Bone and joint alterations in acromegaly

Growth hormone (GH) is fundamental for the maintenance of bone mass and metabolism both during childhood and in adulthood. This effect is due to a complex interaction between circulating GH and IGF-I produced peripherally. In vitro data and experimental animal models have clarified many of the regulatory mechanisms underlying the characteristic skeletal changes occurring in acromegaly. This review focuses on the effects of GH excess on bone metabolism and mass in acromegalic patients and, in particular, on the influence of factors such as hypogonadism, gender, age and therapy on bone metabolism and arthropathy.     

Expression of IGF-I and IGF-II mRNA in breast tissue

Summary Expression of IGF-I and IGF-II was studied in human breast cancer tissues by in situ hybridization. IGF-I mRNA was detected only in stromal cells adjacent to normal breast epithelial cells. Stromal cells associated with the tumor cells did not contain IGF-I, nor did malignant or benign breast epithelial cells. In contrast, IGF-II mRNA was found in both the malignant epithelial cells and their adjacent stromal cells. These data imply that stromal cells associated with breast epithelium may switch expression from IGF-I to IGF-II during breast cancer evolution. This appearance of IGF-II expression may identify cancer-associated stromal cells that have a fetal phenotype.     

Serum Levels of Free Insulin-Like Growth Factor (IGF)-I in Normal Children

Serum levels of free insulin-like growth factor (IGF)-I were measured by immunoradiometric assay (IRMA) in fasting sera of 137 normal boys and 120 normal girls aged from 8 to 15 yr to study relationships between free IGF-I levels and ages, total IGF-I, IGF binding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit (ALS) levels. In both sexes, serum free IGF-I levels and the ratios of free IGF-I to total IGF-I were significantly higher in the pubertal age groups than in the prepubertal age groups. Serum levels of free IGF-I showed a significant positive correlation with those of total IGF-I, IGFBP-3 and ALS, while they showed a significant negative correlation with those of IGFBP-1. These observations suggest that increase in serum free IGF-I levels during puberty is caused by a dramatic increase in total IGF-I, rather than IGFBP-3, and a decrease in IGFBP-1. Also, high free IGF-I levels may play an important role in pubertal growth spurt.     

Neuroprotective effects of IGF-I against TNFalpha-induced neuronal damage in HIV-associated dementia

Human immunodeficiency virus type 1 (HIV-1) infection often results in disorders of the central nervous system, including HIV-associated dementia (HAD). It is suspected that tumor necrosis factor-alpha (TNFalpha) released by activated and/or infected macrophages/microglia plays a role in the process of neuronal damage seen in AIDS patients. In light of earlier studies showing that the activation of the insulin-like growth factor I receptor (IGF-IR) exerts a strong neuroprotective effect, we investigated the ability of IGF-I to protect neuronal cells from HIV-infected macrophages. Our results demonstrate that the conditioned medium from HIV-1-infected macrophages, HIV/CM, causes loss of neuronal processes in differentiated PC12 and P19 neurons and that these neurodegenerative effects are associated with the presence of TNFalpha. Furthermore, we demonstrate that IGF-I rescues differentiated neurons from both HIV/CM and TNFalpha-induced damage and that IGF-I-mediated neuroprotection is strongly enhanced by overexpression of the wt IGF-IR cDNA and attenuated by the antisense IGF-IR cDNA. Finally, IGF-I-mediated antiapoptotic pathways are continuously functional in differentiated neurons exposed to HIV/CM and are likely supported by TNFalpha-mediated phosphorylation of I(kappa)B. All together these results suggest that the balance between TNFalpha and IGF-IR signaling pathways may control the extent of neuronal injury in this HIV-related experimental setting.     

Muscle satellite (stem) cell activation during local tissue injury and repair

In post-mitotic tissues, damaged cells are not replaced by new cells and hence effective local tissue repair mechanisms are required. In skeletal muscle, which is a syncytium, additional nuclei are obtained from muscle satellite (stem) cells that multiply and then fuse with the damaged fibres. Although insulin-like growth factor-I (IGF-l) had been previously implicated, it is now clear that muscle expresses at least two splice variants of the IGF-I gene: a mechanosensitive, autocrine, growth factor (MGF) and one that is similar to the liver type (IGF-IEa). To investigate this activation mechanism, local damage was induced by stretch combined with electrical stimulation or injection of bupivacaine in the rat anterior tibialis muscle and the time course of regeneration followed morphologically. Satellite cell activation was studied by the distribution and levels of expression of M-cadherin (M-cad) and related to the expression of the two forms of IGF-I. It was found that the following local damage MGF expression preceded that of M-cad whereas IGF-IEa peaked later than M-cad. The evidence suggests therefore that an initial pulse of MGF expression following damage is what activates the satellite cells and that this is followed by the later expression of IGF-IEa to maintain protein synthesis to complete the repair.     

