In vitro efficacy of transferrin-toxin conjugates against glioblastoma multiforme.
The cytotoxic activity of immunotoxins constructed with human diferric transferrin (Tfn) as the carrier ligand and an abrin variant Pseudomonas exotoxin A (PE) and the diphtheria toxin mutant cross-reacting material (CRM) 107 as the toxin moieties were studied in vitro. Three malignant human cell lines, the glioblastomas multiforme SNB19 and SF295 and the LOX melanoma, and a nonhuman control murine melanoma cell line B16 were assessed. The presence of transferrin receptors on the cell lines was confirmed by direct 125I-Tfn binding assays. The 50% protein synthesis inhibitory concentration (IC50) values for all cell lines demonstrated that Tfn-abrin variant and Tfn-PE had comparable potency and were both more effective than Tfn-CRM 107. Monensin, a carboxylic ionophore, potentiated the effect of Tfn-abrin variant against glioma cells approximately 35-fold with IC50 values of 4.0 x 10(-13) M and 4.7 x 10(-12) M for SNB19 and SF295, respectively. Cytotoxic activity of Tfn-abrin variant (with or without monensin) and Tfn-PE was correlated with the degree of Tfn receptor expression measured on the cell lines. The exquisite in vitro cytotoxicity of Tfn-abrin variant and Tfn-PE immunotoxins against glioma and melanoma cells warrants further in vivo evaluation and future consideration of these agents for potential clinical application against glioblastoma multiforme and leptomeningeal neoplasia.
Hall
W A
WA
Department of Tumorbiology, Norwegian Radium Hospital, Oslo.
Godal
A
A
Juell
S
S
Fodstad
O
O
D036002:ADP Ribose Transferases; D000818:Animals; D001427:Bacterial Toxins; D001932:Brain Neoplasms / Q000188:drug therapy; D005098:Exotoxins / Q000494:pharmacology*; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D011990:Receptors, Transferrin / Q000378:metabolism; D014168:Transferrin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D011990:Receptors, Transferrin; D014168:Transferrin; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A