Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied 24-h hormone profiles and hormonal responses to insulin-induced hypoglycaemia prospectively in 23 children of similar age and pubertal stage, nine of whom had received prior cranial irradiation (group 1) and fourteen of whom had not (group 2), before and 6-12 months after total body irradiation (TBI) for bone marrow transplantation in leukaemia. Fourier transformation demonstrated that group 1 children had a faster periodicity of GH secretion before TBI than group 2 children (160 vs 200 min) but the amplitude of their GH peaks was similar. There were no differences between the groups in circadian cortisol rhythm, serum concentrations of insulin-like growth factor-I (IGF-I), sex steroids and basal thyroxine (T4). The peak serum GH concentrations observed after insulin-induced hypoglycaemia were similar between the two groups but the majority of patients had blunted responses. TBI increased the periodicity of GH secretion in both groups (group 1 vs group 2; 140 vs 180 min), but the tendency to attenuation of amplitude was not significant. There were no significant changes in the peak serum GH concentration response to insulin-induced hypoglycaemia which remained blunted. Serum IGF-I, sex steroid, cortisol or T4 concentrations were unchanged. Low-dose cranial irradiation has an effect on GH secretion affecting predominantly frequency modulation leading to fast frequency, normal amplitude GH pulsatility. This change is accentuated by TBI. In patients with leukemia, there is a marked discordance between the peak serum GH response to insulin-induced hypoglycaemia compared with the release of GH during 24-h studies, irrespective of the therapeutic regimen used.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Short-term endocrine consequences of total body irradiation and bone marrow transplantation in children treated for leukemia. 845 99

GH is the hormone primarily responsible for regulating body size within the genetic program. While GH has pleiotropic actions on cellular growth and metabolism, most of its effects are believed to be mediated by a single GH receptor. This receptor is not functional in tissues from patients with Laron dwarfism. We used human T-cell leukemia virus-immortalized T-lymphoblast cell lines from Laron dwarfs and normal individuals to examine the mechanism of GH-induced insulin resistance at the cellular level. GH (5-500 micrograms/L) caused a profound decrease in the sensitivity of normal T-lymphoblasts in response to all insulin concentrations (P < 0.0001 vs. insulin alone); pretreatment with GH and GH receptor antibody significantly improved sensitivity to all concentrations of insulin (P = NS vs. insulin alone). Preincubation with GH and PRL receptor antibody was associated with partial improvement in insulin sensitivity (P = 0.004 vs. insulin alone). Thus, in normal T-cell lines, the major pathway of GH-induced insulin resistance appears to be directed by the GH receptor, with a smaller effect mediated through the PRL receptor. While T-cell lines from Laron dwarfs do not respond to GH in clonal proliferation assays, GH (50 and 100 micrograms/L) caused profound insulin resistance in these cells (P = 0.008 and P < 0.0001, respectively, vs. insulin alone). GH receptor antibody did not abrogate this effect at any insulin concentration (P = NS vs. insulin alone), but there was partial restoration of insulin sensitivity when GH and PRL receptor antibody were coincubated (P = 0.0069 vs. insulin alone). Thus, in Laron T-cell lines, PRL and perhaps other lactogenic receptors appear to mediate GH-induced insulin resistance. The kinetics of GH-induced insulin resistance in Laron T-cells were also distinct from the pattern seen in normal T-cells, and unlike in normal cells, GH had no effect on insulin-like growth factor-I-induced clonal expansion of Laron T-cell lines (P = NS vs. insulin-like growth factor-I alone). These results provide evidence for an alternative pathway of GH action revealed in cells lacking classical growth responses to GH.
 ...
PMID:Growth hormone induces insulin resistance in Laron dwarf cells via lactogenic receptors. 847 79

