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PubMed1990

Corticotropin-releasing hormone inhibition of growth hormone-releasing hormone-induced growth hormone release in man.

Recent studies in the rat have shown that intracerebroventricular administration of CRH inhibited spontaneous pulsatile GH secretion and prevented GH-releasing hormone (GHRH)-induced GH release. We have studied the effect of CRH on GHRH-induced GH release in man. In the first study, CRH was injected iv at three different doses (100, 50, or 25 micrograms) at 0800 h together with 50 micrograms GHRH in six men and six women. In a second study, 100 micrograms CRH were given iv at 0800 h, 1 h before the administration of 50 micrograms GHRH in five men and five women. Each subject demonstrated a normal GH response after the administration of 50 micrograms GHRH plus saline. All doses of CRH administered simultaneously with GHRH significantly inhibited GHRH-induced GH release in women [peak value +/- SE after GHRH plus saline, 28.9 +/- 2.9 micrograms/L; after GHRH plus 100 micrograms CRH, 9.9 +/- 0.7 micrograms/L (P less than 0.001); after GHRH plus 50 micrograms CRH, 8.7 +/- 0.8 micrograms/L (P less than 0.001); after GHRH plus 25 microgram CRH, 9.5 +/- 1.6 microgram/L (P less than 0.001]). In contrast, in men, while a dose of 100 micrograms CRH was capable of suppressing GHRH-induced GH secretion (peak value +/- SE, 8.1 +/- 0.6 vs. 20 +/- 2.9 micrograms/L; P less than 0.001), no inhibition was observed after 50- and 25-micrograms doses. When 100 micrograms CRH were injected 1 h before the administration of 50 micrograms GHRH, it strongly inhibited GHRH-induced GH secretion in both men (peak value +/- SE, 6.2 +/- 2.8 vs. 24.6 +/- 5.9 micrograms/L; P less than 0.02) and women (peak value +/- SE, 14.2 +/- 4.5 vs. 37.8 +/- 6.7 micrograms/L; P less than 0.005), and this inhibition lasted up to 2 h post-CRH administration. These results demonstrate that CRH is capable of inhibiting GHRH-induced GH release in both men and women. Furthermore, the findings suggest that a sexual dimorphism in the neuroregulation of GH secretion may be present in man. In view of the inhibitory action of CRH on GH secretion, simultaneous administration of CRH and GHRH for testing should be avoided in clinical practice.

Adult↗
PubMed1997

Growth hormone down-regulates growth hormone receptor mRNA in chickens but developmental increases in growth hormone receptor mRNA occur independently of growth hormone action.

The purpose of this study was to determine the role of growth hormone (GH) in regulating expression of the chicken GH receptor (cGHR) gene by comparing the levels of cGHR mRNA in livers of normal chickens with that of GHR-deficient dwarf chickens. Since the sex-linked dwarf chicken lacks a functional cGHR, there are no genes activated as a result of GH action. Examination of the early developmental profile of hepatic cGHR mRNA in normal and dwarf chickens should yield information on the relative contribution of developmental and hormonal factors to the regulation of cGHR gene expression. Using a sensitive RNase protection assay, we found that the abundance of the major cGHR transcripts (4.3, 3.2 and 0.8 kb) in normal chickens increases about 2-fold between 1 and 7 weeks of age. Due to a splice site mutation in the dwarf chicken, the two larger transcripts encoding the full-length cGHR are not expressed. However, the expression of the truncated cGHR transcript (0.8 kb) in dwarf chickens increases about 5-fold between 1 and 7 weeks of age which suggests that the cGHR gene is overexpressed when not down-regulated by GH. Furthermore, a single promoter, appears to control expression of cGHR transcripts in liver since primer extension analysis revealed the same 5'-end in both full-length and 0.8 kb transcripts. These observations suggest that even though developmental increases in cGHR gene expression occur independently of GH action, GH, either directly or indirectly, down-regulates expression of the cGHR gene in normal chickens.