Autocrine and paracrine growth regulation of human breast cancer

Summary We consider the hypothesis that estrogen control of hormone dependent breast cancer is mediated by autocrine and paracrine growth factors secreted by the breast cancer cells themselves. Though we show direct, unmediated effects of estrogen on specific cell functions, we also provide evidence that human breast cancer cells secrete a collection of growth factors (IGF-I, TGF, TGF, a PDGF-like competency factor, and at least one new epithelial colony stimulating factor). Some of these are estrogen-regulated in hormone dependent cells, and are constitutively increased in cells which acquire independence either spontaneously or byras transfection. Collectively, the secreted growth factors are capable of promoting tumor formation by MCF-7 cells in nude mice, though not to the same extent as estrogens. There would seem to be potential for clinical intervention in the autocrine and paracrine control of breast cancer cells, including some cells which are no longer dependent on estrogens.     

胰岛素样生长因子-Ⅰ及胰岛素样生长因子结合蛋白-3与胎儿宫内发育的关系

目的 检测孕妇静脉血、脐血中胰岛素样生长因子－Ⅰ (IGF－Ⅰ )及胰岛素样生长因子结合蛋白-3(IGFBP-3)水平,探讨 IGF－Ⅰ、 IGFBP-3与胎儿宫内发育的关系。方法 采用美国 DSL公司试剂盒。总计 81例孕妇,其中正常孕妇 38例,妊娠糖尿病孕妇 20例,正常妊娠分娩巨大儿孕妇 23例,采用放射免疫方法测定。 结果 正常组及巨大儿组孕妇静脉血 IGF-I与新生儿体重呈正相关 (r=0.653, r=0.640,两组 P均     

IGF-I and NGFβ enhance in vitro progressive motility and vitality of human spermatozoa

Purpose

Progressive motility (PM) and vitality are positively associated with fertilization ability of spermatozoa. Here, the effects of IGF-I and NGFβ on PM and vitality of human spermatozoa were investigated.

Methods

Forty-three volunteers gave semen samples after 2-3 days of sexual abstinence. Each sample was processed with density gradient centrifugation and sperm washing. The pellet was divided into 3 aliquots. An aliquot containing one million of progressively motile spermatozoa was incubated for an hour (37°C) in standard culture medium (control group), and two aliquots with the same number of progressively motile spermatozoa were incubated in medium supplemented with IGF-I or NGFβ. Two concentrations of IGF-I (100 ng/ml and 1000 ng/ml) and NGFβ (0,5 ng/ml and 5 ng/ml) were tested.

Results

Both growth factors significantly increased PM and vitality in comparison with control either at the low or the high concentration. IGF-I seemed to be more effective than NGFβ. The effects did not seem to be dose dependent with the exception of the effect of IGF-I on vitality.

Conclusions

The enhancement of PM and vitality of human spermatozoa by IGF-I and NGFβ opens new ways for the improvement of sperm processing. Further research is needed to determine the most effective concentrations.

     

Specific inhibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines

Summary Since the mitogenic action of EGF is mediated by ligand-induced autophosphorylation of the EGF receptor (EGFR), and EGFR is commonly overexpressed in solid human tumours, inhibitors of receptor tyrosine kinase activity (RTK) could prove to be effective antitumour agents. Screening of a compound library using an EGF-RTK enzyme prepared from human tumour derived A431 cells identified a series of potent (IC₅₀<1µM) enzyme inhibitors. These inhibitors are quinazolines bearing a variety of substituted anilines at the 4-position. The most potent 4-anilinoquinazolines (IC₅₀ 20nM) have small non-polar meta substituents on the aniline ring, and are competitive with ATP and non-competitive with substrate. The growth inhibitory activity of these agents was assessed in vitro using KB cells (human oral squamous tumour) grown in the absence or presence of EGF. A selected compound, 4-(3-chloroanilino)quinazoline (CAQ), inhibited EGF-stimulated growth in a concentration dependent manner and complete blockade was observed at concentrations (1–10 µM) which had no effect on basal growth. Selectivity of growth inhibition by CAQ was further exemplified in IGF1-stimulated KB cells where no effect was detected at concentrations which completely blocked EGF-stimulated growth. Similarly, CAQ blocked TGF-stimulated growth in MCF-7 human breast cancer cells without affecting insulin-stimulated growth. These studies define a novel class of EGF-RTK inhibitors which are also potent and selective inhibitors of EGF-stimulated human tumour cell growthin vitro. Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb.     

反义IGF—I基因转染人肝癌细胞分泌CEA和AFP水平的研究

本研究利用基因治疗方法中的反义RNA技术，通过脂质体包裹反义胰岛素样生长因子－I（IGF－I）基因导入人HepG2肝癌细胞株，NorthernBlot分析显示反义IGF－IRNA表达阳性。研究反义IGF－I基因转染的HePG2细胞分泌CEA和AFP的水平，放射性同位素的测定结果表明细胞培养上清中的CEA的水平显著地低于亲本细胞（P＜0．05），而分泌AFP的水平更显著地低于亲本细胞（P＜0．01）。预示着阳性克隆细胞的恶性程度低于亲本细胞，细胞内原有的生物学过程发生改变。