Somatostatin analogues inhibit growth of pancreatic cancer by stimulating tyrosine phosphatase.
Several analogues of somatostatin were examined in the Mia PaCa-2 human pancreatic cancer cell line for their ability to promote tyrosine phosphatase activity affecting the receptors for the epidermal growth factor. The inhibition of growth of the Mia PaCa-2 cells in culture was also evaluated to determine the mechanism of action of somatostatin analogues and their relative effectiveness in inhibiting cancer growth. Of the analogues tested D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) caused the greatest stimulation of tyrosine phosphatase activity. Analogue D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121) had less effect but was more potent than somatostatin-14. Analogue D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr(ol) (SMS 201-995) produced no significant dephosphorylation. The analogues displayed the same order of activity in assays on growth inhibition of Mia PaCa-2 cells in cultures. Analogue (SMS-201-995) caused virtually no tyrosine phosphatase stimulation or growth inhibition in this cancer cell line, although it possesses a much higher antisecretory activity than somatostatin-14 in normal tissues. These observations indicate that somatostatin and some of its analogues can act as growth inhibitors in cancer cells through the activation of tyrosine phosphatase. These data reinforce the view that somatostatin analogue RC-160 and related compounds could be used for treatment of pancreatic cancer.
Liebow
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Department of Oral Surgery, State University of New York, Buffalo School of Dental Medicine 14214.
Reilly
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Serrano
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Schally
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AV
D000970:Antineoplastic Agents; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D015282:Octreotide / Q000494:pharmacology / Q000031:analogs & derivatives; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C051458:vapreotide; D013004:Somatostatin; D013007:Growth Hormone-Releasing Hormone; C053408:RC 121; D066246:ErbB Receptors; D010749:Phosphoprotein Phosphatases; D017027:Protein Tyrosine Phosphatases; D015282:Octreotide