Animals↗
PubMed1981

A new hypothalamic substance, and not luteinizing hormone-releasing hormone, is detected immunocytochemically by antibody to luteinizing hormone-releasing hormone.

Adjacent paraffin sections of rat hypothalami fixed in Bouin's fluid were treated either with buffer or with luteinizing hormone-releasing hormone (LHRH) before immunocytochemical staining with anti-LHRH. Upon buffer pretreatment, pituitary gonadotrophs were unstained and hypothalamic fibers were stained. Upon LHRH pretreatment, pituitary gonadotrophs were stained (receptor reaction) and hypothalamic fibers were unstained. Extension of washes and use of series of neutralizing antisera between LHRH application and immunocytochemical staining, as well as the absence of inhibiting concentrations of LHRH in the later washes and neutralizing antisera removed from the sections, excluded the possibility that the disappearance of visualization of hypothalamic fibers was due to blockage of anti-LHRH in immunocytochemical staining. The results suggested that LHRH removed from the sections an immunocytochemically stainable but as yet unknown analog of LHRH and replaced it with LHRH, which in turn became lost during subsequent immunocytochemical processing. This idea was confirmed by the isolation by high-pressure liquid chromatography of a peak, distinct from LHRH, upon treatment of hypothalami with LHRH. It is suggested that the new substance may be carrier-held and that this substance, rather than LHRH, is normally detected by immunocytochemistry with anti-LHRH. Added LHRH binds not only to high-affinity pituitary receptors but also to low-affinity hypothalamic carriers.

Animals↗
PubMed1988

Receptors for prolactin, somatostatin, and luteinizing hormone-releasing hormone in experimental prostate cancer after treatment with analogs of luteinizing hormone-releasing hormone and somatostatin.

Membrane receptors for luteinizing hormone-releasing hormone (LH-RH), somatostatin, and prolactin (PRL) were investigated in the Dunning R-3327H rat prostate adenocarcinoma specimens after in vivo treatment with microcapsules of the agonist [D-Trp6]LH-RH and the somatostatin analog RC-160. The LH-RH receptors showed a low-binding affinity (Kd = 54 nM) and high capacity (Bmax = 12.0 pmol/mg). Treatment with the [D-Trp6]LH-RH decreased the binding affinity (Kd = 0.52 microM). Specific somatostatin receptors, with Kd = 1.3 nM and Bmax = 543 fmol/mg, were also found. Treatment with [D-Trp6]LH-RH lowered Bmax to 44 fmol/mg, and administration of RC-160 reduced Kd to 30 nM. After the combined treatment with the two analogs, Kd and Bmax were decreased. Specific PRL receptors (Kd = 0.72 nM; Bmax = 161 fmol/mg) were also detected. Treatment with either analog reduced Bmax by 50%, but a much greater reduction of PRL binding capacity was revealed after in vitro dissociation of the bound endogenous PRL by MgCl2. The dramatic fall in the total number of PRL receptors after combination treatment with both analogs could be partially responsible for the decrease in the weight and volume of prostate tumors. The findings support the concept that analogs of LH-RH and somatostatin can inhibit tumors directly through their own respective receptors. One of several mechanisms of the antineoplastic activity of these analogs could be the elimination of tumor growth-promoting effect of PRL by the reduction of the total number of PRL receptors.

Adenocarcinoma↗
PubMed2005

Human malignant melanomas express receptors for luteinizing hormone releasing hormone allowing targeted therapy with cytotoxic luteinizing hormone releasing hormone analogue.

