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.