1,721,118 research outputs found
Gonadotropin-releasing hormone receptors as molecular therapeutic targets in prostate cancer : Current options and emerging strategies
No full textProstate cancer is androgen-dependent in its early stages and androgen deprivation therapy represents the most effective first-line therapeutic approach. However, after an initial remission, prostate cancer progresses towards the castration resistant prostate cancer (CRPC) stage, with increased malignancy and resistance to conventional chemotherapy.
Pituitary gonadotropin-releasing hormone receptors (GnRH-Rs) represent the most effective molecular target for the treatment of steroid-dependent prostate cancer. GnRH agonists (through GnRH-Rs desensitization) suppress the pituitary-testicular axis and, therefore, represent the treatment of choice for prostate cancer patients.
GnRH-Rs are also expressed in prostate cancer, even when the tumor has reached the CRPC stage, and are endowed with antitumor activity, supporting the notion that they might represent a molecular target for GnRH analog-based therapeutic strategies. In addition to GnRH agonists and antagonists, GnRH-based bioconjugates (cytotoxic GnRH bioconjugates, GnRH-conjugated lytic peptides and GnRH-toxin bioconjugates) have been developed and are now undergoing intensive investigations; some of them (i.e., AN-152, Dox-[D-Lys6]-GnRH) have entered clinical trials. The advantage of these treatments is the specific delivery of cytotoxic agents to cancer cells. Interestingly, other isoforms of the peptide have been identified. One of them is GnRH-III, which was isolated from see lamprey. GnRH-III specifically binds to GnRH-Rs in cancer cells and exerts antiproliferative effects; on the other hand, its endocrine effects at pituitary level are insignificant, supporting its selective antitumor activity. Based on these observations, different cytotoxic GnRH-III bioconjugates have recently been synthesized; preliminary in vitro studies suggest that these compounds might represent a new promising treatment strategy for prostate cancer
LHRH analogues as anticancer agents: pituitary and extrapituitary sites of action
No full textTwo classes of luteinising hormone-releasing hormone (LHRH) analogues have been developed so far to be used for oncological therapies: LHRH agonists and antagonists. LHRH agonists are widely and successfully used for the management of steroid-dependent malignancies. Chronic administrations of these compounds result in downregulation and desensitisation of pituitary LHRH receptors and, therefore, in a complete suppression of gonadal function. LHRH agonist administration is effective, safe and reversible, suffering only from the 'flare-up' phenomenon at the beginning of treatment. LHRH antagonists suppress the pituitary-gonadal function by competing with native LHRH for binding to its pituitary receptor but without giving rise to the intracellular cascade of events evoked by the natural hormone or LHRH agonists. Synthetic peptides belonging to the last generations of LHRH antagonists have already been successful in clinical trials. They are completely devoid of the 'flare-up' phenomenon and seem to be free of side effects, such as histamine release. Recently, the expression of LHRH and LHRH receptors has been reported in a number of hormone-responsive tumours. In contrast with the pituitary LHRH receptor which is coupled to the Gq/11-PLC intracellular system of events, stimulation of the tumour LHRH receptor by LHRH is followed by the activation of a Gi protein and a decrease in cAMP levels. This intracellular pathway mediates the inhibitory action of the autocrine/paracrine LHRH system on tumour cell proliferation. The activation of LHRH receptors at tumour level may then represent an additional and more direct mechanism of action for the antitumoural activity of LHRH agonists. Surprisingly, LHRH antagonists also exert a marked antimitogenic activity on a number of hormone-responsive cancer cell lines, indicating that these compounds might behave as antagonists at pituitary level and as agonists at the level of the tumour. The observation that the inhibitory LHRH autocrine system is also present in some steroid-unresponsive cancer cell lines might suggest a possible clinical utility of LHRH analogues also for those tumours that have escaped the initial phase of hormone dependency
Role of serotoninergic neurones in the control of gonadotrophin and prolactin secretion in the rat
No full textThe role of brain serotonin (5-hydroxytryptamine, 5-HT) in the control LH, FSH and prolactin secretion was studied in two groups of experimental animals: intact adult male rats and ovariectomized adult female rats. 5-Hydroxytryptophan (5-HTP), a precursor of serotonin synthesis, and fluoxetine, a specific inhibitor of 5-HT uptake, were given either alone or together. 5-Hydroxyptophan (50 mg/kg) was administered intraperitoneally and fluoxetine (20 μg/rat) was given into one of the lateral ventricles of the brain. Neither 5-HTP nor fluoxetine given alone affected LH secretion but combined treatment with the two drugs elicited a significant increase in serum LH levels in both intact male and ovariectomized female rats. Fluoxetine and 5-HTP, alone or together, did not modify FSH secretion in either kind of animal. In intact males and in ovariectomized females, 5-HTP induced a significant increase in prolactin release; fluoxetine alone was ineffective. In male animals treated with fluoxetine plus 5-HTP, serum prolactin levels increased but such an increase was lower than that found in the animals treated only with 5-HTP. In ovariectomized rats, the combined treatment induced an increase in serum prolactin levels similar to that found in animals treated with 5-HTP alone. These data suggested that brain serotonin exerts a stimulating effect on LH secretion in both intact male and ovariectomized rats, but that it does not play any role in the control of FSH release in either kind of animal and that central serotoninergic pathways participate in the stimulating control of prolactin release from the anterior pituitary gland. However, some of the data also suggested the possibility of the existence in the brain of serotoninergic systems inhibiting prolactin secretion
Involvement of amygdalar receptors in the control of anterior pituitary function
No full textDrugs stimulating adrenergic, cholinergic or serotoninergic receptors have been implanted in the basomedial area of the amygdala in long-term castrated female rats, which were sacrificed at different time intervals after implantation. The data obtained show that: α-adrenergic receptors present in the amygdala exert an inhibitory tone on LH and FSH secretion and a stimulatory one on prolactin release; amygdalar β-adrenergic receptors exert an inhibitory influence on LH secretion and a stimulatory one on prolactin; and cholinergic receptors of the muscarinic type exert an inhibitory influence on LH but not on FSH release. Receptors of the nicotinic type exert the opposite effect. Cholinergic receptors of the muscarinic type seem to participate in the stimulatory control of prolactin secretion, while nicotinic receptors exert an inhibitory influence on this hormone. Serotoninergic receptors exert a stimulatory action on LH and prolactin secretion
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