Effect of bromocriptine and SMS 201-995 on growth of human somatotrophic and non-functioning pituitary adenoma cells in vitro

Abstract

The effect of the dopamine agonist bromocriptine and the somatostatin analog SMS 201-995 on growth of 12 human somatotrophic and 13 non-functioning adenoma cell cultures was investigated. When adenoma cells were maintained in medium supplemented with 5% fetal calf serum, cell counts of 10 of 12 somatotrophic cultures increased to 145 +/- 6 and 171 +/- 9% (mean +/- SD) and in 12 of 13 non-functioning cell cultures up to 125 +/- 12 and 217 +/- 15% after 3 days of incubation. In most cases bromocriptine and SMS 201-995 dose dependently (1 nmol/l to 10 mumol/l) inhibited adenoma cell growth but there was only (1, 10 mumol/l) a significant inhibitory effect at high doses of both drugs. A 1 mumol/l concentration of bromocriptine decreased cell counts of 5 of 12 somatotrophic cell cultures (range 84 +/- 3 to 76 +/- 6% vs control = 100%) and in 5 of 13 non-functioning cell cultures (range 85 +/- 4 to 71 +/- 7%). A 10 mumol/l concentration of bromocriptine decreased cell counts in all 12 somatotrophic (range 87 +/- 1 to 61 +/- 8%) and in 12 of 13 non-functioning adenoma cultures (range 87 +/- 6 to 57 +/- 3%). Bromocriptine specifically inhibited growth because its effect could be reversed by the dopamine D2-receptor antagonist haloperidol. Both 1 and 10 mumol/l SMS 201-995 significantly decreased cell counts in three of six somatotrophic (87 +/- 3 to 38 +/- 3%) cell cultures. In two of five cases growth of non-functioning adenoma cultures was suppressed by 1 mumol/l SMS 201-995, and in four of five cases by 10 mumol/l (86 +/- 3 to 74 +/- 4%). The growth inhibitory effect of both bromocriptine and SMS 201-995 was not just due to an effect on growth of fibroblasts contaminating the adenoma cell cultures, because it could be observed also when adenoma cells were maintained in a D-valine-supplemented medium that suppresses fibroblast growth. In summary, both bromocriptine and SMS 201-995 at high doses were able to inhibit cell growth of cultured somatotrophic and non-functioning adenomas in vitro. However, the mechanism of this inhibitory effect is not yet well understood.

Dopamine agonist therapy of clinically non-functioning pituitary macroadenomas. Is there a role for 123I-epidepride dopamine D2 receptor imaging?

“…However, the effects of the DA agonist bromocriptine on reducing NFPA size has been disappointing, as most studies have shown only modest size reduction in a minority of treated tumors (12,14,17,21,25). Therefore, bromocriptine therapy has not been advocated on a routine basis.…”

“…Radiotherapy is the only modality shown to be effective in the prevention of residual tumor growth (7)(8)(9). The use of dopamine (DA) agonists has been previously explored as a treatment alternative for NFPA (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Greenman and co-workers have shown that postoperative DA treatment resulted in a decrease or stabilization of tumor mass in 90% of patients in contrast to 2 and 5 years re-growth rates of 30 and 70% in untreated patients respectively (26).…”

Reduction of Plasma Gonadotropin Levels and Pituitary Tumor Size by Treatment with Bromocriptine in a Patient with Gonadotropinoma.

“…In healthy subjects, bromocriptine decreases the plasma prolactin level, but not the gonadotropin level (16). Sufficient effects of this drug were reported in some patients with growth hormone- ( 14,17,18) or corticotropin-(19) producing pituitary adenoma. In patients with thyrotropin-producing adenomabromocriptine is generally not effective (20).…”

Combined therapy of somatostatin analogues and dopamine agonists in the treatment of pituitary tumours

“…The bioactivity of bromocriptine increases when administered alongside octreotide (17). In vitro studies highlighted that both bromocriptine and octreotide at high doses are able to inhibit cell growth from human somatotroph adenomas (18). A dose of 1 nmol/l bromocriptine decreased cell growth in 40% of somatotroph cell cultures, whereas 10 mmol/l decreased cell counts in all somatotrophs and in 92% of non-functioning adenoma cultures.…”

“…The use of a combined somatostatin analogue and dopamine agonist treatment schedule seems to be of particular interest in growth hormone (GH)-secreting adenomas that are known to be potentially responsive to both classes of compounds (16)(17)(18)(19)(20)(21)(22)(23)(24)(25). More recently, nonfunctioning pituitary adenomas were shown to be sensitive to a combined treatment, whereas the response rate to somatostatin analogues or dopamine agonists alone is limited.…”