Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-like growth factors (IGFs) regulate important cellular activities involving cell proliferation, differentiation, and apoptosis. Emerging evidence suggests that members of the IGF family, including IGF-1, IGF-2, the IGF-1 receptor (IGF-1R), and the IGF binding proteins (IGFBPs), play important roles in the development and progression of cancer. Both in vitro and in vivo studies show that IGFs are strong mitogens for a variety of cancer cells. IGF-1 also has an antiapoptotic action on cancer. IGF-1R, overexpressed in cancer cells, mediates the effects of IGFs and plays a role in cell transformation induced by tumor virus and oncogene products. IGFBPs inhibit the actions of IGFs and mediate the anti-proliferative effect of wild-type p53 protein, retinoic acid, vitamin D, and transforming growth factor-beta (TGF-beta). Findings from epidemiologic studies support the involvement of IGF in cancer etiology. Diet, nutrition, and other lifestyle features affect the expression and production of IGF-1 and other members of the IGF family. This may provide new approaches for cancer prevention. Growth hormone (GH) stimulates the production of IGF-1. Use of GH replacement therapy to improve physiological and psychological well-being and to prevent aging-related diseases has been recommended. Given the close relationship between GH and IGF-1, the long-term safety of GH treatment warrants a serious concern.
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PMID:Insulin-like growth factors and cancer. 1023 99

Growth hormone (GH) is essential for rodent mammary gland development during puberty. It binds to GH receptors in the stromal compartment of the mammary gland and stimulates IGF-I mRNA expression. These findings lead to the hypothesis that GH acts through locally produced IGF-I, which in turn, causes development of terminal end buds (TEBs), the structures that lead the process of mammary gland development during puberty. Subsequent studies have in large measure proven this hypothesis. They include the observations that mammary development was grossly impaired in female mice deficient in IGF-I (IGF-I(-/-) knockout mice), and treatment of these mice with IGF-I plus estradiol (E2) restored pubertal mammary development while treatment with GH + E2 did not. Thus, the full phenotypic action of GH in mammary gland development is mediated by IGF-I. We have demonstrated one effect of GH on the mammary gland that does not appear to be mediated by the action of IGF-I. GH increased the level of estrogen receptor (ER) mRNA and protein in the nuclei of mammary fat pad cells, but IGF-I did not. In addition to the critical role of the GH/IGF-I axis during pubertal mammary development, other data suggest that IGF-I might also be of importance during pregnancy and lactation. In summary, the earliest phase of pubertal mammary development (formation of TEBs) requires IGF-I or GH in IGF-I sufficient animals. No other hormones have been shown to stimulate formation of TEBs unless GH or IGF-I is present. GH-induced IGF-I is of major importance in ductal morphogenesis, and may, in fact, be necessary for later stages of mammary development, as well.
J Mammary Gland Biol Neoplasia 2000 Jan
PMID:IGF-I: an essential factor in terminal end bud formation and ductal morphogenesis. 1079 64

The first step in pubertal mammary development is the appearance of terminal end buds arising from pleuropotent stem cells present in the immature ductal tree of the prepubertal animal. Work from this laboratory indicates that growth hormone is the pituitary hormone responsible for terminal end bud development. Growth hormone likely acts through the production of IGF-1. This minireview focuses on the hormonal control of early mammary development with special emphasis on the roles of growth hormone and IGF-1.
J Mammary Gland Biol Neoplasia 1997 Jan
PMID:Early mammary development: growth hormone and IGF-1. 1088 19

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are known to be mitogens for many types of neoplasms. To investigate their role in tumors of glial origin, in vitro and in vivo experiments were performed with a panel of immortalized glioma cell lines (D54, SNB-19, U87, U251 and U373). Initial analysis for mRNA expression demonstrated the following: GH receptor (5/5 cell lines positive), IGF-I (0/5), IGF-II (0/5), IGF-I receptor (5/5), IGF-II receptor (2/5). Thus, each cell line expressed the necessary receptors to respond to GH and the IGFs but there was no autocrine IGF production by the tumors themselves. IGF-I stimulated mitogenesis as measured by [(3)H]thymidine uptake experiments in U251 and U373 cells. However, when these two IGF-responsive cell lines were xenografted into mice, tumor development and growth rates were not significantly different in GH-deficient animals (despite having IGF-I serum concentrations only 31% of normal). Because our studies were performed in immunocompromised animals, GH or IGF effects on immune surveillance, known to be important from some syngeneic glioma models, would not be likely to contribute to our findings. Nevertheless, these studies are important because they demonstrate that the growth of glioma cell lines in an in vivo environment can remain robust in a GH/IGF-I-deficient setting, even if in vitro experiments indicate that IGF-I is mitogenic.
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PMID:Growth hormone and insulin-like growth factor-I: effects on the growth of glioma cell lines. 1147 74

