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In Vivo Localization of [¹¹¹In]-DTPA-D-Phe¹ -Octreotide to Human Ovarian Tumor Xenografts Induced to Express the Somatostatin Receptor Subtype 2 Using an Adenoviral Vector^,1

Departments of Radiation Oncology [B. E. R., S. F. M., R. L. K., D. D. M., S. J. B., C. C. O., A. D. M., D. J. B.] and Medicine [M. S. M., D. T. C.], and Gene Therapy Program [D. T. C.], University of Alabama at Birmingham, Birmingham, Alabama 35294

ABSTRACT

Adenoviral vectors, encoding genes for cell surface antigens or receptors, have been used to induce their high level expression on tumor cells in vitro and in vivo. These induced antigens and receptors can then be targeted with radiolabeled antibodies or peptides for potential radiotherapeutic applications. The purpose of this study was to determine a dosing schema of an adenoviral vector encoding the human somatostatin receptor subtype 2 (AdCMVhSSTr2) for achieving the highest tumor localization of [¹¹¹In]-DTPA-D-Phe¹-octreotide, which binds to this receptor, in a human ovarian cancer model as a prelude to future therapy studies. AdCMVhSSTr2 was produced and used to induce hSSTr2 on A427 human nonsmall cell lung cancer cells and on SKOV3.ip1 human ovarian cancer cells in vitro, as demonstrated by competitive binding assays using [¹²⁵I]-Tyr¹-somatostatin and [¹¹¹In]-DTPA-D-Phe¹- octreotide. Mice bearing i.p. SKOV3.ip1 tumors administered 1 x 10⁹ plaque-forming units of AdCMVhSSTr2 i.p. 5 days after tumor cell inoculation, followed by an i.p. injection of [¹¹¹In]-DTPA-D-Phe¹-octreotide 2 days later, showed a range of 15.3–60.4% median injected dose/gram (ID/g) in tumor at 4 h after injection compared with 3.5% ID/g when [¹²⁵I]-Tyr¹-somatostatin was administered and 0.3% ID/g when the negative control peptide [¹²⁵I]-mIP-bombesin was administered. Mice administered a control adenoviral vector encoding the gastrin-releasing peptide receptor did not have tumor localization of [¹¹¹In]-DTPA-D-Phe¹-octreotide (<1.6% ID/g), demonstrating specificity of [¹¹¹In]-DTPA-D-Phe¹-octreotide for the AdCMVhSSTr2 induced tumor cells. In another set of experiments, the tumor localization of [¹¹¹In]-DTPA-D-Phe¹-octreotide was not different 1, 2, or 4 days after AdCMVhSSTr2 injection (31.8, 37.7, and 40.7% ID/g, respectively; P = 0.88), indicating that multiple injections of radiolabeled peptide can be administered with equivalent uptake over a 4-day period. [¹¹¹In]-DTPA-D-Phe¹-octreotide tumor localization in animals administered AdCMVh-SSTr2 on consecutive days or 2 days apart was 22.4% ID/g and 53.2% ID/g, respectively (P = 0.009) when [¹¹¹In]-DTPA-D-Phe¹-octreotide was given 1 day after the second AdCMVhSSTr2 injection. There was no difference in [¹¹¹In]-DTPA-D-Phe¹-octreotide localization after a single AdCMVhSSTr2 injection (40.7% ID/g) or two injections of AdCMVhSSTr2 given 1 (45.9% ID/g) or 2 (53.2% ID/g) days apart, where [¹¹¹In]-DTPA-D-Phe¹-octreotide was given in each case 4 days after the first AdCMVhSSTr2 injection (P = 0.65). Therefore, two AdCMVhSSTr2 injections did not increase [¹¹¹In]-DTPA-D-Phe¹-octreotide tumor localization compared with one injection, which eliminates concerns about an immune response to a second dose of AdCMVhSSTr2. This will be the basis for a therapeutic protocol with multiple administrations of an octreotide analogue labeled with a therapeutic radioisotope.

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