Adult T cell leukemia derived factor (ADF), which was first reported as a cytokine-like factor produced by human T lymphotropic virus I (HTLV-I)-transformed T cells, is a human homologue of thioredoxin (TRX). ADF/TRX has multiple functions including growth promoting, antiapoptotic and radical scavenging activities, and is also involved in a wide variety of intracellular processes as a dithiol reducing agent in cooperation with the NADPH-TRX reductase system. In HTLV-1(+) T cell lines, HuT 102 and MT-2, which are ADF/TRX high producing cells, we found that the expression of ADF/TRX was dependent on the cell cycle and peaked at S phase. The reducing activity of ADF/TRX in these cells was also dependent on the cell cycle and elevated in S phase as determined by NADPH-dependent insulin degradation assay. Furthermore, inhibitors of TRX reductase, 13-cis-retinoic acid (13-cis-RA) and azelaic acid, inhibited the DNA synthesis of these cells. In contrast, the residual expression and reducing activity of ADF/TRX in HTLV-I(-) T cell lines did not show any significant correlation with the cell cycle. There was no distinct inhibitory effect of 13-cis-RA or azelaic acid on the growth of these ADF/TRX low producing cells. These results indicate that a high level of reducing activity of the ADF/TRX system may be required for the cell division of these virally transformed cells. This suggests that the TRX reductase inhibitors including retinoid derivatives have a potential therapeutic utility for treatment of HTLV-1(+) T cell leukemia without any effect on HTLV-I(-) cells.
 ...
PMID:Cell cycle inhibition of HTLV-I transformed T cell lines by retinoic acid: the possible therapeutic use of thioredoxin reductase inhibitors. 855 52

Current data on patients treated with human growth hormone (GH) were analyzed for the following safety topics. New leukemia. Thirteen of 46 new cases of leukemia were in non-Japanese patients without risk factors for leukemia (compared with at least 13 new cases expected). A possible increased occurrence of leukemia with GH treatment appears to be limited to patients with risk factors. Nonleukemic extracranial neoplasms. The number of cases reported (10) does not differ significantly from the number expected. Acute pancreatitis. In five of the seven cases reported risk factors (renal failure, valproic acid use, insulin-dependent diabetes mellitus) were present. The available data do not indicate a clear cause-and-effect relation between GH therapy and pancreatitis. Prepubertal gynecomastia. Of 15 possible cases, two were pubertal, eight resolved or improved with continued GH therapy, and two resolved with the cessation of GH therapy. An effect of GH treatment on prepubertal gynecomastia remains unknown. Scoliosis. Scoliosis is reported in fewer than 1 percent of the patients in the National Cooperative Growth Study (general-population prevalence, 1.5% to 3%). Curvature progression can occur during growth acceleration, and a causal association with GH treatment is not substantiated. Pigmented nevi. Nevi growth may be increased with GH treatment. Biopsies have detected no neoplasia or premalignant nevi transformations.
 ...
PMID:Safety of human growth hormone therapy: current topics. 1124 Oct 65

The decrease in adult height of children who have been given cranial irradiation (24 Gy) for acute lymphoblastic leukaemia is attributed to chemotherapy, growth hormone (GH) deficiency and early puberty. This study evaluates the factors involved in the height loss between irradiation and adult height and its markers in 43 patients irradiated at 5.8 +/- 0.4 (SEM) years. The mean height loss was 0.9 +/- 0.2 SD in the children with a normal GH peak (n = 11), 1.7 +/- 0.2 SD in those with a low GH peak and untreated (n = 15) and 0.6 +/- 0.2 SD in those treated with GH (n = 17). The adult height was significantly lower than target height in all three groups. The height loss correlated negatively with the GH peak (p < 0.02) and with the age at onset of puberty (p < 0.05) in the first two groups with spontaneous growth, but not with the chemotherapy regimen or its duration, or the plasma insulin-like growth factor I (IGFI) and its GH-dependent binding protein (BP-3). Early puberty (onset at 8-10 years) occurred in 6 girls from the first two groups. At the first evaluation, 5.6 +/- 0.4 years after irradiation, the GH peak values after arginine-insulin stimulation correlated with the age at irradiation (p < 0.03), taking into account the time since irradiation. The plasma IGFI and BP-3 values were correlated with each other, but not with the GH peak. In conclusion, this study demonstrates the impact of GH deficiency and GH replacement therapy on adult height in children given cranial irradiation for leukaemia. They therefore should be evaluated for their GH secretion 1-2 years after the end of chemotherapy. GH therapy is indicated for those with low GH peak and decreased growth rate or no increase in growth rate despite puberty.
 ...
PMID:Adult height after cranial irradiation with 24 Gy: factors and markers of height loss. 888 25

