Receptor-mediated photo-cytotoxicity: synthesis of a photoactivatable psoralen derivative conjugated to insulin.
4'-Aminomethyl-4,5',8-trimethylpsoralen has been chemically conjugated to insulin using a carbodiimide derivative. The psoralen moiety retains its photochemical reactivity as evidenced by its ability to crosslink DNA after exposure to long wavelength ultraviolet light (UVA, 320-400 nm). This chimeric molecule has been used to selectively kill a population of lymphocytes whose expression of insulin receptors has been stimulated with phytohemagglutinin. Insulin carries the psoralen into the cell via receptor-mediated endocytosis, where it is subsequently activated by exposure to UVA light. The UVA induced activity of AMT-insulin can be blocked by the presence of native insulin. The viability of unstimulated lymphocytes was not affected by AMT-insulin and UVA light. The hybrid insulin-psoralen molecule may be a prototype for a family of phototoxic drugs which can be selectively delivered to subsets of lymphocytes.
D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D004705:Endocytosis; D011564:Furocoumarins / Q000008:administration & dosage*; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000008:administration & dosage; D008213:Lymphocyte Activation; D010777:Photochemistry; D011972:Receptor, Insulin / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects*; D014307:Trioxsalen / Q000008:administration & dosage* / Q000031:analogs & derivatives
D011564:Furocoumarins; D007328:Insulin; D004247:DNA; C018822:aminomethyltrioxsalen; D011972:Receptor, Insulin; D014307:Trioxsalen