THE SOMATOSTATIN RECEPTOR-TARGETED RADIOTHERAPEUTIC [Y-90-DOTA-DPHE(1),TYR(3)]OCTREOTIDE (Y-90-SMT-487) ERADICATES EXPERIMENTAL RAT PANCREATIC CA-20948 TUMORS

Somatostatin receptor-expressing tumours are potential targets for the rapy with radiolabelled somatostatin analogues. We have synthesized a number of such analogues in the past and identified [DOTA-DPhe(1), Tyr (3)]octreotide (SMT 487) as the most promising candidate molecule beca use of its advantageous properties in cellular and in vivo tumour mode ls. In the current paper we describe the radiotherapeutic effect of yt trium-90 labelled SMT 487 in Lewis rats bearing the somatostatin recep tor-positive rat pancreatic tumour CA 20948. SMT 487 binds with nanomo lar affinity to both the human and the rat somatostatin receptor subty pe 2 (sst(2)) (human sst(2) IC50=0.9 nM, rat sst(2) IC50=0.5 nM). In v ivo, Y-90-SMT 487 distributed rapidly to the sst(2) expressing CA 2094 8 rat pancreatic tumour, with a tumour-to-blood ratio of 49.15 at 24 h post injection. A single intravenous administration of 10 mCi/kg Y-90 -SMT 487 resulted in a complete remission of the tumours in five out o f seven CA 20948 turnour-bearing Lewis rats. No regrowth of the tumour s occurred 8 months post injection. Control animals that were treated with 30 mu g/kg of unlabelled SMT 487 had to be sacrificed 10 days pos t injection due to excessive growth or necrotic areas on the tumour su rface. Upon re-inoculation of tumour cells into those rats that had sh own complete remission, the tumours disappeared after 3-4 weeks of mod erate growth without any further treatment. The present study shows fo r the first time the: curative potential of Y-90-SMT 487-based radioth erapy for somatostatin receptor-expressing rumours. Clinical phase I s tudies with yttrium-labelled SMT 487 have started in September 1997.