LHRH agonists and antagonists containing very hydrophobic amino acids

NestorJr., J. J.; Ho, Teck-Hua; Tahilramani, R.; Horner, Bonnie L.; Simpson, R.; Jones, Gordon H.; McRae, G.I.; Vickery, B. H.

doi:10.1007/978-94-009-5588-2_3

Cited by 19 publications

(11 citation statements)

References 24 publications

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“…The relative contribution of these various growth factors to the growth of primary isolates of human breast adenocarcinomas, however, remains to be determined. The specificity of the growth-inhibitory effect by the TGF-a peptide A was shown in that 1) it did not inhibit MCF-7 cell growth stimulation due to the unrelated growth factor IGF-1; 2) peptide C, which is unrelated to TGF-W, but contains the same diethyl-homoarginine membrane binding moiety as is in peptide A (Nestor et al, 1984(Nestor et al, , 1985a, was without effect on EGF-stimulated cell growth; 3) TGF-a peptide B, which contains the third disulfide loop region of TGF-a but has no modifications designed to increase membrane binding affinity, showed no growth-inhibitory activity; 4) reduction of the disulfide loop of TGF-a peptide A abolished its inhibitory activity; and 5) the TGF-a peptide A also inhibited EGF-(but not FGF-or PDGF-) stimulated growth of NIH 3T3 cells but did not inhibit growth of the EGF nonresponsive NR-6 cells. Interestingly, the peptide had no inhibitory effects on EGFstimulated growth or mitogenesis of Go-arrested cells, suggesting that a factor(s) or process(es) present in growing cells facilitates the inhibitory activity.…”

Section: Discussionmentioning

confidence: 99%

“…Additional modifications designed to increase the membrane binding affinity of this ten-amino-acid TGF-a peptide were necessary before inhibitory activity was obtained. Such membranebinding modification additions to small peptide analogs are believed to contribute to increasing the apparent overall specific membrane receptor binding (Nestor et al, 1984(Nestor et al, , 1985a. To confirm that the biological effects obtained with the hArg(EtI2-containing TGF-a peptide were specific for TGF-a-related sequences and were not due to nonspecific membrane binding by the hArg(EtI2 group, an unrelated PTH peptide containing hArg(EtI2 was tested.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of epidermal growth factor/transforming growth factor‐α–stimulated cell growth by a synthetic peptide

Da¹,

Yv²,

Bb³

et al. 1989

Journal Cellular Physiology

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Estrogen-stimulated growth of the human mammary adenocarcinoma cell line MCF-7 is significantly inhibited by monoclonal antibodies to the epidermal growth factor (EGF) receptor that act as antagonists of EGF's mitogenic events by competing for high-affinity EGF receptor binding sites. These antibodies likewise inhibit the EGF or transforming growth factor-alpha (TGF-alpha)-stimulated growth of these MCF-7 cells. An analogous pattern of specific EGF or TGF-alpha growth inhibitory activity was obtained using a synthetic peptide analog encompassing the third disulfide loop region of TGF-alpha, but containing additional modifications designed for increased membrane affinity [( Ac-D-hArg(Et)2(31),Gly32,33]HuTGF-alpha(31-43)NH2). The growth factor antagonism by this synthetic peptide was specific in that it inhibited EGF, TGF-alpha, or estrogen-stimulated growth of MCF-7 cells but did not inhibit insulin-like growth factor-1 (IGF-1)-stimulated cell growth. Altogether, these results suggest that a significant portion of the estrogen-stimulated growth of these MCF-7 cells is mediated in an autocrine/paracrine manner by release of EGF or TGF-alpha-like growth factors. The TGF-alpha peptide likewise inhibited EGF- but not fibroblast growth factor (FGF)- or platelet-derived growth factor (PDGF)-stimulated growth of NIH-3T3 cells in completely defined media; but had no effect on growth or DNA synthesis of G0-arrested cells, nor did it effect growth of NR-6 cells, which are nonresponsive to EGF. Although this synthetic peptide did not directly compete with EGF for cell surface receptor binding, it exhibited binding to a cell surface component (followed by internalization), which likewise was not competed by EGF. The peptide did not directly inhibit EGF-stimulated phosphorylation of the EGF receptor, nor did it inhibit phosphorylation of an exogenous substrate, angiotensin II, by activated EGF receptor. The TGF-alpha peptide did, however, affect the structure of laminin as manifested by laminin self-aggregation; this affect on laminin may, in turn, have a modulatory effect on EGF-mediated cell growth.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of epidermal growth factor/transforming growth factor‐α–stimulated cell growth by a synthetic peptide

