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ABSTRACT
Analogues of LHRH can be used for the treatment of sex hormone-dependent tumours. The nude mouse is a valuable model for the investigation of transplanted human cancers, but there is a body of literature reporting that the function of the pituitary-gonadal axis in normal (immunocompetent) and nude (immunocompromized) mice, unlike that of other species, cannot be suppressed by the administration of LHRH agonists and antagonists. To explore this view further, long-term experiments were carried out in nude male mice, in which sustained-release formulations of the agonist [d-Trp6]-LHRH and of two new potent antagonists were used which permitted a continuous release of the peptides into the circulation. Nude male mice were treated for 28-30 days with 50 μg of antagonists [Ac-d-Nal(2)1,d-Phe(4Cl)2,d-Trp3,d-Cit6,d-Ala10]-LHRH (SB-30) or [Ac-d-Nal(2)1,d-Phe(4Cl)2,d-Pal(3)3,d-Cit6,d-Ala10]-LHRH (SB-75)/day delivered by osmotic minipumps. Some mice were injected twice a day with 25 μg SB-75. Other groups received microcapsule preparations of the agonist [d-Trp6]-LHRH, releasing 25 or 12·5 μg/day for 30 days. At autopsy, in mice which received 50 μg SB-30 or SB-75/day by minipumps, there was a significant decrease in weights of testes, ventral prostate and seminal vesicles compared with controls. [d-Trp6]-LHRH microcapsules at either dose also reduced weights of testes and accessory sex organs. Serum LH and testosterone were significantly reduced in all groups treated with analogues. There was a greater decrease in testicular weights and serum testosterone in nude mice which received SB-75 in a continuous fashion from minipumps than in animals injected twice a day. These results clearly demonstrate, contrary to the existing data, that the pituitary-gonadal axis of nude mice can be inhibited by LHRH agonists or antagonists if they are administered by continuous release systems. This study indicates that when the sustained-release formulations are used, nude mice can be valuable for studying the effects of analogues of LHRH on tumour biology
Journal of Endocrinology (1990) 126, 309–315
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During recent experiments in our laboratories it was noted that rats pharmacologically blocked with dexamethasone, morphine and sodium pentobarbitone showed increased plasma levels of melanocyte-stimulating hormone (MSH) and suppressed plasma levels of corticosterone. Since there exists increasing evidence that MSH has an extra-pigmentary function in mammals (DeWied, Bohus & Greven, 1968; Kastin, Kullander, Borglin, Dahlberg, Dyster-Aas, Krakau, Ingvar, Miller, Bowers & Schally, 1968; Kastin, Miller, Gonzalez-Barcena, Hawley, Dyster-Aas, Schally, DeParra & Velasco, 1971) and since there appears to be some discrepancy regarding the relationship of MSH and corticotrophin (ACTH) to various stimuli (Abe, Nicholson, Liddle, Orth & Island, 1969; Kastin, Schally, Viosca & Miller, 1969), it seemed appropriate to determine the effect of the pharmacological block — dexamethasone, morphine and sodium pentobarbitone — on the release of MSH and ACTH.
Experiments were performed using adult (160–200 g) female Sprague—Dawley rats (Southern Farms) that were housed two to a cage for
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SUMMARY
The distribution of radioactivity after intrajugular injection of 125Ilabelled α-melanocyte-stimulating hormone (α-MSH) was studied by whole-body autoradiography of the mouse and by direct measurement of radioactivity in individual organs of the rat. Very high uptake of radioactivity in the pineal gland was measured 5 min after the injection of [125I]α-MSH. Lower levels of accumulation of radioactivity were found in the kidney and in the posterior (including intermediate) lobe of the pituitary. High uptake was also found in the thyroid, stomach, and oesophagus. The specificity of uptake of [125I] α-MSH into the pineal and pituitary is suggested by the very low uptake of Na125I into those tissues.
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A number of extra-pigmentary effects have been found to occur after injection of melanocyte-stimulating hormone (MSH) in mammals (Kastin, Kullander, Borglin, Dahlberg, Dyster-Aas, Krakau, Ingvar,Miller, Bowers & Schally, 1968). In the rabbit's eye, the blood-aqueous humour barrier is transitorily damaged leading to leakage of serum proteins into the aqueous humour (Dyster-Aas & Krakau, 1964; Dyster-Aas, 1965). This increase in protein can be visualized and measured by the Tyndall effect (Dyster-Aas & Krakau, 1963).
It seems that the flare-inducing effects of MSH are elicited indirectly, the inter-mediate step being the release or activation of a serum factor. The question was raised whether this serum factor could be MSH attached to some carrier protein or whether a new factor had been formed (Dyster-Aas & Krakau, 1966). The latter view was indirectly supported by recent experiments in which exogenous MSH could be excluded as the direct cause (Dyster-Aas & Krakau, 1968). However, involvement
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SUMMARY
The distribution of radioactivity after intrajugular injection of l-[3H]prolyl-l-leucyl-glycinamide has been studied by whole-body autoradiography in the mouse and by direct measurement of radioactivity in individual organs of the rat. There is good agreement between results obtained with the two techniques and animal species. High levels of radioactivity were found in the pineal gland, anterior pituitary, posterior (including intermediate) lobe of the pituitary, and epididymal and brown fat. Lower uptake of radioactivity occurred in the submaxillary gland, kidney, and adrenal gland. The preferential uptake of radioactivity by the pineal gland after injection of the labelled tripeptide suggests a role for this hypothalamic hormone in the control of pineal activity.