Cytotoxic analogue of luteinizing hormone releasing hormone (LHRH), AN-207, binds with high affinity to LHRH receptors and can be targeted to tumors expressing these receptors. We investigated the expression of LHRH receptors in surgical specimens of human malignant melanoma and evaluated the effects of AN-207 in models of human melanoma. Human melanoma specimens derived from primary tumors or metastases were examined for LHRH receptor expression by immunohistochemistry. Binding assays, Western immunoblotting, and reverse transcription-PCR analyses were used to investigate LHRH receptors in MRI-H255 and MRI-H187 transplantable human melanoma tumor lines. Antitumor effects of AN-207 and its components were evaluated in vivo in nude mice bearing xenografts of either melanoma tumor line. All 19 human melanoma specimens examined showed positive staining for LHRH receptors. The mRNA for LHRH receptors, receptor protein and binding sites for LHRH were detected in both transplantable melanoma tumor lines. AN-207 significantly inhibited the growth of MRI-H255 and MRI-H187 xenografts in vivo, reducing tumor volume by 59.9% to 79.2% and tumor weight by 61.0% to 76.9% (all P < 0.05). The components of AN-207 (LH-RH analogue carrier and cytotoxic radical AN-201 as single drugs or as an unconjugated mixture) had no significant effects. Blockade of LHRH receptors by an excess of LHRH agonist Decapeptyl suppressed the effects of AN-207. LHRH receptors are expressed in a very high percentage of human malignant melanoma specimens and can be used for targeted chemotherapy with cytotoxic LHRH analogue AN-207.

Animals↗
PubMed1992

5-alpha androstane diol stimulates the pituitary growth hormone responsiveness to growth hormone releasing hormone more effectively than testosterone or dihydrotestosterone in rats.

The effect of different androgens and estradiol on pituitary responsiveness to growth hormone releasing hormone was studied in intact and orchidectomized adult male Wistar rats, by injecting subcutaneously immediately after orchidectomy for two weeks with testosterone, dihydrotestosterone, 5-alpha androstane, 3-alpha,17 beta-diol or estradiol dissolved in olive oil (in doses of 0.2 or 2.0 mg.kg-1.day-1) or vehicle. Pituitary responsiveness was tested in pentobarbital anaesthetized rats by measuring growth hormone plasma levels at different times after administration of growth hormone releasing hormone (1-29) NH2. We found that: (a) High doses of testosterone, dihydrotestosterone and 5-alpha androstane, 3-alpha,17 beta-diol restored gonadotropin plasma concentrations and organ weights altered by orchidectomy; (b) both pituitary growth hormone content and concentration remained unaffected after orchidectomy or androgen replacement and decreased significantly after estradiol injection; (c) orchidectomy significantly reduced growth hormone-stimulated growth hormone releasing hormone secretion; (d) treatment with 5-alpha androstane,3-alpha,17 beta-diol increased more than testosterone or dihydrotestosterone both the peak concentration and the mean growth hormone secretion after growth hormone releasing hormone stimulation; (e) no differences were observed in the treatment with testosterone or dihydrotestosterone; (f) estradiol given at a dose of 0.2 mg.kg-1.day-1 increased pituitary responsiveness to growth hormone releasing hormone.(ABSTRACT TRUNCATED AT 250 WORDS)

Androstane-3,17-diol↗
PubMedDate not supplied

Growth hormone response after administration of L-dopa, clonidine, and growth hormone releasing hormone in children with Down syndrome.

We studied the response of growth hormone secretion after the administration of L-dopa, clonidine, and growth hormone releasing hormone in eight growth-retarded children with Down syndrome aged 1 to 6.5 years. After L-dopa administration, five children had low growth hormone secretion (M = 3.7 ng/ml, SD = 2.12 at 30 min) and three children had elevated growth hormone levels (> 30 ng/ml). After clonidine administration, six children had relatively low growth hormone levels (M = 3.15 ng/ml, SD = 2.53 at 60 min) and two children had high levels (38.3 ng/ml and 16.8 ng/ml, respectively). There was a better response after growth hormone releasing hormone administration; only one child had a growth hormone level of < 10 ng/ml. Most of the children had a modified response of growth hormone secretion subsequent to the various stimulation tests. All children, however, were able to secrete some growth hormone (> or = 10 ng/ml) at least during one of the stimulation tests. In comparison with peak growth hormone levels reported in normal children, our cohort had significantly lower growth hormone levels only after clonidine administration. It is postulated that children with Down syndrome have both anatomical and biochemical hypothalamic derangements that may result in decreased growth hormone secretion and reduced linear growth. In addition, other mechanisms that may be in part responsible for the observed growth retardation are discussed.

