Pellegrini I, Rasolonjanahary R, Gunz G, Bertrand P, Delivet S, Jedynak C P, Kordon C, Peillon F, Jaquet P, Enjalbert A
Laboratoire de Neuroendocrinologie Expérimentale, INSERM U. 297, Marseille, France.
J Clin Endocrinol Metab. 1989 Sep;69(3):500-9. doi: 10.1210/jcem-69-3-500.
Bromocriptine therapy normalizes PRL secretion in most, but not all, patients with prolactinomas. This study was undertaken to determine the mechanism(s) responsible for bromocriptine resistance in patients with a PRL-secreting macroadenomas (n = 5) or microadenomas (n = 3). Their mean basal plasma PRL value was 807 +/- 220 (+/- SE) micrograms/L before treatment, and their nadir mean value was 354 +/- 129 micrograms/L during chronic therapy with 15-30 mg bromocriptine daily; four of the eight patients had an increase in tumor size during therapy. In cultures of prolactinoma cells from patients normally responsive to bromocriptine therapy (n = 10), considered as controls, 10(-9) mol/L bromocriptine inhibited PRL release by 71 +/- 6% (+/- SE), and the half-inhibitory dose was 7 x 10(-11) mol/L. In contrast, in cultures of prolactinoma cells from five patients resistant to bromocriptine, PRL release was inhibited by only 3-42% at 10(-9) mol/L bromocriptine. This partial inhibition was reversed by a 100-fold excess of haloperidol. In contrast, the effects of other inhibitors of PRL release (10(-8) mol/L T3 and 10(-8) mol/L somatostatin) or of a stimulator (10(-8) mol/L angiotensin-II) on cells from resistant and normally responsive patients were similar. In cell membranes from five bromocriptine-responsive adenomas the density of dopaminergic binding sites, labeled by [3H] spiroperidol was 243 +/- 65 (+/- SE) fmol/mg protein. In adenomas from the eight patients resistant to bromocriptine therapy the density of [3H]spiroperidol-binding sites lower (145 +/- 31 fmol/mg protein). In adenomas from five resistant patients whose tumor had grown during therapy the density of binding sites was 25 +/- 3 fmol/mg protein, 10% of that in normally responsive patients. The effects of dopamine on adenylate cyclase activity also were different in the three groups of adenomas. Dopamine inhibited adenylate cyclase activity by 28.8 +/- 5.6% in five bromocriptine-responsive tumors and by 16.5 +/- 4.3% in adenomas from eight resistant patients. In contrast, in the five patients whose tumors grew during therapy dopamine paradoxically stimulated adenylate cyclase activity (+26.4 +/- 9.8%). There was a very good correlation between the density of dopaminergic binding sites and maximal inhibition of adenylate cyclase activity in bromocriptine-responsive prolactinoma patients (r = 0.90) and resistant patients who had no tumor growth during therapy (r = 0.94).(ABSTRACT TRUNCATED AT 400 WORDS)
溴隐亭疗法可使大多数（但并非全部）催乳素瘤患者的催乳素分泌恢复正常。本研究旨在确定分泌催乳素的大腺瘤（n = 5）或微腺瘤（n = 3）患者对溴隐亭耐药的机制。治疗前，他们的基础血浆催乳素平均水平为807±220（±SE）μg/L，在每日使用15 - 30 mg溴隐亭进行长期治疗期间，其最低平均值为354±129μg/L；8名患者中有4名在治疗期间肿瘤大小增加。在被视为对照的、对溴隐亭疗法正常反应的患者（n = 10）的催乳素瘤细胞培养物中，10⁻⁹mol/L溴隐亭可使催乳素释放抑制71±6%（±SE），半抑制剂量为7×10⁻¹¹mol/L。相比之下，在5名对溴隐亭耐药患者的催乳素瘤细胞培养物中，10⁻⁹mol/L溴隐亭仅使催乳素释放抑制3% - 42%。这种部分抑制可被100倍过量的氟哌啶醇逆转。相比之下，其他催乳素释放抑制剂（10⁻⁸mol/L T3和10⁻⁸mol/L生长抑素）或刺激剂（10⁻⁸mol/L血管紧张素II）对耐药患者和正常反应患者细胞的作用相似。在5个对溴隐亭有反应的腺瘤的细胞膜中，用[³H]螺哌啶标记的多巴胺能结合位点密度为243±65（±SE）fmol/mg蛋白。在8名对溴隐亭疗法耐药患者的腺瘤中，[³H]螺哌啶结合位点密度较低（145±31 fmol/mg蛋白）。在5名治疗期间肿瘤生长的耐药患者的腺瘤中，结合位点密度为25±3 fmol/mg蛋白，仅为正常反应患者的10%。多巴胺对腺苷酸环化酶活性的影响在三组腺瘤中也有所不同。多巴胺在5个对溴隐亭有反应的肿瘤中使腺苷酸环化酶活性抑制28.8±5.6%，在8名耐药患者的腺瘤中抑制16.5±4.3%。相比之下，在5名治疗期间肿瘤生长的患者中，多巴胺反而刺激腺苷酸环化酶活性（+26.4±9.8%）。在对溴隐亭有反应的催乳素瘤患者（r = 0.90）和治疗期间无肿瘤生长的耐药患者（r = 0.94）中，多巴胺能结合位点密度与腺苷酸环化酶活性的最大抑制之间存在非常良好的相关性。（摘要截断于400字）
