DOTA-lanreotide: A novel somatostatin analog for tumor diagnosis and therapy

Long acting somatostatin-14 (SST) analogs are used clinically to inhibit tu mor growth and proliferation of various tumor types via binding to specific receptors (R). We have developed a In-111-/Y-90-labeled SST analog, DOTA-( D)beta Nal(1)-lanreotide (DOTALAN), for tumor diagnosis and therapy. In-111 -/Y-90-DOTALAN bound with high affinity (dissociation constant, K-d, 1-12 n M) to a number of primary human tumors (n = 31) such as intestinal adenocar cinoma (n = 17; 150-4000 fmol/mg protein) or breast cancer (n = 4; 250-9000 fmol/mg protein). In-111-/Y-90-DOTALAN exhibited a similar high binding af finity(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 mela noma cell Line 518A2. When expressed in COS7 cells, In-111-DOTALAN bound wi th high affinity to hsst(2) (K-d, 4.3 nM), hsst(3) (K-d, 5.1 nM), hsst(4) ( K-d 3.8 nM), and hsst(5) (K-d, 10 nM) and with lower affinity to hsst(1) (K -d, similar to 200 nM). The rank order of displacement of [I-125]Tyr(11)-SS T binding to hsst(1) was: SST (IC50, 0.5 nM) " DOTALAN (IC50, 154 nM) > lan reotide (LAN) similar to Tyr(3)-octreotide (TOCT) similar to DOTA-Tyr(3)-oc treotide (DOTATOCT) similar to DOTA-vapreotide (DOTAVAP; IC50, >1000 nM); t hat to hsst(2) was: DOTATOCT similar to TOCT similar to DOTALAN similar to SST similar to LAN similar to DOTAVAP (IC50, 1.4 nM); that to hsst(3) was: SST (IC50, 1.2 nM) > DOTALAN = LAN (IC50, 15 nM) similar to TOCT (IC50, 20 nM) similar to DOTAVAP (IC50, 28 nM) > DOTATOCT (IC50, 73 nM); that to hsst , was: SST (IC50, 1.8 nM) similar to DOTALAN (IC50, 2.5 nM) > LAN (IC50, 22 nM) "DOTATOCT similar to DOTAVAP similar to TOCT (IC50, >500 nM); and that to hsst(5) 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), Y-90-DOTALAN was rapidly cleared from the circulation and concentrated in hsst-positive tissues such as pancreas or pituitary. Taken together, our results indicate that In-111-/Y-90-DOTAL AN binds to a broad range of primary human tumors and tumor cell lines, pro bably via binding to hsst(2-5). We conclude that this radiolabeled peptide can be used for hsst-mediated diagnosis (In-111-DOTALAN) as well as systemi c radiotherapy (Y-90-DOTALAN) of human tumors.