Endothelin-1 (ET-1) is present in ovine endometrium, primarily in epithelial cells, and increases around the time of implantation. We examined the cell type expressing ET-binding sites in vitro and whether ET-1 has mitogenic actions in the endometrium, alone or in synergy with other growth factors. Purified epithelial and stromal cells were prepared from luteal-phase endometrium. Specific receptors were demonstrated by binding of 125I-ET-1 and proliferative effects of ET-1 and/or other growth factors determined by uptake of [3H]thymidine by cells in serum-free culture. 125I-ET-1 bound to both epithelial (2516 +/- 820 c.p.m./well) and stromal (6368 +/- 1350 c.p.m./well) cells and was displaced by ET-1 (1 mumol l-1). There were no proliferative effects of ET on epithelial cells. ET-1 (10 nmol l-1) stimulated uptake of [3H]thymidine by stromal cells under serum-free conditions in 13/20 individual cell preparations, to 149 +/- 13% of control (untreated = 100%) with dose-dependence between the range of 1 to 100 nmol l-1. Stimulation by fetal calf serum was to 377 +/- 126% of control. The effects on proliferation by other growth factors (dose; % of control +/- S.E.M., number of positive/total number of cell preparations) were: IGF-I (13 nmol l-1; 182 +/- 14, 4/4), epidermal growth factor (EGF; 4.8 nmol l-1; 132 +/- 5%, 7/7), platelet-derived growth factor-BB (0.4 nmol l-1; 146 +/- 3, 2/2) and leukaemia inhibitory factor (0.4 nmol 1-1; 110 +/- 2, 3/3). All stimulations except that of EGF were significant and dose-responsive but only insulin was additive with ET (350 +/- 35, 5/5). ET-1 also stimulated expression of the the AP-1 cis element c-jun, this being maximal at 60 min of exposure to mitogen. ET-1, along with other growth factors has a likely paracrine role in cellular proliferation in the endometrium, possibly in association with blastocyst implantation.
 ...
PMID:Mitogenic actions of endothelin and other growth factors in ovine endometrium. 907 86

Serum leptin levels are elevated in subjects with exogenous obesity, indicating that obesity is associated with leptin resistance. Since in man no abnormalities have yet been found in either the genes for leptin or its receptor, the mechanism of leptin resistance in obesity remains unknown. To determine if resistance might be related to leptin binding by a serum component, we assessed the carrier status of leptin in serum. The presence of a specific leptin binding factor in human serum has been established by (1) demonstrating [125I]-leptin binding to a serum component that is saturable and specifically displaceable only by unlabeled leptin and not by human growth hormone, pork insulin, insulin-like growth factors I and II, luteinizing or follicle stimulating hormones, transforming growth factor-beta 1, interleukin-6, or leukemia inhibiting factor; (2) fractionating the leptin bound serum complex and the serum leptin binding component on a molecular sieving column revealing a mass of approximately 450 kDa; and (3) identifying an inverse correlation between the concentration of serum leptin and the quantity of the leptin binding component. It is suggested that binding of leptin by this serum component may influence the physiologic response to leptin.
 ...
PMID:Demonstration of a leptin binding factor in human serum. 916 40

Leukaemia inhibitory factor (LIF) stimulates cellular DNA synthesis in confluent quiescent Swiss 3T3 cells. Insulin and prostaglandin E1 (PGE1), which fail to stimulate DNA synthesis alone, potentiate this effect. Prostaglandin F2alpha (PGF2alpha), which is mitogenic in these cells, enhances the effect of LIF on DNA synthesis. TGFbeta1 increases the effect of PGF2alpha but not that of LIF. R-59022, a diacylglycerol kinase inhibitor which increases protein kinase C (PKC) activity, enhances only the PGF2alpha response. 13-Tetradecanoyl-12-phorbolacetate-mediated PKC depletion prevents the action of PGF2alpha but not that of LIF, nor the PGF2alpha potentiation of LIF-stimulated DNA synthesis. 1-Oleoyl-2acetylglycerol, a PKC and tyrosine kinase (TK) activator which mimics some of the PGF2alpha effects, enhances only LIF-induced DNA synthesis in cells possessing intact PKC activity. These results suggest that stimulation of DNA synthesis by LIF, as well as its enhancement by PGF2alpha, may occur via a signalling pathway independent of PKC activation.
 ...
PMID:Leukaemia inhibitory factor induces mitogenesis in Swiss 3T3 cells and selective enhancement via a variety of signalling events. 924 39

