In vivo localization of [In-111]-DTPA-D-Phe(1)-octreotide to human ovariantumor xenografts tnduced to express the somatostatin receptor subtype 2 using an adenoviral vector

Adenoviral vectors, encoding genes for cell surface antigens or receptors, have been used to induce their high level expression on tumor cells in vitr o and in vivo. These induced antigens and receptors can then be targeted wi th radiolabeled antibodies or peptides for potential radiotherapeutic appli cations, The purpose of this study was to determine a dosing schema of an a denoviral vector encoding the human somatostatin receptor subtype 2 (AdCMVh SSTr2) for achieving the highest tumor localization of [In-111]-DTPA-D-Phe( 1)-octreotide, which binds to this receptor, in a human ovarian cancer mode l 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 SKOV 3.ip1 human ovarian cancer cells in vitro, as demonstrated by competitive b inding assays using [I-125]-Tyr(1)-somatostatin and [In-111]-DTPA-D-Phe(1)- octreotide, Mice bearing i.p. SKOV3.ip1 tumors administered 1 x 10(9) plaqu e-forming units of AdCMVhSSTr2 i.p. 5 days after tumor cell inoculation, fo llowed by an i.p. injection of [In-111]-DTPA-DPhe(1) octreotide 2 days late r, showed a range of 15.3-60.4% median injected dose/gram (ID/g) in tumor a t 4 h after injection compared with 3.5% ID/g when [I-125]-Tyr(1)-somatosta tin was administered and 0.3% ID/g when the negative control peptide [I-125 ]-mIP-bombesin was administered. Mice administered a control adenoviral vec tor encoding the gastrin-releasing peptide receptor did not have tumor loca lization of [In-111]-DTPA-D-Phe(1)-octreotide (<1.6% ID/g), demonstrating s pecificity of [In-111]-DTPA-D-Phe(1)-octreotide for the AdCMVhSSTr2 induced tumor cells, In another set of experiments, the tumor localization of [In- 111]-DTpA-DPhe(1)-octreotide was not different 1, 2, or 4 days after AdCMVh SSTr2 injection (31.8, 37.7, and 40.7% ID/g, respectively; P = 0.88), indic ating that multiple injections of radiolabeled peptide can be administered with equivalent uptake over a 4-day period. [In-111]-DTPA-D-Phe(1)-octreoti de tumor localization in animals administered AdCMVhSSTr2 on consecutive da ys or 2 days apart was 22.4% ID/g and 53.2% ID/g, respectively (P = 0.009) when [In-111]DTPA-D-Phe(1)-octreotide was given 1 day after the second AdCM VhSSTr2 injection. There was no difference in [In-111]-DTPA-D-Phe(1)-octreo tide 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 [In-111]-DTPA-D-Phe(1)-octreotide was given in each case 4 days aft er the first AdCMVhSSTr2 injection (P = 0.65), Therefore, two AdCMVhSSTr2 i njections did not increase [In-111]-DTPA-D-Phe(1)-octreotide tumor localiza tion compared with one injection, which eliminates concerns about an immune response to a second dose of AdCMVhSSTr2. This will be the basis for a the rapeutic protocol with multiple administrations of an octreotide analogue l abeled with a therapeutic radioisotope.