Tumor localization of a radiolabeled bombesin analogue in mice bearing human ovarian tumors induced to express the gastrin‐releasing peptide receptor by an adenoviral vector

• Published in: Cancer 1997-12, Vol.80 (S12), p.2419-2424
• Main Authors: Rogers, Buck E., Curiel, David T., Mayo, Matthew S., Laffoon, Kim K., Bright, Sheila J., Buchsbaum, Donald J.
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; adenovirus; Animals; Biological and medical sciences; bombesin; Bombesin - pharmacokinetics; Female; gastrin‐releasing peptide receptor; gene transfer; Genetic Vectors; Humans; Iodine Radioisotopes - therapeutic use; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Ovarian Neoplasms - radiotherapy; Radiation therapy and radiosensitizing agent; Receptors, Bombesin - biosynthesis; Receptors, Bombesin - genetics; Tissue Distribution; Treatment with physical agents; Treatment. General aspects; Tumor Cells, Cultured; Tumors
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/(SICI)1097-0142(19971215)80:12+<2419::AID-CNCR13>3.0.CO;2-F

BACKGROUND The adenoviral vector, AdCMVGRPr, has been used to induce the expression of the murine gastrin‐releasing peptide receptor (GRPr) both in vitro and in vivo. A bombesin analogue ([125I]‐mIP‐bombesin) has been shown to bind with high affinity to GRPr and to localize to intraperitoneal (i.p.) ovarian tumors 2 days after induction of GRPr in an athymic nude mouse model. The present study was conducted to determine the level of localization of [125/131I]‐mIP‐bombesin in the tumors at 2, 4, and 7 days after AdCMVGRPr administration and to determine the feasibility of giving multiple doses of [131I]‐mIP‐bombesin for therapy. METHODS Human ovarian cancer cells (SKOV3.ip1) were infected in vitro with AdCMVGRPr and were assayed for receptor expression at 2, 4, and 7 days after infection by using a radiolabeled bombesin‐binding assay. Biodistribution studies utilized athymic nude mice inoculated i.p. with SKOV3.ip1 cells. The tumors were induced to express GRPr with an i.p. injection of AdCMVGRPr followed by administration of [125I]‐mIP‐bombesin 2 days later (AdCMVLacZ or saline was used for negative controls). In addition, the tumor localization of [125I]‐mIP‐bombesin was determined 4 and 7 days after AdCMVGRPr administration. The tumor localization of [131I]‐mIP‐bombesin was compared with [125I]‐mIP‐bombesin in this in vivo model. RESULTS SKOV3.ip1 cells infected with AdCMVGRPr resulted in 80.3 ± 5.9% binding of [125I]‐Tyr4‐bombesin at 2 days after infection, which decreased to 46.8 ± 0.4% at 4 days and to 17.7 ± 0.1% at 7 days. The biodistribution study showed that the tumor localization (14.9 ± 8.2% injected dose/gram; ID/g) of [125I]‐mIP‐bombesin 2 days after administration of AdCMVGRPr was significantly greater than its localization in other organs (P < 0.003) and was significantly greater than in AcCMVLacZ‐ and saline‐treated mice (P < 0.003). Injections of [125I]‐mIP‐bombesin at 4 and 7 days after a single AdCMVGRPr administration showed tumor localization of 4.5 ± 3.0% ID/g at Day 4 and 3.9 ± 3.5% ID/g at Day 7. The decreased localization at longer times after AdCMVGRPr infection correlated with in vitro results. The tumor uptake of [125I]‐mIP‐bombesin was comparable to the uptake of [131I]‐mIP‐bombesin (21.2 ± 8.3% ID/g versus 15.4 ± 5.6% ID/g, respectively), as was the normal tissue biodistribution. CONCLUSIONS The expression of GRPr in human ovarian cancer cells can be accomplished both in vitro and in vivo by using AdCMVGRPr, with the in vivo t