ADENOVIRAL-MEDIATED DELIVERY OF GASTRIN-RELEASING PEPTIDE RECEPTOR RESULTS IN SPECIFIC TUMOR-LOCALIZATION OF A BOMBESIN ANALOG IN-VIVO

Radioimmunotherapy is hindered by a variety of factors linked to the u tilization of monoclonal antibodies, These limitations include restric ted tumor penetration as well as low levels of intratumoral antigen ex pression. To address the latter problem, we used a gene therapy approa ch to induce tumor cells to express enhanced levels of receptor with h igh binding affinity for a radiolabeled peptide. In this regard, a rad iolabeled bombesin analogue was used in conjunction with a recombinant adenoviral vector encoding the murine gastrin-releasing peptide recep tor (mGRPr). A panel of human carcinoma cell lines was infected in vit ro with the recombinant adenoviral vector encoding the mGRPr vector to examine the induced binding of a I-125-labeled bombesin peptide. All cell lines examined displayed high levels of induced peptide binding, with approximately 60-80 % of the radioactivity bound to the cells, in a live-cell binding assay. The human ovarian carcinoma cell line SKOV 3.ipl was chosen for in vivo analysis of radiolabeled bombesin analogu e tumor localization in biodistribution and pharmacokinetic studies in athymic nude mice. Genetic induction of mGRPr in vivo resulted in sel ective tumor uptake of the radiolabeled peptide and high tumor:blood r atios. The biodistribution results compared favorably to those obtaine d with I-125-labeled e21 anti-erbB-2 monoclonal antibody in animals be aring i.p. SKOV3.ipl tumors that endogenously express erbB-2. Thus, a novel method to combine gene transfer and radioimmunotherapy may resul t in augmented tumor cell targeting of radiopharmaceuticals.