Adenoviral-mediated delivery of gastrin-releasing peptide receptor results in specific tumor localization of a bombesin analogue in vivo.
Radioimmunotherapy is hindered by a variety of factors linked to the utilization of monoclonal antibodies. These limitations include restricted tumor penetration as well as low levels of intratumoral antigen expression. To address the latter problem, we used a gene therapy approach to induce tumor cells to express enhanced levels of receptor with high binding affinity for a radiolabeled peptide. In this regard, a radiolabeled bombesin analogue was used in conjunction with a recombinant adenoviral vector encoding the murine gastrin-releasing peptide receptor (mGRPr). A panel of human carcinoma cell lines was infected in vitro with the recombinant adenoviral vector encoding the mGRPr vector to examine the induced binding of a 125I-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 SKOV3.ip1 was chosen for in vivo analysis of radiolabeled bombesin analogue tumor localization in biodistribution and pharmacokinetic studies in athymic nude mice. Genetic induction of mGRPr in vivo resulted in selective tumor uptake of the radiolabeled peptide and high tumor:blood ratios. The biodistribution results compared favorably to those obtained with 131I-labeled e21 anti-erbB-2 monoclonal antibody in animals bearing i.p. SKOV3.ip1 tumors that endogenously express erbB-2. Thus, a novel method to combine gene transfer and radioimmunotherapy may result in augmented tumor cell targeting of radiopharmaceuticals.
Rosenfeld
M E
ME
Medical Genetics Program, Gene Therapy Program, University of Alabama, Birmingham, Alabama 35294, USA.
Rogers
B E
BE
Khazaeli
M B
MB
Mikheeva
G
G
Raben
D
D
Mayo
M S
MS
Curiel
D T
DT
Buchsbaum
D J
DJ
D000256:Adenoviridae; D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000532:radiotherapy*; D016499:Radioimmunotherapy / Q000379:methods*; D011869:Radioligand Assay; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D018004:Receptors, Bombesin / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D014018:Tissue Distribution; D014162:Transfection / Q000379:methods; D014407:Tumor Cells, Cultured
D001839:Bombesin; D007457:Iodine Radioisotopes; D018719:Erb-b2 Receptor Tyrosine Kinases; D018004:Receptors, Bombesin; D011994:Recombinant Proteins