Child, Preschool↗
PubMed1994

Lowering cortisol enhances growth hormone response to growth hormone releasing hormone in healthy subjects.

Cortisol is known to influence growth hormone release probably by modulating somatostatin tone. We examined the effect of metyrapone (the 11 beta-hydroxylase inhibitor) treatment on growth hormone response to growth hormone releasing hormone (1 microgram kg-1 body wt). Six healthy male subjects were tested on two occasions 1 wk apart. On one occasion they received metyrapone followed by growth hormone releasing hormone and on the other placebo followed by growth hormone releasing hormone. In all subjects metyrapone produced a significant drop in cortisol levels. Together with this drop there was a significant enhancement of growth hormone response to growth hormone releasing hormone. The GH response was negatively correlated with the cortisol level. Growth hormone release in response to growth hormone releasing hormone challenge is thus seen to be heavily influenced by cortisol levels.

Adult↗
PubMed1986

Luteinizing hormone response to pulsatile luteinizing hormone-releasing hormone in prepubertal heifers.

The effects of 12 hourly 5-micrograms injections of luteinizing hormone-releasing hormone on luteinizing hormone release, were examined in 18 prepubertal Holstein heifers at 4, 7, or 10 mo of age. During a 6-h pretreatment period, mean serum luteinizing hormone concentrations and mean number of endogenous luteinizing hormone episodes per hour were not influenced by age. The 12-h treatment regimen induced a pulsatile release of luteinizing hormone in all heifers. The magnitude, pattern, and total amount of luteinizing hormone released were not influenced by age. However, in the 4 and 10-mo-old age groups, magnitude of luteinizing hormone response to the 3rd hourly injection of luteinizing hormone-releasing hormone was greater than the response to the second injection. Magnitudes of luteinizing hormone responses decreased with time after the 4th hourly injection through the 12th injection and patterns of decline appeared similar among the three age groups. The pituitary of the prepubertal dairy heifer is able to respond to an hourly pulsatile administration of luteinizing hormone-releasing hormone and this treatment regimen appears to produce a self-priming effect on luteinizing hormone release.

Animals↗
PubMed1993

Physiological levels of growth hormone fail to suppress growth hormone releasing hormone (1-29) NH2-stimulated growth hormone secretion in man.

We studied 11 normal adult males. Six subjects (Study A) received a bolus of saline or of 50 mU biosynthetic human growth hormone (r-hGH) or a one hour iv infusion of r-hGH (80 mU/h) in random order. On each occasion this was followed by an iv bolus of GHRH (1-29) NH2 (100 micrograms) 90 minutes after the first event. Five subjects (Study B) received a bolus iv injection of saline or of 500 mU r-hGH followed by iv GHRH (1-29) NH2 (100 micrograms) 90 minutes later. There was no significant difference in the serum GH concentrations achieved following the 50 mU bolus or iv infusion of r-hGH (range 5.6-67.0 mU/l). Higher concentrations of GH (mean +/- SE, 238.4 +/- 21.3 mU/l) were achieved with the 500 mU bolus of r-hGH. The peak GH responses to iv GH-RH (1-29) NH2 were similar in all instances. The most important factor determining the response to exogenous GHRH (1-29) NH2 was the serum GH concentration at the time that the GHRH (1-29) NH2 was administered and the mode of r-hGH administration (iv bolus or iv infusion). These data demonstrate that within the range of physiological serum GH concentrations the mode of presentation of GH (bolus or infusion) and GH secretory status are the most important factors in determining GH responsivity to GHRH. Under these circumstances GH would appear not to participate in a rapid-acting short-loop negative feedback mechanism in man as the response to exogenous GHRH was not attenuated.

Adolescent↗
PubMed1993

Effects of injection of anti-luteinizing hormone (LH)-releasing hormone serum and anti-gonadotropin-releasing hormone-associated peptide serum into neonatal rats on LH and follicle-stimulating hormone cells.

