In vitro and in vivo variation in transferrin receptor expression on a human medulloblastoma cell line.
The poor prognosis associated with pediatric central nervous system tumors such as medulloblastoma has led to the development and investigation of a variety of new treatment techniques. Therapeutic agents include targeted-toxin conjugates or immunotoxins that show significant in vitro activity against many brain tumors. Transferrin receptors (TRs) are specific, cell-surface antigens that are expressed preferentially on brain tumors rather than on normal human brain tissue. This antigen has been successfully targeted in human and nonhuman brain tumors in vitro and in vivo. In this study, when TRs were used as a target in the DAOY human medulloblastoma-derived cell line in vitro, a significant level of expression was confirmed by testing the sensitivity to different immunotoxins. To ensure the relevance of the in vitro data to the in vivo situation, we also analyzed TR expression in DAOY tumors growing in athymic mice and rats. Immunocytochemistry, immunohistochemistry, immunobead binding, immunofluorescence, 125iodine-transferrin binding, and Northern blot analysis were used to compare TR expression in DAOY cells in vitro and in vivo. All in vitro assays demonstrated significant TR expression, whereas in vivo, the TR expression was negligible in the DAOY tissue. The results caution against extrapolating in vitro antigen and receptor expression data directly to the in vivo situation. Using a transferrin-toxin conjugate in a nude rat model of leptomeningeal carcinomatosis, we achieved therapeutic efficacy, despite demonstrating reduced TR expression on tumor tissue. With respect to clinical efficacy, the reduced expression of TR on DAOY medulloblastoma in vivo may be less significant than expected because of the extreme potency of immunotoxins observed in central nervous system tumors.
Wen
D Y
DY
Department of Neurosurgery, University of Minnesota Hospital and Clinic, Minneapolis, USA.
Hall
W A
WA
Conrad
J
J
Godal
A
A
Flørenes
V A
VA
Fodstad
O
O
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002648:Child; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D051381:Rats; D011923:Rats, Nude; D011990:Receptors, Transferrin / Q000187:drug effects / Q000235:genetics*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology*
D000922:Immunotoxins; D011990:Receptors, Transferrin