Da¹,

Yv²,

Bb³

et al. 1989

Journal Cellular Physiology

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“…In the present study we have investigated the role of the pituitary gonadotrophins in controlling luteal function in the stumptailed macaque by two approaches. First, by examining profiles of serum concentrations of LH, follicle-stimulating hormone (FSH), prolactin, oestradiol and progesterone from blood samples collected hourly between 09.00 and 21.00 h on different days of the luteal phase and, secondly, by observing the effects of a single injection of a potent LHRH antagonist (RS 68439) (Nestor, Ho, Tahilramani, et al 1984) on these profiles when administered at different stages of the luteal phase. We have previously demonstrated that administration of this antagonist suppressed serum concentrations of LH and progesterone when administered during the mid-late luteal phase (Fraser, Baird, McRae et al 1985).…”

mentioning

confidence: 99%

Effects of an LH-releasing hormone antagonist on the secretion of LH, FSH, prolactin and ovarian steroids at different stages of the luteal phase in the stumptailed macaque (Macaca arctoides)

Fraser¹,

Abbott²,

Laird³

et al. 1986

Journal of Endocrinology

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The role of the pituitary gonadotrophins in controlling luteal function in the stumptailed macaque has been investigated by examining profiles of serum concentrations of LH, FSH, progesterone and oestradiol in daily blood samples from 13 monkeys during the menstrual cycle, and in blood samples taken at hourly intervals between 09.00 and 21.00 h on different days of the luteal phase in 13 cycles. The effects of acute withdrawal of gonadotrophins was investigated by administering a single injection of 300 micrograms LHRH antagonist/kg body weight at different stages of the luteal phase during 28 cycles. Although there were high basal values and marked fluctuations of bioactive LH during the first 4 days after the LH peak, progesterone profiles showed no corresponding short-term changes, there being a slow and steady rise in progesterone concentrations during the sampling periods. After day 5, basal LH secretion decreased, but high amplitude LH pulses were identified which were associated with episodes of progesterone secretion. Administration of the LHRH antagonist caused a suppression of bioactive LH and progesterone concentrations at all stages of the luteal phase, although some basal secretion of progesterone was maintained through the 24-h period of effective antagonist gonadotroph blockade. Luteal function recovered apparently normally in all monkeys treated in the early-mid-luteal phase. Serum concentrations of FSH and oestradiol fluctuated comparatively less during the 12-h sampling periods, and the antagonist had less suppressive effects on the concentrations of these hormones. The LHRH antagonist had no apparent effect on prolactin release.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…Specifically, the aims were to investigate (1) the effect of third ventricular injection of LHRH on the pulsatile properties of LH secretion, (2) the effect of an LHRH antagonist on this response [ 18], and (3) the possible role of endogenous LHRH in the feedback con trol of pulsatile LHRH secretion.…”

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confidence: 99%

Inhibitory Effect of Central LHRH on LH Secretion in the Ovariectomized Ewe

Naylor

Porter

Lincoln³

1989

Neuroendocrinology

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The role of central luteinizing hormone releasing hormone (LHRH) in the control of pulsatile LHRH and luteinizing hormone (LH) secretion was investigated in ovariectomized adult ewes. Injection of LHRH (2.1–21 pmol) into the third cerebral ventricle caused a delayed but sustained inhibition of LH secretion. Pulse frequency, pulse amplitude and mean LH levels were reduced significantly when compared with the responses to the control injection of saline (50 µl). The inhibitory effect of centrally administered LHRH was not accompanied by a reduction in the pituitary responsiveness to intravenous LHRH. In contrast to the effect on LH, plasma levels of follicle-stimulating hormone (FSH) and prolactin were unaffected by central LHRH. The inhibitory action of LHRH was antagonized by prior injection of an LHRH antagonist ([N-Ac-D-Nal(2)¹ , D-p-Cl-Phe², D-Trp³, D-hArg (Et₂)⁶, D-Ala¹⁰] LHRH, 69 pmol) into the third ventricle. Central injection of the LHRH antagonist alone (at the same concentration) did not influence any characteristic of pulsatile LH secretion. In conclusion, these data indicate that exogenous administration of LHRH into the brain exerts a dose-related and receptor-mediated inhibition of LHRH pulse generator activity. However, the physiological significance of endogenous LHRH in the regulation of the LHRH pulse generator remains unresolved.

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LHRH agonists and antagonists containing very hydrophobic amino acids

Cited by 19 publications

References 24 publications

Inhibition of epidermal growth factor/transforming growth factor‐α–stimulated cell growth by a synthetic peptide

Inhibition of epidermal growth factor/transforming growth factor‐α–stimulated cell growth by a synthetic peptide

Effects of an LH-releasing hormone antagonist on the secretion of LH, FSH, prolactin and ovarian steroids at different stages of the luteal phase in the stumptailed macaque (Macaca arctoides)

Inhibitory Effect of Central LHRH on LH Secretion in the Ovariectomized Ewe

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