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DOTA-Lanreotide: A Novel Somatostatin Analog for Tumor Diagnosis and Therapy¹

Departments of Nuclear Medicine (P.M.S.-J., C.B., M.L., D.G., T.P., T.T., I.V.), Gastroenterology (M.P.-R.), Surgery (G.H.), Pathology (K.K.), Urology (A.K.), Dermatology (H.S.-W.), University of Vienna,A-1090 Vienna; and the Department of Radiochemistry, Research Center (P.A.), A-2444 Seibersdorf, Austria

Address all correspondence and requests for reprints: Irene Virgolini, M.D., Department of Nuclear Medicine, University of Vienna, Währinger Gürtel 18–20, Ebene 3L, A-1090 Vienna, Austria. E-mail: irene.virgolini{at}akh-wien.ac.at

Long acting somatostatin-14 (SST) analogs are used clinically to inhibit tumor growth and proliferation of various tumor types via binding to specific receptors (R). We have developed a ¹¹¹In-/⁹⁰Y-labeled SST analog, DOTA-(D)ßNal¹-lanreotide (DOTALAN), for tumor diagnosis and therapy. ¹¹¹In-/⁹⁰Y-DOTALAN bound with high affinity (dissociation constant, K_d, 1–12 nM) to a number of primary human tumors (n = 31) such as intestinal adenocarcinoma (n = 17; 150-4000 fmol/mg protein) or breast cancer (n = 4; 250-9000 fmol/mg protein). ¹¹¹In-/⁹⁰Y-DOTALAN exhibited a similar high binding affinity (K_d, 1–15 nM) for the human breast cancer cell lines T47D and ZR75–1, the prostate cancer cell lines PC3 and DU145, the colonic adenocarcinoma cell line HT29, the pancreatic adenocarcinoma cell line PANC1, and the melanoma cell line 518A2. When expressed in COS7 cells, ¹¹¹In-DOTALAN bound with high affinity to hsst₂ (K_d, 4.3 nM), hsst₃ (K_d, 5.1 nM), hsst₄ (K_d, 3.8 nM), and hsst₅ (K_d, 10 nM) and with lower affinity to hsst₁ (K_d, 200 nM). The rank order of displacement of [¹²⁵I]Tyr¹¹-SST binding to hsst₁ was: SST (IC₅₀, 0.5 nM) >> DOTALAN (IC₅₀, 154 nM) > lanreotide (LAN) Tyr³-octreotide (TOCT) DOTA-Tyr³-octreotide (DOTATOCT) DOTA-vapreotide (DOTAVAP; IC₅₀, >1000 nM); that to hsst₂ was: DOTATOCT TOCT DOTALAN SST LAN DOTAVAP (IC₅₀, 1.4 nM); that to hsst₃ was: SST (IC₅₀, 1.2 nM) > DOTALAN = LAN (IC₅₀, 15 nM) TOCT (IC₅₀, 20 nM) DOTAVAP (IC₅₀, 28 nM) > DOTATOCT (IC₅₀, 73 nM); that to hsst₄ was: SST (IC₅₀, 1.8 nM) DOTALAN (IC₅₀, 2.5 nM) > LAN (IC₅₀, 22 nM) >> DOTATOCT DOTAVAP TOCT (IC₅₀, >500 nM); and that to hsst₅ was: DOTALAN (IC₅₀, 0.45 nM) > SST (IC₅₀, 0.9 nM) > TOCT (IC₅₀, 1.5 nM) > DOTAVAP (IC₅₀, 5.4 nM) >> LAN (IC₅₀, 21 nM) > DOTATOCT (IC₅₀, 260 nM). In Sprague Dawley rats (n = 10), ⁹⁰Y-DOTALAN was rapidly cleared from the circulation and concentrated in hsst-positive tissues such as pancreas or pituitary. Taken together, our results indicate that ¹¹¹In-/⁹⁰Y-DOTALAN binds to a broad range of primary human tumors and tumor cell lines, probably via binding to hsst_2-5. We conclude that this radiolabeled peptide can be used for hsst-mediated diagnosis (¹¹¹In-DOTALAN) as well as systemic radiotherapy (⁹⁰Y-DOTALAN) of human tumors.

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