New somatostatin analogues for radiotherapy of somatostatin receptor expressing tumours

Among various newly synthesized chelator-linked octreotide analogues Y-90-[ DOTA-DPhe(1), Thyr(3)]-octreotide (Y-90-SMT 487) was finally selected for c linical development. In vitro, SMT 487 binds selectively with nanomolar aff inity to the somatostatin receptor subtype 2 (IC30 = 0.39 nM +/- 0.02). In vivo, Y-90-[DOTA-DPhe(1), Thyr(3)]-octreotide shows a rapid blood clearance (T-1/2 alpha<5 min) and high accumulation in somatostatin subtype 2 recept or expressing tumours. The in vivo administration of Y-90-[DOTA-DPhe(1), Th yr(3)]-octreotide induces a rapid tumour shrinkage in three different somat ostatin receptor positive tumour models: CA20948 rat pancreatic rumours gro wn in normal rats, AR42J mt pancreatic tumours and NCI-H69 human small cell lung cancer both grown in nude mice. The radiotherapeutic efficacy of Y-90 -SMT 487 was enhanced in combination with standard anticancer drugs, such a s mitomycin C, which resulted in a tumour decrease of 70% of the initial vo lume. In the CA 20948 syngeneic rat tumour model, a single treatment with 1 0 mu Ci/kg Y-90-SMT 487 resulted in the disappearance of 5 out of 7 tumours . Thus the new radiotherapeutic agent showed its curative potential for the selective treatment of SRIF receptor-expression tumours. Clinical Phase I studies with Y-90-SMT 487 were started in September 1997.