Selective toxicity of TGF-alpha-PE40 to EGFR-positive cell lines: selective protection of low EGFR-expressing cell lines by EGF.
The sensitivity of human breast and lung cancer cell lines to TGF-alpha-PE40, a novel chimeric recombinant cytotoxin composed of two independent domains, (i) TGF-alpha and (ii) a 40 kDa segment of the Pseudomonas exotoxin protein, PE-40, was investigated. Toxicity varied widely, correlated with epidermal growth factor receptor (EGFR) levels (P = 0.01) and was greatly reduced by EGF, indicating that binding of TGF-alpha-PE40 to EGFR is important in mediating toxicity. Cell lines expressing low EGFR levels were most highly protected by EGF, indicating that normal (low EGFR-expressing) tissue may be selectively protected by EGF in vivo. P-glycoprotein did not confer resistance to TGF-alpha-PE40, and toxicity was unaffected by multidrug resistance-modulating agents (cyclosporin A, tamoxifen, verapamil), indicating a role for TGF-alpha-PE40 in the clinical management of drug-resistant tumours.
Kirk
J
J
ICRF Laboratories, Institute of Molecular Medicine, Headington, UK.
Carmichael
J
J
Stratford
I J
IJ
Harris
A L
AL
D001943:Breast Neoplasms; D002289:Carcinoma, Non-Small-Cell Lung; D018288:Carcinoma, Small Cell; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016572:Cyclosporine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000032:analysis / Q000187:drug effects / Q000378:metabolism*; D005098:Exotoxins / Q000633:toxicity*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D011993:Recombinant Fusion Proteins / Q000633:toxicity; D011994:Recombinant Proteins / Q000633:toxicity; D013629:Tamoxifen / Q000633:toxicity; D016211:Transforming Growth Factor alpha / Q000633:toxicity*; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D005098:Exotoxins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D016211:Transforming Growth Factor alpha; C062005:transforming growth factor type alpha-Pseudomonas exotoxin A; D013629:Tamoxifen; D004815:Epidermal Growth Factor; D016572:Cyclosporine; D014700:Verapamil; D066246:ErbB Receptors