The prognosis for patients with glioblastoma multiforme (GBM) remains poor despite intensive conventional therapy. An alternative potentially efficacious therapeutic strategy against this dreaded disease might be administration of immunotoxins (IT), macromolecules formed by conjugation of tumor-specific monoclonal antibodies (mab) with intracellular ribosomal inhibitory proteins. One potential antigen which may serve as a target for such therapy is the transferrin receptor (Tfr), which is overexpressed in GBM compared to normal surrounding brain. Furthermore, 7D3-A, an IT constructed by conjugating a mab directed against Tfr with ricin A chains, potentially inhibits GBM protein synthesis in vitro and its administration to nude mice harboring subcutaneous xenografts can result in apparent tumor eradication in a high percentage of animals. In the following proposal, we seek to evaluate further the potential of this therapy using both the nude mouse xenograft model and an in situ rat glioma model whereby intratumoral cannulae are placed to assess local delivery. Experiments are specifically designed to assess in vivo stability, potency, penetrability and toxicity of this IT. With the results obtained from these studies, it will have been ascertained whether this macromolecule merits clinical trial or if not, what impediments exist that hamper its efficacy.
| Lachyankar, M B; Condon, P J; Quesenberry, P J et al. (1997) Embryonic precursor cells that express Trk receptors: induction of different cell fates by NGF, BDNF, NT-3, and CNTF. Exp Neurol 144:350-60 |
| Lachyankar, M B; Ross, A H; Litofsky, N S et al. (1997) TrkA expression decreases the in vivo aggressiveness of C6 glioma cells. Cancer Res 57:532-6 |
| Recht, L D; Raso, V; Davis, R et al. (1996) Immunotoxin sensitivity of Chinese hamster ovary cells expressing human transferrin receptors with differing internalization rates. Cancer Immunol Immunother 42:357-61 |
