New somatostatin analogues for radiotherapy of somatostatin receptor expressing tumours.

Among various newly synthesized chelator-linked octreotide analogues 90Y-[DOTA-DPhe1, Thyr3]-octreotide (90Y-SMT 487) was finally selected for clinical development. In vitro, SMT 487 binds selectively with nanomolar affinity to the somatostatin receptor subtype 2 (IC30 = 0.39 nM +/- 0.02). In vivo, 90Y-[DOTA-DPhe1, Thyr3]-octreotide shows a rapid blood clearance (T1/2 alpha < 5 min) and high accumulation in somatostatin subtype 2 receptor expressing tumours. The in vivo administration of 90Y-[DOTA-DPhe1, Thyr3]-octreotide induces a rapid tumour shrinkage in three different somatostatin receptor positive tumour models: CA20948 rat pancreatic tumours grown in normal rats, AR42J rat pancreatic tumours and NCI-H69 human small cell lung cancer both grown in nude mice. The radiotherapeutic efficacy of 90Y-SMT 487 was enhanced in combination with standard anticancer drugs, such as mitomycin C, which resulted in a tumour decrease of 70% of the initial volume. In the CA 20948 syngeneic rat tumour model, a single treatment with 10 microCi/kg 90Y-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 90Y-SMT 487 were started in September 1997.