Epidermal growth factor-toxin A chain conjugates: EGF-ricin A is a potent toxin while EGF-diphtheria fragment A is nontoxic.
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 X 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.[1]References
- Epidermal growth factor-toxin A chain conjugates: EGF-ricin A is a potent toxin while EGF-diphtheria fragment A is nontoxic. Cawley, D.B., Herschman, H.R., Gilliland, D.G., Collier, R.J. Cell (1980) [Pubmed]
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