The role of insulin (INS), and insulin-like growth factor-I (IGF-I) in the regulation of human erythropoiesis is not completely understood. To address this issue we employed several complementary strategies including: serum free cloning of CD34+ cells, RT-PCR, FACS analysis, and mRNA perturbation with oligodeoxynucleotides (ODN). In a serum-free culture model, both INS and IGF-I enhanced survival of CD34+ cells, but neither of these growth factors stimulated their proliferation. The influence of INS and IGF-I on erythroid colony development was dependent on a combination of growth factors used for stimulating BFU-E growth. When BFU-E growth was optimally stimulated with erythropoietin (EpO) + kit ligand (KL) the large erythroid colonies developed normally even in the absence of INS or IGF-I. However, the addition of both of these growth factors slightly enhanced colony size. On the other hand, if erythroid colonies were stimulated suboptimally with EpO + IL-3 only, INS or IGF-I increased the number of small erythroid bursts by approximately 30%. Both INS and IGF-I activated signal transduction in maturing human erythropoietic cells as determined by phosphorylation of the insulin receptor substrate-2 (IRS-2) protein. We also found by RT-PCR that mRNA coding for INS-R is expressed in FACS sorted CD34+, c-kit-R+ marrow cells, and in cells isolated from BFU-E and CFU-GM colonies. Expression of INS-R protein on these cells was subsequently confirmed by cytofluorometry. In contrast, the receptor for insulin-like growth factor-I (IGF-IR) was not detected on CD34+ cells, and was first easily detectable on more differentiated cells derived from day 6 BFU-E and CFU-GM colonies. We conclude that INS and IGF-I may be survival factors for human CD34+ cells, but are not required during early erythropoiesis. In contrast, both growth factors may play some role at the final stages of erythroid maturation.
Leukemia 1998 Mar
PMID:The role of insulin (INS) and insulin-like growth factor-I (IGF-I) in regulating human erythropoiesis. Studies in vitro under serum-free conditions--comparison to other cytokines and growth factors. 952 32

We recently found evidence indicating that the source of elevated serum insulin-like growth factor binding protein (IGFBP)-2 in leukemia was the leukemic T-cells. Here we report that locally produced IGF-II affects IGFBP-2 expression and growth of leukemic cells through the IGF type I receptor. We measured IGFBP-2, -4 and IGF type I receptor (IGF-I-R) mRNA by RT-PCR, cell growth and IGFBP-2 secretion (per 10(6) cells). IGF-I-R binding sites were assessed by 125I-IGF replacement studies. Inhibition using an IGF-II antibody showed that tumor cell-derived IGF-II accounts for a significant 25% (P < 0.001) increase in IGFBP-2 secretion and enhanced growth (P < 0.01) of leukemic T-cells after 7 days in culture. IGFBP-2 secretion, but not IGFBP-2 mRNA was specifically increased by IGFs, while no specific effect of insulin was detectable. The addition of 100 ng/ml IGF-II enhanced the IGFBP-2 secretion 2.8-fold, while the use of IGF-I only enhanced IGFBP-2 secretion 1.7-fold, although IGF-I enhanced IGF-II action. Through inhibition using JB1, a peptide inhibiting the IGF signal transduction by blocking the IGF-I-R, we demonstrated the involvement of the IGF-I-R in IGFBP-2 and -4 expression and leukemic cell growth. However, only slight differences in the IGF-I-R mRNA expression were seen for T- and B-cells compared with the differences found for the IGFBP-2 and -4 mRNA or IGFBP-2 secretion. Thus, although IGF-I-R mediates the autocrine/paracrine effects of the IGFs, IGF-I-R mRNA expression is most probably not involved in the differential IGFBP-2/IGFBP-4 expression in leukemic cells.
 ...
PMID:Elevated insulin-like growth factor (IGF) binding protein (IGFBP)-2 and IGFBP-4 expression of leukemic T-cells is affected by autocrine/paracrine IGF-II action but not by IGF type I receptor expression. 953 10


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>