Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have reported previously that parathyroid hormone (PTH) acts on cultured bone cells to stimulate creatine kinase (CK) activity and [3H]thymidine incorporation into DNA via phosphoinositide turnover, in addition to its other actions via increased cyclic AMP production. We also found that mid-region fragments of PTH stimulate [3H]thymidine incorporation into avian chondrocytes. In the present study of mammalian systems, we demonstrate differential effects of defined synthetic PTH fragments on CK activity and DNA synthesis, as compared with cyclic AMP production, in osteoblast-enriched embryonic rat calvaria cell cultures, in an osteoblast-like clone of rat osteosarcoma cells (ROS 17/2.8) and in chondroblasts from rat epiphysial cartilage cell cultures. Unlike full-length bovine (b)PTH-(1-84) or the fully effective shorter fragment human (h)PTH-(1-34), fragments lacking the N-terminal region of the hormone did not increase cyclic AMP formation, whereas they did stimulate increases in both DNA synthesis and CK activity. Moreover, the PTH fragment hPTH-(28-48) at 10 microM inhibited the increase in cyclic AMP caused by 10 nM-bPTH-(1-84). The increase of CK activity in ROS 17/2.8 cells caused by bPTH-(1-84) or hPTH-(28-48) was completely inhibited by either cycloheximide or actinomycin D, as was shown previously for rat calvaria cell cultures. These results indicated the presence of a functional domain of PTH in the central part of the molecule which exerts its mitogenic-related effects on osteoblast- and chondroblast-like cells in a cyclic AMP-independent manner. Since cyclic AMP formation by PTH leads to bone resorption, specific mid-region fragments of PTH might prove suitable for use in vivo to induce bone formation without concomitant resorption.
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PMID:Stimulation by defined parathyroid hormone fragments of cell proliferation in skeletal-derived cell cultures. 217 78

The recent demonstration of estrogen receptors in bone derived cells has stimulated the study of direct effects of sex steroids on bone. We have shown direct stimulation of proliferation by 17 beta-estradiol (E2) of ROS 17/2.8 rat osteogenic osteosarcoma cells, and other bone-derived cells in culture, as well as sex-specific stimulation of diaphyseal bone in vivo by estrogen and testosterone, using [3H]thymidine incorporation into DNA and stimulation of the specific activity of creatine kinase as markers. ROS 17/2.8 cells were used as models of osteoblast-like cells to study the reciprocal modulation of stimulation of bone cell proliferation by sequential treatment by sex steroid and calciotrophic hormones. Pretreatment with 1,25(OH)2D3 and PTH augmented stimulation by E2, while pretreatment with PGE2 followed by E2 resulted in no additional stimulation. Reciprocally, pretreatment with E2 significantly reduced the response to PGE2 while showing an insignificant effect on the response to the other hormones. Gonadectomized Wistar-derived rats provided a useful model system for study of postmenopausal osteoporosis. In diaphyseal bone, [3H]thymidine incorporation and creatine kinase activity decreased 4 weeks after gonadectomy. At that time, a single i.p. injection of E2 in females, and testosterone in males, resulted in a highly significant increase in both these parameters within 24 h.
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PMID:Hormonal stimulation of bone cell proliferation. 225 46

Postmenopausal women lose bone mineral density and this loss can be prevented by estrogen administration. Although the skeletal effects of estrogens have been regarded previously as indirect, estrogen receptors have been discovered in cultured human osteoblasts and related cell lines. The UMR106 cell line derived from a rat osteogenic osteosarcoma is such an osteoblast model. We have shown direct effects of estradiol (E) on these cells in vitro, inhibiting growth and stimulating alkaline phosphatase activity (AP) corrected for cell number. This response was maximal at E conc. of 10(-10) M in serum and Phenol Red free medium, was metabolite specific and cell cycle-dependent. These cells contain high affinity binding sites with a Kd of 0.5 nM. Estrogen receptors were detected by the monoclonal antibody H-222 on Western blot after initial immunoprecipitation to concentrate the proteins. E treatment increased several enzymes including creatine kinase and LDH isoenzymes along with increments in intracellular transferrin. Transforming growth factor-beta is secreted by these cells. Secretion of this peptide was stimulated by E. TGF-beta mediated the transient growth inhibition associated with E treatment. Insulin like growth factors (IGF) are also secreted by these cells with IGF-II concentrations in the culture medium being eight times higher than IGF-I levels. E treatment increased the concentrations of both IGFs in the culture medium after a 3 day incubation. Exposure of E treated cells manifested a mitogenic response and reduced AP, indicating that E induced receptors for IGFs. These findings establish direct effects of E on osteoblastic cells in vitro and demonstrate responses to E at many levels. These osteoblast responses in vitro suggest an important role for sex steroids in the development and function of the osteoblast lineage.
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PMID:Estrogens and the skeleton: cellular and molecular mechanisms. 262 18