Relatively little is known regarding the potential importance of LHRH and of gonadotropin-releasing hormone-associated peptide (GAP) on the postnatal development of gonadotrophs. We investigated the effects of administration of anti (A)-LHRH serum or A-GAP serum to neonatal rats on the development of LH and FSH immunoreactivity in anterior pituitary gland (APG) cells. Serum (sheep non-immune [NSS], sheep A-LHRH, sheep A-LHRH/GAP [which bound LHRH and GAP], rabbit non-immune [NRS], or rabbit A-GAP) was injected s.c. into neonatal female and male rats on Days 1 and 3 or Days 1, 3, 5, and 7 after birth. Pups were killed on Day 5 or 9, two days after the last injection. The percentages of APG cells immunoreactive for LH or FSH increased from Day 1 to Day 5 and did not change between Days 5 and 9 in female pups treated with NSS or NRS. There was a trend for the percentages of LH and FSH cells to increase from Day 1 to Days 5 and 9 in male pups treated with NSS or NRS, but the increases were not statistically significant. In both females and males, treatment with antisera that recognized LHRH reduced the percentage of FSH cells on Day 5 and the percentages of LH and FSH cells on Day 9. Treatment with A-GAP was without effect in both sexes. There were similar percentages of LH and FSH cells in females and a lower percentage of FSH than of LH cells in males in the Day 5 and 9 controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Modification of 24-hour growth hormone secretion after continuous subcutaneous infusion of growth hormone-releasing hormone (GHRH (1-29)NH2) in short children with low 24-hour growth hormone secretion.

Six short children with low 24-hour growth hormone (GH) secretion were treated with continuous subcutaneous infusion of GHRH (1-29)NH2 for 3 weeks using a portable infusion pump. Restoration of pulsatile GH secretion was observed in all three children treated with 40 micrograms/kg/day of GHRH, but in only one of the three children treated with 20 micrograms/kg/day. All parameters of 24-hour GH secretion increased, but in five children the magnitude of the GH response was greater on day 1 than on day 21 of GHRH treatment. This decrease was not observed in the single child who responded to a low dose of GHRH (20 micrograms/kg/day); on the contrary, the response in this patient was greater after 21 days of GHRH treatment. Plasma levels of GHRH (1-29)NH2 were significantly higher on day 21 than on day 1 of treatment, suggesting altered pharmacokinetics over time. The effect of GHRH treatment on growth could not be determined because of the short duration of the study, but the data obtained on 24-hour GH secretion and GHRH metabolism suggest that a long-acting analogue of GHRH could be useful for the treatment of GH deficient or insufficient children.

Adolescent↗
PubMed1989

Repetitive growth hormone-releasing hormone administration restores the attenuated growth hormone (GH) response to GH-releasing hormone testing in normal aging.

The plasma GH response to human pituitary GH (hpGH)-releasing hormone-40 (hpGHRH-40; 1 microgram/kg BW) was significantly lower in seven healthy aged men (age range, 65-78 yr) than in seven healthy young men (age range, 18-31 yr) 30, 60, and 90 min after acute hpGHRH-40 administration (P less than 0.0001, by Student's unpaired t test). To verify whether a priming regimen might be able to reverse the reduced GH response to GHRH, elderly subjects underwent repetitive administration of hpGHRH-40 and placebo in a double blind design (100 micrograms hpGHRH-40 or volume-matched saline iv as a single morning dose, every 2 days for 12 days). After the hpGHRH-40-priming regimen, plasma GH values 30, 60, and 90 min after the acute GHRH test were significantly higher than values at the corresponding time points after placebo treatment. These findings suggest that somatotroph cells become less sensitive to GHRH with normal aging and demonstrate that repetitive administration of GHRH restores the attenuated response.

Adult↗
PubMed2001

Growth hormone/insulin-like growth factor-1 response to acute and chronic growth hormone-releasing peptide-2, growth hormone-releasing hormone 1-44NH2 and in combination in older men and women with decreased growth hormone secretion.

