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 tu mors such as medulloblastoma has led to the development and investigat ion of a variety of new treatment techniques. Therapeutic agents inclu de 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 th e DAOY human medulloblastoma-derived cell line in vitro, a significant level of expression was confirmed by testing the sensitivity to diffe rent immunotoxins. To ensure the relevance of the in vitro data to the in vivo situation, we also analyzed TR expression in DAOY tumors grow ing in athymic mice and rats. Immunocytochemistry, immunohistochemistr y, immunobead binding, immunofluorescence, (125)iodine-transferrin bin ding, and Northern blot analysis were used to compare TR expression in DAOY cells in vitro and in vivo. All in vitro assays demonstrated sig nificant TR expression, whereas in vivo, the TR expression was negligi ble in the DAOY tissue. The results caution against extrapolating in v itro antigen and receptor expression data directly to the in vivo situ ation. Using a transferrin-toxin conjugate in a nude rat model of lept omeningeal carcinomatosis, we achieved therapeutic efficacy, despite d emonstrating reduced TR expression on tumor tissue. With respect to cl inical efficacy, the reduced expression of TR on DAOY medulloblastoma in vivo may be less significant than expected because of the extreme p otency of immunotoxins observed in central nervous system tumors.