A direct in vitro effect of 17 beta-estradiol (E2) was demonstrated on bone and cartilage cell energy metabolism. Sex-specific stimulation by E2 and testosterone was shown in diaphyseal bone of weanling rats. E2 (30 nM) caused, within 24 hr, a 70-200% increase in creatine kinase (CK; ATP:creatine N-phosphotransferase, EC 2.7.3.2) specific activity in ROS 17/2.8 rat osteogenic sarcoma cells, MC3T3-E1 mouse calvaria-derived cells, and rat fetal calvaria cells, and a 40% increase in rat epiphyseal cartilage cells. Stimulation of CK activity by E2 was dose and time dependent: in ROS 17/2.8 cells, a highly significant increase was found at 3 nM E2 and a greater than 100% increase in CK activity was found 1 hr after E2 administration. In female 20-day-old Wistar-derived rats, E2 (5 micrograms per rat) increased CK activity in diaphyseal bone by 82% within 1 hr of i.p. injection, with a maximal increase of 200% after 24 hr; neither the weakly estrogenic agonist 17 alpha-estradiol, testosterone, nor progesterone showed this effect. Conversely, in male rat diaphyseal bone, testosterone or dihydrotestosterone increased CK activity after 24 hr by approximately 100%, while E2 was ineffective. In epiphyseal cartilage, both E2 and testosterone increased CK activity. Stimulation of CK activity by sex hormones was paralleled by significant increases in [3H]thymidine incorporation into DNA. Therefore, it is possible that direct sex-specific actions of gonadal steroids may contribute to stimulating bone growth and maintaining balanced bone turnover.
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PMID:Direct and sex-specific stimulation by sex steroids of creatine kinase activity and DNA synthesis in rat bone. 271 19

We have previously shown that both parathyroid hormone (PTH) and prostaglandin E2 (PGE2) stimulate the activity of creatine kinase BB (CKBB) in rat bone cells in culture. Therefore, morphologically distinct rat osteogenic sarcoma cells in culture were tested for stimulation of CKBB activity by hormones that regulate skeletal tissues. PTH stimulated CKBB in the osteoblast-like clone ROS 17/2; 1 alpha,25(OH)2D3 inhibited this activity while PGE2, CT and 24R,25(OH)2D3 had no significant effect. PGE2 stimulated CKBB activity in the fibroblast-like clone ROS 24/1, which was unresponsive to PTH, CT and Vitamin D metabolites. 24R,25(OH)2D3 as well as PGE2 (but not PTH, CT or 1 alpha 25(OH)2D3) stimulated CKBB in clone ROS 25/1, suggesting that this fibroblast-like clone has some chondroblast-like character. Both PTH and PGE2 stimulated the brain type isoenzyme of CK (CKBB), although the osteogenic sarcoma cell clones contain a significant proportion of the muscle type of CK (CKMM). Thus, increased CKBB activity can serve as an additional characteristic marker for the action of steroid and polypeptide hormones and for prostaglandins.
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PMID:Regulation of creatine kinase activity in rat osteogenic sarcoma cell clones by parathyroid hormone, prostaglandin E2, and vitamin D metabolites. 393 88