The primary aim of therapy should be to remove symptoms, reduce tumor bulk, prevent relapse, and improve long-term outcome. Surgery, radiotherapy and medical therapies are used to achieve these aims. Post-treatment mean "safe" serum growth hormone values of < 2.5 ng/ml should be the therapeutic goal. Transsphenoidal surgery remains the first line treatment for acromegaly. Patients with microadenoma can expect 85%, while those with macroadenoma 50% chance to achieve safe serum growth hormone levels. Less than 20% of acromegalics respond to treatment with bromocriptine, while quinagolide and cabergoline may show better clinical response; the success rate is higher for tumors secreting both growth hormone and prolactin. Dopamine agonists may be considered either in combination with somatostatin-analogues or as monotherapy in selected patients, and in those with co-secretion of prolactin. Octreotide (Sandostatin, Novartis) is a synthetic somatostatin-analogue, which is administered subcutaneously in doses between 100 and 250 micrograms 3 times daily. Long-acting octreotide (Sandostatin LAR, Novartis) contains octreotide incorporated into microspheres of biodegradable polymer. To effectively lower serum growth hormone levels, monthly injections of 10-30 mg of long-acting octreotide are needed, serum growth hormone falls to 2.5 ng/ml in 70% of cases, and serum insulin-like growth factor I normalizes in 67%. Slow release lanreotide (Somatuline SR, Ipsen) is an alternative depot long-acting somatostatin-analogue, which is administered in a dose of 30 mg intramuscularly every 14, 10 or 7 days. Both compounds are equally, if not more, effective than subcutaneous octreotide, and significantly improve patient compliance. Pegvisomant (Sensus Drug Development Corporation) is a genetically engineered growth hormone receptor antagonist, which inhibits growth hormone action. When given subcutaneously in a dose of 20 mg/day, serum insulin-like growth factor I levels return to normal in 90% of patients. Theoretical concerns of tumor expansion have not been a problem to date, but long term studies are needed. Primary medical--somatostatin-analogue--therapy is recommended if surgery fails, if the patient refuses or unsuited for surgery and it may be also considered in patients with macroadenoma with extra--but not suprasellar extension, since the surgical "cure" rates of these tumors are low.
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PMID:[Novel pharmacologic therapies in acromegaly]. 1206 60

During the year 2000, several original studies were published regarding the metabolic effects of growth hormone therapy in pediatric patients. Pharmacologic doses of growth hormone were rarely associated with abnormalities in glucose tolerance in children with intrauterine growth retardation and Turner syndrome; however, serum insulin levels were elevated. A report from the Pharmacia International Growth Study database suggested a possible increase in type 2 diabetes in growth hormone-treated patients, indicating the need for continued surveillance for this condition. Growth hormone therapy increased markers of bone turnover and bone mineral density in children with chronic renal failure and Prader-Willi syndrome. In Prader-Willi syndrome, 2 years of growth hormone therapy also induced a sustained decrease in body fat, improvement in strength and physical skills, and increased lean body mass. Serum leptin, a reflection of body fat, declined with growth hormone therapy in a dose-dependent manner in intrauterine growth retardation children; the magnitude of the decline correlated with linear growth response. Skin is a target organ for growth hormone in children; growth hormone increased dermal thickness and reduced skin stiffness in growth hormone-deficient children. Reassuring data were published regarding the risk of tumor recurrence and mortality in children with brain tumors treated with growth hormone. Growth hormone administered to short children prior to kidney transplantation did not have adverse effects on subsequent graft survival or number of rejection episodes.
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PMID:Metabolic effects of growth hormone in the child and adolescent. 1213 Sep 8

Growth hormone releasing hormone receptor (GHRH-R) is a class II G protein-coupled receptor required for normal growth hormone (GH) synthesis and release from the pituitary, and for the normal growth and proliferation of somatotrophs within the pituitary. Mutations of this receptor in mouse and human are associated with GH deficiency, short stature, and pituitary hypoplasia. This signaling system plays important roles in growth and development, metabolism of muscle and fat, and, possibly, the aging process. Among topics touched on in this article are the receptor gene's organization and promoter regulation, receptor signaling pathways, and receptor domains involved in interaction with ligand. Also discussed are alternative mRNA splicing and proposed functions of these splice variants as dominant negative inhibitors of wild-type receptor and in tumor proliferation. Homology among GHRH-Rs from different species is shown and a map of receptor mutations reported to effect function is presented.
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PMID:Growth hormone releasing hormone receptor. 1252 33

