title: Somatostatin analogues for somatostatin-receptor-mediated radiotherapy of cancer.
abstract: The aim of the present study was to selectively target a beta-emitter-labelled octreotide analogue to somatostatin (SRIF)-receptor-expressing tumours and to evaluate the feasibility of SRIF-receptor-mediated radiotherapy by delivering a lethal dose of radiation to the tumour. The most promising compound in a series of DTPA-coupled octreotide analogues was DTPA-benzyl-acetamido-D-Phe1, Tyr3-octreotide (SDZ413). 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 with [90Y]SDZ413 demonstrated a fast and significant SRIF-receptor-specific accumulation of the labelled conjugate (tumour/muscle ratio after 24 h: 52/1). [90Y]SDZ413 was effective in the radiotherapy of SRIF-receptor-positive tumours in a nude mouse model. A single treatment with [90Y]SDZ413 led to a significant decrease (25%) of tumour mass. This effect was mediated by the intact radioligand, since treatment with [90Y]SDZ978, a derivative of SDZ413 which does not bind with high affinity to SRIF-receptors or with the unlabelled SDZ413 alone, failed to affect tumour growth. These results suggest that receptor-targeted radiotherapy with a 90Y-labelled octreotide analogue represents a new strategy for the treatment of SRIF-receptor-positive tumours that have been previously diagnosed with OctreoScan111 (pentetreotide).
authors.affiliation: Sandoz Pharma Ltd., Preclinical Research, Basel, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Stolz
authors.forename: P
authors.initials: P
authors.lastname: Smith-Jones
authors.forename: R
authors.initials: R
authors.lastname: Albert
authors.forename: L
authors.initials: L
authors.lastname: Tolcsvai
authors.forename: U
authors.initials: U
authors.lastname: Briner
authors.forename: G
authors.initials: G
authors.lastname: Ruser
authors.forename: H
authors.initials: H
authors.lastname: Mäcke
authors.forename: G
authors.initials: G
authors.lastname: Weckbecker
authors.forename: C
authors.initials: C
authors.lastname: Bruns
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology; D006727:Hormone Antagonists / Q000378:metabolism / Q000627:therapeutic use*; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000532:radiotherapy*; D015282:Octreotide / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D004369:Pentetic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017481:Receptors, Somatostatin / Q000502:physiology*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use*; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes
chemical_list: D002614:Chelating Agents; C102734:DTPA-benzyl-acetamido-D-Phe(1),Tyr(3)-octreotide; D006727:Hormone Antagonists; D017481:Receptors, Somatostatin; D015021:Yttrium Radioisotopes; D013004:Somatostatin; D004369:Pentetic Acid; D015282:Octreotide