Insulin-like growth factor-I (IGF-I) has been reported to mediate the effects of oestradiol-17 beta in the osteoblast-like osteosarcoma cell line ROS 17/2.8 and to stimulate directly cell proliferation in cell cultures derived from rat calvaria. Few data are available on the role of IGF-I in androgen stimulation of cultured skeletal cells and in oestrogen and androgen stimulation of bone and cartilage in vivo. The purpose of the present study was to compare the effect of IGF-I in rats in vivo with its effect in vitro on calvarial bone cells from females (responding only to oestrogens) and from males (responding only to androgens, such as testosterone and dihydrotestosterone). We found that IGF-I stimulated, in a dose- and time-dependent manner, the specific activity of creatine kinase (CK, a marker of skeletal cell division), in both female and male calvarial bone cells, in ROS 17/2.8 cells and in epiphyseal cartilage cell cultures. Maximal stimulation occurred at 30 or 100 nM within 1-2 h after stimulation. In ROS 17/2.8 cells, IGF-I stimulated [3H]thymidine incorporation, after 22 h of treatment, in parallel with CK activity. IGF-II, at higher doses than IGF-I (maximal stimulation at 300 nM), stimulated CK specific activity in female- and male-derived calvarial cell cultures. When IGF-I (50 nM) was applied together with oestradiol-17 beta (30 nM) or with dihydrotestosterone (300 nM) there was no additional response in the cultures.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulation by insulin-like growth factor-I of creatine kinase activity in skeletal-derived cells and tissues of male and female rats. 782 90

We have compared the cell and tissue selective estrogenic and antiestrogenic activities of tamoxifen, raloxifene, ICI 164,384 and a permanently ionized derivative of tamoxifen--tamoxifen methiodide (TMI). This non-steroidal antiestrogen has limited ability to cross the blood brain barrier and is therefore less likely to cause the central nervous system disturbances caused by tamoxifen. We have used the stimulation of the specific activity of the "estrogen induced protein", creatine kinase BB, as a response marker in bone, cartilage, uterine and adipose cells and in rat skeletal tissues, uterus and mesometrial adipose tissue. In vitro, TMI, tamoxifen and raloxifene mimicked the agonistic action of 17beta-estradiol in ROS 17/2.8 rat osteogenic osteosarcoma, female calvaria, and SaOS2 human osteoblast cells. In Ishikawa endometrial cancer cells, tamoxifen showed reduced agonistic effects and raloxifene showed no stimulation. However, as antagonists, tamoxifen and raloxifene were equally effective in Ishikawa or SaOS2 cells. In immature rats, all four of the antiestrogens inhibited estrogen action in diaphysis, epiphysis, uterus and mesometrial adipose tissue; when administered alone, tamoxifen stimulated creatine kinase (CK) specific activity in all these tissues. Raloxifene and TMI, however, stimulated only the skeletal tissues and had no stimulatory effect in the uterus or mesometrial fat, and the pure antiestrogen ICI 164,384 showed no stimulatory effect in any of the tissues. The simultaneous injection of estrogen, plus an antiestrogen which acted as an agonist, resulted in lower CK activity than after injection of either agent alone. These differential effects, in vivo and in vitro, may point the way to a wider therapeutic choice of an appropriate antiestrogen which, although antagonizing E2 action in mammary cancer, can still protect against osteoporosis and cardiovascular disease and not stimulate the uterus with its attendant undesirable changes, or interfere with the beneficial action of E2 in the brain.
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PMID:Tissue selective action of tamoxifen methiodide, raloxifene and tamoxifen on creatine kinase B activity in vitro and in vivo. 901 Mar 44

This study sought to use a microdialysis technique to relate clinical and biochemical responses to the time course of melphalan concentrations in the subcutaneous interstitial space and in tumour tissue (melanoma, malignant fibrous histiocytoma, Merkel cell tumour and osteosarcoma) in patients undergoing regional chemotherapy by Isolated Limb Infusion (ILI). 19 patients undergoing ILI for treatment of various limb malignancies were monitored for intra-operative melphalan concentrations in plasma and, using microdialysis, in subcutaneous and tumour tissues. Peak and mean concentrations of melphalan were significantly higher in plasma than in subcutaneous or tumour microdialysate. There was no significant difference between drug peak and mean concentrations in interstitial and tumour tissue, indicating that there was no preferential uptake of melphalan into the tumours. The time course of melphalan in the microdialysate could be described by a pharmacokinetic model which assumed melphalan distributed from the plasma into the interstitial space. The model also accounted for the vascular dispersion of melphalan in the limb. Tumour response in the whole group to treatment was partial response: 53.8% (n = 7); complete response: 33.3% (n = 5); no response: 6.7% (n = 1). There was a significant association between tumour response and melphalan concentrations measured over time in subcutaneous microdialysate (P< 0.01). No significant relationship existed between the severity of toxic reactions in the limb or peak plasma creatine phosphokinase levels and peak melphalan microdialysate or plasma concentrations. It is concluded that microdialysis is a technique well suited for measuring concentrations of cytotoxic drug during ILI. The possibility of predicting actual concentrations of cytotoxic drug in the limb during ILI using our model opens an opportunity for improved drug dose calculation. The combination of predicting tissue concentrations and monitoring in microdialysate of subcutaneous tissue could help optimise ILI with regard to post-operative limb morbidity and tumour response.
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PMID:Microdialysis and response during regional chemotherapy by isolated limb infusion of melphalan for limb malignancies. 1146 Oct 70

