Differential regulation of somatostatin receptor type 2 (sst 2) expressionin AR4-2J tumor cells implanted into mice during octreotide treatment

Octreotide is a somatostatin analogue that is widely used for cancer therap y and tumor imaging, Its efficacy in tumors depends mainly on the expressio n of the somatostatin receptor type 2 (sst 2). Desensitization and down-reg ulation 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 L-based tamer scintigraphy. Therefore , we have investigated the effect of octreotide on sst 2 expression in vitr o, as well as in a tumor mouse model. lit vitro, short exposure to octreoti de induced rapid dose-dependent down-regulation of sst 2 in the rat pancrea tic 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 pro tein synthesis, but not on new sst 2 mRNA transcription, indicating that ss t 2 was probably degraded during the down-regulation process. Similar resul ts were obtained in vivo. On the other hand, long-term continuous release o f octreotide for 7 days, as achieved with octreotide-containing osmotic min ipumps, 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 oetreotide, as it was not observed w hen octreotide was given discontinuously in two s.c. daily injections. Thes e results demonstrate that the continuous release of a small amount of octr eotide, which in cancer therapy may be achieved with long-acting release fo rmulations of the peptide, can induce sst 2 up-regulation on cancer cells. This may improve the efficacy of both tumor imaging and long-term octreotid e therapy.