Efficacy of transferrin receptor-targeted immunotoxins in brain tumor cell lines and pediatric brain tumors.
The efficacy and cytotoxic properties of immunotoxin conjugates directed against the transferrin receptor were examined in cell lines and operative specimens from pediatric brain tumors. Dose-response relationships were assessed for immunotoxin-mediated inhibition of protein synthesis for two immunotoxins, 454A12-rRA and anti-tfnR-CRM 107. Three target medulloblastoma cell lines (DAOY, D283MED, and D341MED), a glioblastoma (U373), and a neuroblastoma (SH-SY5Y) cell line exhibited similar sensitivity to both immunotoxins with IC50s in the 10(-9)-10(-10) M range. The time course of protein synthesis inhibition by the immunotoxins in DAOY cells showed that inhibition by anti-tfnR-CRM 107 was rapid and apparent by 6 h of incubation. In contrast, a response to 454A12-rRA was not observed until 16 h. Cell viability was decreased 30-40% by 24 h after removing 454A12-rRA (1 x 10(-9) M) and was maximally decreased 70-80% after 3 days. The efficacy of the immunotoxins on a variety of fresh specimens of pediatric brain tumors was also examined. The more aggressive and malignant tumor types such as glioblastoma multiforme and medulloblastoma had low IC50 values (10(-12) M), indicating that these tumors were extremely sensitive to transferrin receptor-targeted immunotoxins. In general, protein synthesis in slow-growing and benign tumors was not as greatly affected by immunotoxins. Immunoblots showed expression of transferrin receptors on the cell lines and tumors which correlated with in vitro sensitivity to immunotoxin. The results demonstrate that two immunotoxins targeted to the transferrin receptor are efficacious in killing brain tumor cell lines and primary tumor cultures at very low concentrations and that highly malignant tumors are especially sensitive to this cytotoxic response.
Martell
L A
LA
Department of Surgery, University of Michigan Medical Center, Ann Arbor 48109.
Agrawal
A
A
Ross
D A
DA
Muraszko
K M
KM
D001932:Brain Neoplasms / Q000473:pathology* / Q000628:therapy; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D005910:Glioma / Q000473:pathology / Q000628:therapy; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology* / Q000627:therapeutic use; D008527:Medulloblastoma / Q000473:pathology / Q000628:therapy; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009447:Neuroblastoma / Q000473:pathology / Q000628:therapy; D011990:Receptors, Transferrin / Q000032:analysis / Q000276:immunology*; D012276:Ricin / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000922:Immunotoxins; D009363:Neoplasm Proteins; D011990:Receptors, Transferrin; D012276:Ricin