The nematode Spirocerca lupi is a parasite of dogs with beetles of several species serving as intermediate hosts. The medical records of 50 dogs diagnosed with spirocercosis at the Hebrew University Veterinary Teaching Hospital (HUVTH) in Israel during 1991-1999 were retrospectively reviewed and compared to a control group (n=100). There was a seven-fold increase in the annual number of dogs diagnosed with spirocercosis during these years while the hospital caseload increased by 80%, indicating an emerging outbreak of this infection. Dogs from the greater Tel Aviv area were at the highest risk of being diagnosed with spirocercosis with 74% of the cases originating from this region compared to only 17% of the controls. The disease appeared to have a primarily urban pattern of distribution with a significantly higher percentage (P=0.025) of dogs from cities versus rural areas, as compared to the control group. Sixty-two percent of the cases were diagnosed during the colder months of December through April. The median age of infected dogs was 5 years, with dogs 1 year old or younger at the lowest risk of being diagnosed with spirocercosis. Large breeds were at a higher risk of infection in comparison to small breeds and the Labrador Retriever was significantly over represented (P=0.027) in the study group compared to the control population. The most common signs were vomiting or regurgitation (60%), pyrexia (24%), weakness (22%), respiratory abnormalities (20%), anorexia (18%), melena (18%) and paraparesis (14%). A caudal esophageal mass was identified by radiography in 53% of the dogs and spondylitis of the thoracic vertebrae in 33%. Fecal flotation was positive for S. lupi eggs in 80% of the dogs, and endoscopy was found to be the most sensitive diagnostic procedure and allowed diagnosis in 100% of the examined dogs. Fifty-three percent of the dogs were anemic and creatine kinase (CK) activities were elevated in 54%. Necropsy of 14 dogs revealed esophageal or gastric granulomas in 13 dogs, and an esophageal osteosarcoma in a single animal. Aortic aneurysms were found in six (43%) dogs. Out of 24, 15 dogs (63%) for which follow-up information was available died or were euthanized within 1 month of admission. The case-fatality rate decreased toward the end of the study period when improved therapy with avermectins became available.
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PMID:Canine spirocercosis: clinical, diagnostic, pathologic, and epidemiologic characteristics. 1212 53

In yeast, mitochondrial dysfunction activates a specific pathway, termed retrograde regulation, which alters the expression of specific nuclear genes and results in increased replicative life span. In mammalian cells, the specific nuclear genes induced in response to loss of mitochondrial function are less well defined. This study characterizes responses in nuclear gene expression to loss of mitochondrial DNA sequences in three different human cell types: T143B, an osteosarcoma-derived cell line; ARPE19, a retinal pigment epithelium cell line; and GMO6225, a fibroblast cell population from an individual with Kearns-Sayre syndrome (KSS). Quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was used to measure gene expression of a selection of glycolysis, TCA cycle, mitochondrial, peroxisomal, extracellular matrix, stress response, and regulatory genes. Gene expression changes that were common to all three cell types included up-regulation of GCK (glucokinase), CS (citrate synthase), HOX1 (heme oxygenase 1), CKMT2 (mitochondrial creatine kinase 2), MYC (v-myc myelocytomatosis viral oncogene homolog), and WRN (Werner syndrome helicase), and down-regulation of FBP1 (fructose-1, 6-bisphosphatase 1) and COL4A1 (collagen, type IV, alpha 1). RNA interference experiments show that induction of MYC is important in rho0 cells for the up-regulation of glycolysis. In addition, a variety of cell type-specific gene changes was detected and most likely depended upon the differentiated functions of the individual cell types. These expression changes may help explain the response of different tissues to the loss of mitochondrial function due to aging or disease.
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PMID:Common and cell type-specific responses of human cells to mitochondrial dysfunction. 1556 Nov 7


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