To better appreciate the interactions of GHRP-2 and GHRH 1-44NH2 on the release of GH in normal adult men and women with decreased GH secretion and low serum IGF-1 levels, a series of acute and chronic studies have been performed (n = 5 men, 5 women). The acute iv bolus GH responses of these subjects to the two peptides alone and together suggest that the decreased GH secretion may be primarily due to a deficiency of the natural endogenous GHRP, ghrelin, rather than a decreased secretion of endogenous GHRH or excess secretion of SRIF. To determine whether the low GH response to GHRH was due to a limited capacity of pituitary to release GH, higher dosages of GHRP-2 alone were administered. At a dose of 1 microg/kg GHRP-2 the GH response was essentially the same as that elicited by 1 microg/kg GHRH + 0.1 microg/kg GHRP-2 while the GH response to 10 microg/kg GHRP-2 sc was about twice as high in both men and women. Although these subjects have a limited pituitary capacity to release GH, which is also an indication of decreased GH secretion in the presence of low serum IGF-1 levels, this alone would not explain the low GH response to GHRH. Furthermore, the finding that a low dose of 0.1 microg/kg GHRP-2 augments the GH response to 1 microg/kg GHRH is strongly against an excess secretion of SRIF. Twenty-four hour profiles of GH secretion during placebo, GHRP-2, and various doses of GHRH alone and together with GHRP-2 were studied. In addition, 1 microg/kg/h GHRP-2 was infused continuously sc to these subjects for 30 d. The normal pulsatile secretion of GH as well as the serum IGF-1 level was increased after 24 h and remained elevated for 30 d. With a deficiency of endogenous GHRH, the GH response of GHRP-2 would be little to none, while in subjects with a deficiency of the natural GHRP, the GH response to GHRH would be more attenuated. Thus, in chronic deficiency the GH response would be expected to depend on the degree of the capacity of the pituitary to release GH as well as the type(s) of hormonal deficiency.

Area Under Curve↗
PubMed1995

Comparison of the effects of growth hormone-releasing hormone and hexarelin, a novel growth hormone-releasing peptide-6 analog, on growth hormone secretion in humans with or without glucocorticoid excess.

The aim of our study was to investigate the effect of hexarelin, a novel GH-releasing peptide-6 analog, and GH-releasing hormone (GHRH) (alone or in combination) on GH secretion in adult patients with increased somatostatin tone due to chronic glucocorticoid excess. We studied seven adult patients undergoing long-term (no less than 6 months) immunosuppressive glucocorticoid treatment for non-endocrine diseases (six females and one male, age range 42-68 years) and one subject (female, age 31 years) with endogenous hypercortisolism due to adrenal adenoma. Six normal subjects (four females and two males) matched for sex and age with the patients and not undergoing any therapy served as controls. All the subjects underwent the following three tests in random order: (1) human GHRH (1-29)NH2 (100 micrograms in 1 ml saline) injected as an i.v. bolus at 0 min, (2) hexarelin (100 micrograms in 1 ml saline) injected as an i.v. bolus at 0 min and (3) hexarelin (100 micrograms in 1 ml of saline) plus GHRH (100 micrograms in 1 ml saline) injected as an i.v. bolus at 0 min. After GHRH alone the patients with glucocorticoid excess showed a blunted GH response as compared with normal subjects (median delta GH: 0.9, range 0-5.6 micrograms/l vs 7:1, range 0.3-14.9 micrograms/l). No significant differences were observed in the steroid-treated group with respect to normal subjects after hexarelin alone (median delta GH: 15.5, range 1.9-45.2 micrograms/l vs 17.9, range 5.5-53.9 micrograms/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2002

Atrial natriuretic hormone, vessel dilator, long acting natriuretic hormone, and kaliuretic hormone decrease circulating prolactin concentrations.

