Human pituitary somatotroph adenomas can be associated with mutations
of the sα-subunit of G proteins. However, the impact of
the gsp mutations on the tumoral phenotype is not well
understood at ...present. This study aims to determine whether the
detection of this mutation could impact on the management of
acromegalic patients. We examined 30 acromegalic patients; 8 were
gsp positive, and 22 were gsp negative.
The gsp-positive adenomas appeared to secrete
significantly more when the ratio of basal GH level/tumor size was
considered. A better octreotide sensitivity of mutated adenomas was
clearly shown under in vivo (short and long term) and
in vitro conditions. During the acute octreotide test,
the GH nadir was significantly lower in the gsp-positive
adenomas (85% of maximal inhibition vs. 52%). Eighteen
patients were treated with octreotide (300 μg/day) for at least 3
months before surgery: the percent inhibition of GH hypersecretion was
higher in gsp-positive adenomas (76% vs.
47%). In cell culture, the octreotide-induced inhibition of GH release
was significantly higher in gsp-positive adenomas (71%
vs. 30%). Finally, during 2 yr of postoperative
follow-up, GH hypersecretion was controlled in all patients with
gsp mutation even in those in whom tumoral tissue
remained after surgery. On the contrary, in the
gsp-negative group, octreotide treatment was unable to
control hypersecretion in 4 patients bearing tumoral remnants. The
Gsα mutation could, therefore, be a new marker to foresee
the susceptibility of the tumor to be controlled by somatostatin
analogs, which improves prognosis.
The binding of omega-conotoxin to isolated rat neurohypophysial nerve terminals, its effect on the depolarization-induced increase of cytoplasmic Ca2+ and on the potassium and electrically-induced ...release of vasopressin (AVP) have been studied. The results show that isolated neurosecretory nerve endings have calcium channels with a high affinity for omega-CgTx and that this toxin inhibits neurohormone release at very low concentration (IC50 = 0. 1nM). Although secretion of vasopressin is inhibited to a great extent by the toxin it is shown that a small but significant amount of the depolarization-induced AVP release is insensitive to omega-CgTx and to the dihydropyridine molecule nicardipine.
We examined the expression of functional growth hormone secretagogue receptors (GHS‐R) in a series of 30 human pituitary adenomas–six secreting GH, three GH‐PRL, six prolactin (PRL), five ...adrenocorticotrophic hormone (ACTH), one thyroid stimulating hormone (TSH), four gonadotroph and five non‐secreting adenomas. By reverse transcriptase polymerase chain reaction (RT‐PCR), the coexpression of the two GHS‐R isoforms (Ia and Ib) was found in all the GH‐, GH‐PRL‐ and PRL‐secreting adenomas, and only in two out of three corticotroph, two out of four gonadotroph and one out of five non‐secreting tumours. They were absent in the TSH‐secreting adenoma. The PCR products of GHS‐R Ia and Ib were identical in size to those from two normal pituitaries. PCR cloning and sequencing of isoforms performed in two somatotroph adenomas revealed only two single, silent base mutations. Triple in‐situ hybridization showed colocalization of GHS‐R mRNA with messengers of GH and PRL, conjointly or separately, in individual cells of somatotroph, mammosomatotroph, and lactotroph adenomas. The presence of GHS‐R mRNA in cells expressing PRL mRNA is emphasized. In cultured cells from six somatotroph and two mammosomatotroph adenomas, the powerful GHS MK‐0677 stimulated GH release in a dose‐dependent manner, with maximal effect at 6 h. Contrarily, when GHRH was applied, only three somatotrophs and two mamosomatotrophs were stimulated. In the two mammosomatotrophs, the PRL response to MK‐0677 and to GHRH was similar to the GH response. An homologous desensitization of the GHS‐R and the GHRH receptor was observed 24 h after a first stimulation by a single dose of the corresponding agonist. Heterologous desensitization was not observed. Interestingly, MK‐0677 also stimulated, in a dose‐dependent way, the hormone release of cells from all tested lactotroph and corticotroph adenomas. The existence of a functional expression of GHS‐R in somatotroph, mammosomatotroph, lactotroph and corticotroph adenomas rises the question of the role played by GHS‐R in pituitary adenomas, particularly those not engaged in GH secretion.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
An endometrioid ovarian adenocarcinoma cell line CAVEOC-2 was characterized. Maintained in monolayered culture, CAVEOC-2 cells exhibited a 33-hr doubling time. When xenografted into nude mice, these ...cells produced fast growing tumors. Colony-forming efficiency in agar was 50%. DNA index was 1.5 and cytogenetic analysis showed a triploid karyotype. CAVEOC-2 cells did not express mdr-1 gene and were chemosensitive to doxorubicin (IC50 = 1.82 +/- 0.76 mumol/l), paclitaxel (IC50 = 3.33 +/- 0.26 nmol/l) and docetaxel (IC50 = 0.68 +/- 0.28 nmol/l), while they showed an intermediate sensitivity to cisplatin (IC50 = 9.40 +/- 1.02 mumol/l). CAVEOC-2 cells seemed highly radioresistant (SF2 = 0.81, alpha = 0.02 Gy-1, beta = 0.025 Gy2, and MID = 4.31 Gy). Activities of glutathione S transferase and gamma-glutamyl transpeptidase were respectively 23.5- and 3.4- fold higher than those of sensitive A2780 cell line. These characteristics make the CAVEOC-2 cells a suitable model for the study of human endometrioid ovarian adenocarcinoma.
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