio, TX, USA

    Daniel D. Von Hoff & Martha H. Marshall

  2. Merck Sharp & Dohme Research Laboratories, West Point, 19486, PA, USA

    David C. Heimbrook, Steven M. Stirdivant, Janet D. Ahern, Wayne K. Herbert, Robert Z. Maigetter & Allen Oliff

Authors
  1. Daniel D. Von Hoff
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  2. Martha H. Marshall
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  3. David C. Heimbrook
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  4. Steven M. Stirdivant
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  5. Janet D. Ahern
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  6. Wayne K. Herbert
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  7. Robert Z. Maigetter
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  8. Allen Oliff
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Von Hoff, D.D., Marshall, M.H., Heimbrook, D.C. et al. Activity of a recombinant transforming growth factor-α-Pseudomonas exotoxin hybrid protein against primary human tumor colony-forming units. Invest New Drugs 10, 17–22 (1992). https://doi.org/10.1007/BF01275472

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