Medical therapy plays an important role in the management of acromegaly. Dopamine agonists and somatostatin analogs are two classes of drugs approved for this purpose worldwide. Pegvisomant, a growth hormone receptor antagonist, has recently been evaluated in clinical trials. Somatostatin analogs have been the mainstay of medical treatment during the last 10 yr with their acceptability enhanced by the development of depot preparations. Somatostatin analogs improve symptoms and signs of acromegaly in the majority, normalize IGF- 1 in up to 60%, and result in tumor shrinkage in up to half of patients. Dopamine agonists have modest efficacy and limited tolerability. They are more effective in mixed GH/prolactin-secreting tumors. Newer agonists with D2 receptor specificity have fewer side effects but are less efficacious than somatostatin analogs. The addition of a dopamine agonist to somatostatin analog therapy can result in greater biochemical control than with individual agents. Pegvisomant is the most effective drug treatment for acromegaly, but it is likely to have a major adjuvant role as its mechanism of action is not directed at the tumor. The availability of more effective and better tolerated drug therapies offers greater flexibility and individualization of therapy that will lead to improved patient care and disease control.
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PMID:Comparison of efficacy and tolerability of somatostatin analogs and other therapies for acromegaly. 1272 11

Growth hormone, prolactin, the fish hormone, somatolactin, and related mammalian placental hormones, including placental lactogen, form a family of polypeptide hormones that share a common tertiary structure. They produce their biological effects by interacting with and dimerizing specific single transmembrane-domain receptors. The receptors belong to a superfamily of cytokine receptors with no intrinsic tyrosine kinase, which use the Jak-Stat cascade as a major signalling pathway. Hormones and receptors are thought to have arisen as a result of gene duplication and subsequent divergence early in vertebrate evolution. Mammalian growth hormone and prolactin show a slow basal evolutionary rate of change, but with episodes of accelerated evolution. These occurred for growth hormone during the evolution of the primates and artiodactyls and for prolactin in lineages leading to rodents, elephants, ruminants, and man. Placental lactogen has probably evolved independently on three occasions, from prolactin in rodents and ruminants and from growth hormone in man. Receptor sequences also show variable rates of evolution, corresponding partly, but not completely, with changes in the ligand. A principal biological role of growth hormone, the control of postnatal growth, has remained quite consistent throughout vertebrate evolution and is largely mediated by insulin-like growth factors. Prolactin has many and diverse roles. In relation to lactation, the relative roles of growth hormone and prolactin vary between species. Correlation between the molecular and functional evolution of these hormones is very incomplete, and it is likely that many important functional adaptations involved changes in regulatory elements, for example, altering tissue of origin or posttranscriptional processing, rather than change of the structures of the proteins themselves.
J Mammary Gland Biol Neoplasia 2002 Jul
PMID:Growth hormone and prolactin--molecular and functional evolution. 1275 93

Growth hormone has been proposed as a potential new therapeutic agent for treatment of myocardial infarction (MI) and congestive heart failure (CHF). The purpose of this study was to evaluate the effects of GH on: (a) myocardial expression of creatine transporter (CreaT) during early postinfarct remodeling, (b) myocardial levels of total creatine (TCr) and adenine pool (TAN) and (c) plasma levels of inflammatory cytokines interleukin-1beta (IL-1beta), tumor-necrosis-factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in rat model of postinfarct cardiac remodeling. Myocardial infarction (MI) was induced by ligation of the left coronary artery in male Sprague-Dawley rats (200-250 g). Three different groups were studied: MI rats treated with GH (n=11) (3 mg/kg/day), MI rats treated with saline (n=10), and sham operated rats (n=7). In the myocardium from GH treated rats the level of mRNA CreaT expression was significantly increased (p<0.01). There was no difference in TCr between the rats with MI and sham-operated rats. Treatment with GH had no effect on TCr. GH had no effect on TAN in left ventricle. All three groups had similar levels of IL-6 and TNF-alpha in plasma. In the rats with MI, treatment with GH normalized the levels of IL-1beta (p<0.05). In conclusion GH increased the expression of CreaT and decreased levels of plasma IL-1beta during postinfarct remodeling in rats. These mechanisms may be responsible for the previously reported beneficial effects of GH on myocardial energy metabolism and preservation of cardiac function in the settings of postinfarct remodeling and CHF.
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PMID:Growth hormone induces myocardial expression of creatine transporter and decreases plasma levels of IL-1beta in rats during early postinfarct cardiac remodeling. 1293 44


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