Epidermal growth factor-toxin A chain conjugates: EGF-Ricin A is a potent toxin while EGF-diphtheria fragment A is nontoxic

Daniel B. Cawley, Harvey R. Herschman, D. Gary Gilliland, R. John Collier

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

We have prepared a 2-pyridyl-dithiopropionate derivative of epidermal growth factor (EGF) and conjugated the derivative by disulfide interchange to the A chain of ricin (RTA) or to fragment A of diphtheria toxin (DTA). The EGF-RTA conjugate was toxic to 3T3 cells at concentrations (10−9–10−11 M) similar to those at which EGF exerts its biological activity and within an order of magnitude of the toxicity of ricin. Ricin A chain alone only exerted toxic effects at concentrations (10−6–10−7 M) three to four orders of magnitude higher than required for the activity of the EGF-RTA conjugate or ricin. An unconjugated mixture of RTA and EGF had no greater effect than RTA alone. Toxicity of the EGF-RTA conjugate on 3T3 cells was competed by EGF and was blocked by antibodies to RTA, but not by lactose or antibodies to the ricin B chain (RTB). In contrast to the EGF-RTA conjugate, the EGF-DTA conjugate proved virtually nontoxic at concentrations as high as 3 × 10−8 M. Control experiments showed that the EGF-DTA conjugate retained EGF receptor binding activity; the DTA moiety of the hybrid retained ADP-ribosyltransferase activity; and the disulfide bridge linking DTA to EGF was readily reducible.

Original languageEnglish (US)
Pages (from-to)563-570
Number of pages8
JournalCell
Volume22
Issue number2
DOIs
StatePublished - Jan 1 1980

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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