Effect of somatostatin on adenylate cyclase activity in normal and neoplastic thyroid tissue.
Thyroid stimulating hormone (TSH) and other substances increase adenylate cyclase (AC) activity and growth of normal and neoplastic thyroid tissue. Factors that inhibit cAMP may provide targeted therapy to tumors dependent on cAMP for growth. Somatostatin has been reported to inhibit the growth of gastrinomas and carcinoid tumors. We therefore studied the effects of somatostatin on basal, TSH, pertussis toxin, and forskolin stimulated adenylate cyclase activity in normal and neoplastic thyroid tissue from 19 patients. Adenylate cyclase (AC) activity was determined by the conversion of alpha 32P-ATP to 32P-cAMP in pmoles/mg protein/30 minutes in an 8000 x g particulate fraction rich in thyroid plasma membranes. TSH (300 mU/ml) and forskolin (100 mM) (a diterpine that directly stimulates the catalytic unit of AC) increased AC activity in normal and neoplastic thyroid tissue. The AC stimulation was greater in the neoplasms (p less than 0.01). Somatostatin (5 x 10(-6)M) decreased basal and TSH stimulated AC activity below basal levels in both normal and neoplastic thyroid tissue (including papillary, follicular, and medullary carcinomas). The inhibition of AC by somatostatin was greater in neoplastic tissue (p less than 0.025). Pertussis toxin (which blocks the inhibitory guanyl nucleotide regulatory protein) was able to partially reverse the effect of somatostatin. Somatostatin partially inhibited forskolin stimulated AC activity. Somatostatin inhibits basal and TSH stimulated AC activity in both normal and neoplastic human thyroid tissue, with a greater effect on neoplasms. These studies establish that somatostatin blocks a major regulator of thyroid growth and provides the rationale for the use of somatostatin analogs in the treatment of thyroid cancers.
Surgical Service, Veterans Administration Medical Center, San Francisco, California.
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Siperstein
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Levin
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Gum
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Clark
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D006801:Humans; D037342:Pertussis Toxin; D013004:Somatostatin / Q000494:pharmacology*; D013961:Thyroid Gland / Q000187:drug effects* / Q000201:enzymology; D013964:Thyroid Neoplasms / Q000201:enzymology*; D013972:Thyrotropin / Q000502:physiology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D013004:Somatostatin; D013972:Thyrotropin; D037342:Pertussis Toxin; D000262:Adenylyl Cyclases