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.