Differential regulation of somatostatin receptor type 2 (sst 2) expression in AR4-2J tumor cells implanted into mice during octreotide treatment.
Octreotide is a somatostatin analogue that is widely used for cancer therapy and tumor imaging. Its efficacy in tumors depends mainly on the expression of the somatostatin receptor type 2 (sst 2). Desensitization and down-regulation of sst 2 after agonist exposure can have important consequences for patients under ongoing octreotide therapy because it may induce temporary tumor unresponsiveness and impair sst 2-based tumor scintigraphy. Therefore, we have investigated the effect of octreotide on sst 2 expression in vitro, as well as in a tumor mouse model. In vitro, short exposure to octreotide induced rapid dose-dependent down-regulation of sst 2 in the rat pancreatic AR4-2J cell line. Within 0.5 h, 80% of sst 2 had disappeared from the cell surface. A total recovery required 24 h and was shown to depend on protein synthesis, but not on new sst 2 mRNA transcription, indicating that sst 2 was probably degraded during the down-regulation process. Similar results were obtained in vivo. On the other hand, long-term continuous release of octreotide for 7 days, as achieved with octreotide-containing osmotic minipumps, caused sst 2 up-regulation in vivo, but not in vitro. Furthermore, this up-regulation of sst 2 in tumor-bearing scid mice was shown to depend on constant exposure of the animals to octreotide, as it was not observed when octreotide was given discontinuously in two s.c. daily injections. These results demonstrate that the continuous release of a small amount of octreotide, which in cancer therapy may be achieved with long-acting release formulations of the peptide, can induce sst 2 up-regulation on cancer cells. This may improve the efficacy of both tumor imaging and long-term octreotide therapy.
Froidevaux
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Department of Research, University Hospital and University Children's Hospital, Basel, Switzerland. Froidevaux@ubaclu.unibas.ch
Hintermann
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Török
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Mäcke
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Beglinger
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Eberle
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D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use*; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D015282:Octreotide / Q000494:pharmacology / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017481:Receptors, Somatostatin / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D013004:Somatostatin / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects*
D018931:Antineoplastic Agents, Hormonal; D009363:Neoplasm Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D011500:Protein Synthesis Inhibitors; D017481:Receptors, Somatostatin; D003609:Dactinomycin; D013004:Somatostatin; D003513:Cycloheximide; C093733:somatostatin receptor 2; D015282:Octreotide