The present investigation was designed to test whether four cardiac hormones--long acting natriuretic hormone, vessel dilator, kaliuretic hormone and atrial natriuretic hormone--decrease the circulating concentration of prolactin in humans (n = 30). Vessel dilator, kaliuretic hormone, long acting natriuretic hormone and atrial natriuretic hormone decreased the circulating concentration of prolactin to 3 %, 31 %, 27 %, and 23 % of control values, respectively, at the end of their infusions when infused at concentrations of 100 ng/kg body weight per minute for 60 minutes (p < 0.001 for each). Vessel dilator, kaliuretic hormone, long acting natriuretic hormone and atrial natriuretic hormone had sustained effects on modulating prolactin's concentrations, with circulating concentrations of 1 %, 64 %, 28 %, and 2 % of control values (p < 0.001) 3 hours after stopping their respective infusions. These results suggest that there are four circulating prolactin-inhibitory hormones in addition to the hypothalamic mediators, dopamine and corticotropin-releasing hormone, which modulate prolactin release. These peptide hormones' ability to decrease circulating prolactin concentrations may be mediated in part by dopamine and in part by their demonstrated ability to decrease corticotropin-releasing hormone concentrations, which stimulate prolactin release.

Adult↗
PubMed2005

Receptors for luteinizing hormone releasing hormone expressed on human renal cell carcinomas can be used for targeted chemotherapy with cytotoxic luteinizing hormone releasing hormone analogues.

PURPOSE: To determine the expression of luteinizing hormone releasing hormone (LHRH) receptors in specimens and cell lines of human renal cell carcinoma (RCC) and to evaluate the antitumor efficacy of targeted therapy with a cytotoxic analogue of LHRH, AN-207, in vivo. AN-207, consisting of [D-Lys(6)] LHRH linked to a cytotoxic radical, 2-pyrrolinodoxorubicin (AN-201), binds with high affinity to LHRH receptors and can be targeted to tumors expressing these receptors. EXPERIMENTAL DESIGN: The expression of LHRH receptors was investigated in 28 surgically removed specimens of human renal cell carcinoma (RCC) by immunohistochemistry and in three human RCC cell lines A-498, ACHN, and 786-0 by radioreceptor assays, Western immunoblotting, and reverse transcription-PCR analysis. Antitumor efficacy of AN-207 was examined in experimental models of these cell lines. RESULTS: Positive staining for LHRH receptors was found in all (28 of 28) of the examined human RCC specimens. mRNA for LHRH receptor, receptor protein, and LHRH binding sites were detected in all three cell lines. AN-207 significantly (P < 0.05) inhibited the growth of A-498, ACHN, and 786-0 xenografts in vivo producing a 67.8% to 73.8% decrease in tumor volume and a 62.2% to 77.3% reduction in tumor weight. Nontargeted cytotoxic radical AN-201 had no significant antitumor effects. Blockade of LHRH receptors by an excess of LHRH agonist Decapeptyl suppressed tumor inhibitory effects of AN-207. CONCLUSIONS: Our findings indicate that LHRH receptors are expressed in human RCC specimens and can be used for targeted chemotherapy with cytotoxic LHRH analogues.

Animals↗
PubMed2001

Bushbaby growth hormone is much more similar to nonprimate growth hormones than to rhesus monkey and human growth hormones.

Unlike other mammals, Old World primates have five growth hormone-like genes that are highly divergent at the amino acid level from the single growth hormone genes found in nonprimates. Additionally, there is a change in the interaction of growth hormone with its receptor in humans such that human growth hormone functions in nonprimates, whereas nonprimate growth hormone is ineffective in humans. A Southern blotting analysis of the genome of a prosimian, Galago senegalensis, revealed a single growth hormone locus. This single gene was PCR-amplified from genomic DNA and sequenced. It has a rate of nonsynonymous nucleotide substitution less than one fourth that of the human growth hormone gene, while the rates of synonymous substitution in the two species are less different. Human and rhesus monkey growth hormones exhibit variation at a number of amino acid residues that can affect receptor binding. The galago growth hormone is conservative at each of these sites, indicating that this growth hormone is functionally like nonprimate growth hormones. These observations indicate that the amplification and rapid divergence of primate growth hormones occurred after the separation of the higher primate lineage from the galago lineage.

Amino Acid Sequence↗