SOMATOSTATIN ANALOGS FOR SOMATOSTATIN-RECEPTOR-MEDIATED RADIOTHERAPY OF CANCER

The aim of the present study was to selectively target a beta-emitter- labelled octreotide analogue to somatostatin (SRIF)-receptor-expressin g tumours and to evaluate the feasibility of SRIF-receptor-mediated ra diotherapy by delivering a lethal dose of radiation to the tumour. The most promising compound in a series of DTPA-coupled octreotide analog ues was DTPA-benzyl-acetamido-D-Phe(1),Tyr(3)-octreotide (SDZL413). In vitro, SDZ413 binds with nanomolar affinity to SRIF-receptors (IC50 = 4.0 nM) and inhibits growth hormone release from primary cultures of rat pituitary cells with an IC50 of 7.2 nM. Biodistribution studies wi th [Y-90]SDZ413 demonstrated a fast and significant SRIF-receptor-spec ific accumulation of the labelled conjugate (tumour/muscle ratio after 24 h: 52/1). [Y-90]SDZ413 was effective in the radiotherapy of SRIF-r eceptor-positive tumours in a nude mouse model. A single treatment wit h [Y-90]SDZ413 led to a significant decrease (25%) of tumour mass. Thi s effect was mediated by the intact radioligand, since treatment with [Y-90]SDZ978, a derivative of SDZ413 which does not bind with high aff inity to SRIF-receptors or with the unlabelled SDZ413 alone, failed to affect tumour growth. These results suggest that receptor-targeted ra diotherapy with a Y-90-labelled octreotide analogue represents a new s trategy for the treatment of SRIF-receptor-positive tumours that have been previously diagnosed with OctreoScan(R)(111) (pentetreotide).