title: DOTA-lanreotide: a novel somatostatin analog for tumor diagnosis and therapy.
abstract: 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)betaNal1-lanreotide (DOTALAN), for tumor diagnosis and therapy. 111In-/90Y-DOTALAN bound with high affinity (dissociation constant, Kd, 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 (Kd, 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 (Kd, 4.3 nM), hsst3 (Kd, 5.1 nM), hsst4 (Kd, 3.8 nM), and hsst5 (Kd, 10 nM) and with lower affinity to hsst1 (Kd, approximately 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) approximate to Tyr3-octreotide (TOCT) approximate to DOTA-Tyr3-octreotide (DOTATOCT) approximate to DOTA-vapreotide (DOTAVAP; IC50, >1000 nM); that to hsst2 was: DOTATOCT approximate to TOCT approximate to DOTALAN approximate to SST approximately LAN approximate to DOTAVAP (IC50, 1.4 nM); that to hsst3 was: SST (IC50, 1.2 nM) > DOTALAN = LAN (IC50, 15 nM) approximate to TOCT (IC50, 20 nM) approximate to DOTAVAP (IC50, 28 nM) > DOTATOCT (IC50, 73 nM); that to hsst4 was: SST (IC50, 1.8 nM) approximate to DOTALAN (IC50, 2.5 nM) > LAN (IC50, 22 nM) >> DOTATOCT approximate to DOTAVAP approximate to 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 hsst2-5. 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.
authors.affiliation: Department of Nuclear Medicine, University of Vienna, Austria.
authors.forename: P M
authors.initials: PM
authors.lastname: Smith-Jones
authors.forename: C
authors.initials: C
authors.lastname: Bischof
authors.forename: M
authors.initials: M
authors.lastname: Leimer
authors.forename: D
authors.initials: D
authors.lastname: Gludovacz
authors.forename: P
authors.initials: P
authors.lastname: Angelberger
authors.forename: T
authors.initials: T
authors.lastname: Pangerl
authors.forename: M
authors.initials: M
authors.lastname: Peck-Radosavljevic
authors.forename: G
authors.initials: G
authors.lastname: Hamilton
authors.forename: K
authors.initials: K
authors.lastname: Kaserer
authors.forename: A
authors.initials: A
authors.lastname: Kofler
authors.forename: H
authors.initials: H
authors.lastname: Schlangbauer-Wadl
authors.forename: T
authors.initials: T
authors.lastname: Traub
authors.forename: I
authors.initials: I
authors.lastname: Virgolini
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002276:Carcinoid Tumor / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D007205:Indium Radioisotopes; D008113:Liver Neoplasms / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism; D008297:Male; D009369:Neoplasms / Q000175:diagnosis* / Q000532:radiotherapy*; D010190:Pancreatic Neoplasms / Q000378:metabolism; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D011471:Prostatic Neoplasms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013964:Thyroid Neoplasms / Q000378:metabolism; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D015021:Yttrium Radioisotopes
chemical_list: C400086:DOTALAN; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D010456:Peptides, Cyclic; D015021:Yttrium Radioisotopes