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)

In humans, apolipoprotein (apo) B48 is synthesized in the intestine as an obligatory constituent of chylomicrons. Apolipoprotein B48 is identical to the amino-terminal 2152 amino acids (240 kDa) of apoB100 and is translated from an edited apoB mRNA in which codon 2153 has been converted from glutamine (CAA) to what is recognized as a premature stop codon (UAA). To determine whether the apoB mRNA editing in fact converts cytosine 6666 in codon 2153 to uracil, we incubated a synthetic apoB RNA containing 32P-labeled cytosines in an in vitro editing system prepared from rabbit enterocytes. The in vitro edited RNA was purified and digested to nucleoside 5'-monophosphates, which were analyzed on two-dimensional thin-layer chromatography. We found that the edited base co-migrated with authentic uridine 5'-monophosphate. Thus, cytosine 6666 is converted to uracil, most likely by a nucleotide-specific cytosine deaminase. To determine whether apoB mRNA editing occurs in cell lines that do not synthesize apoB, we stably transfected a high expression vector containing 354 base pairs of apoB sequence into 18 different cell lines. We found apoB mRNA editing activity in five osteosarcoma cell lines and one epidermoid cell line, none of which synthesizes any detectable apoB. Thus, apoB mRNA editing occurs in cell lines that do not synthesize apoB, which suggests that mRNA editing may be a common biological phenomenon in eukaryotic cells.
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PMID:Apolipoprotein B mRNA editing. Direct determination of the edited base and occurrence in non-apolipoprotein B-producing cell lines. 226 36

UMR-106 rat osteogenic sarcoma cells express two calcium signaling P2 purinergic receptors. One is a P2U receptor with EC50's for adenosine triphosphate (ATP) and uridine triphosphate (UTP) of 2.6 and 2.4 microM, respectively. The other is a novel P2T receptor for adenosine diphosphate (ADP) (EC50 0.4 microM), adenosine 5'-O-(2-thiodiphosphate). (EC50 5 microM), 2-methylthio ATP (EC50 0.2 microM), and 2-methylthio ADP (EC50 0.04 microgram M). Responses to these ligands are desensitized by ADP but not by UTP. Responses to UTP and ATP are desensitized by UTP but not by ADP or adenosine 5'-O-(2-thiodiphosphate). 2-ChloroATP interacts with both receptors at high concentrations but with only the P2T receptor at low concentrations (EC50 0.05 microM). The weak platelet P2T receptor antagonist AMP blocks this P2T and not the P2U receptor. Addition of ATP after UTP desensitization of P2U receptors inhibits subsequent responsiveness to ADP but evidence for rapid conversion of ATP to ADP complicates interpretation of this apparent antagonism of P2T receptors by ATP. A subpassage of UMR-106.P135 cells lose P2U but retain P2T ligand responsiveness. Activation of either P2 receptor increases cellular IP3 concentrations in UMR-106 cells. Neither receptor can activate divalent cation entry as evidenced by their lack of effect on Mn++ quenching of fura-2 fluorescence. Neither receptor can modify parathyroid hormone receptor-mediated elevation of cellular cyclic AMP. This receptor for ADP demonstrates many of the same characteristics of the ADP receptor which we have previously reported as a P2T receptor expressed in K562 and Dami cells.
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PMID:Separate P2T and P2U purinergic receptors with similar second messenger signaling pathways in UMR-106 osteoblasts. 801 49

We have examined the contribution of the mitochondrial genome to the tumorigenic phenotype expressed by human cell lines derived from an ovarian and a cervical carcinoma and from an osteogenic sarcoma. All these continuous cell lines are anchorage-independent in soft agar and form tumors in athymic nude mice. Long-term exposure of the cells to ethidium bromide, an intercalating agent which inhibits mitochondrial DNA replication, gave rise to subclones depleted of mitochondrial DNA and RNA molecules and displaying either anchorage independence or dependence. These respiratory-deficient subclones contain disorganized and enlarged mitochondria, are auxotrophic for uridine and pyruvate, and grow in vitro at a rate nearly identical or moderately slower than their respective parent. The tumor-forming ability of both anchorage-independent and -dependent cell lines was tested by s.c. and intramuscular implantation of the cells in nude mice. We found that the tumorigenic capacity was influenced by the route of inoculation. Subcutaneously, mitochondrial DNA-less cell lines are either poorly or nontumorigenic, while all but one cell line form tumors when implanted into the hind leg muscle. The relative in vivo growth rate of the parent and the mitochondrial DNA-less subclones reflects their respective in vitro rate of growth. All intramuscular tumors introduced into culture mimic the molecular and phenotypic traits of the injected cells, with the exception of the anchorage-dependent cell lines which give rise to anchorage-independent tumor cell lines. The present observations indicate that human cells without mitochondrial DNA have the capacity to proliferate and form tumors in vivo.
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PMID:Tumor-forming ability in athymic nude mice of human cell lines devoid of mitochondrial DNA. 803 12

Glucocorticoid (GC) administration induces atrophy of skin, bone, and other organs, partly by reducing tissue content of glycosaminoglycans, particularly hyaluronic acid (HA). We took advantage of the recent cloning of the three human hyaluronan synthase (HAS) enzymes (HAS1, HAS2 and HAS3), to explore the molecular mechanisms of this side effect. Northern and slot blots performed on RNA extracted from cultured dermal fibroblasts and the MG-63 osteoblast-like osteosarcoma cell line indicated that HAS2 is the predominant HAS mRNA in these cells. Incubation of both cell types for 24 h in the presence of 10(-6) M dexamethasone (DEX) resulted in a striking 97--98% suppression of HAS2 mRNA levels. Time-course studies in fibroblasts demonstrated suppression of HAS2 mRNA to 28% of control by 1 h, and to 1.2% of control by 2 h, after addition of DEX. Dose-response studies in fibroblasts indicated that the majority of the suppressive effect required concentrations characteristic of cell-surface GC receptors, a point confirmed by persistent DEX-induced suppression in the presence of RU486, an antagonist of classic cytosolic steroid hormone receptors. Nuclear run-off experiments showed a 70% suppression of HAS2 gene transcription in nuclei from DEX-treated fibroblasts, which is unlikely to fully explain the rapid 50--80-fold reduction in message levels. Experiments with actinomycin D (AMD) demonstrated that the message half-life was 25 min in cells without DEX, whereas the combination of AMD with DEX dramatically increased the half-life of HAS2 mRNA, suggesting that DEX acts by inducing a short-lived destabilizer of the HAS2 message. Direct assessment of HAS2 mRNA stability by wash-out of incorporated uridine label established a half-life of 31 min in cells without DEX, which substantially shortened in the presence of DEX. In conclusion, GCs induce a rapid and sustained, near-total suppression of HAS2 message levels, mediated through substantial decreases in both gene transcription and message stability. These effects may contribute to the loss of HA in GC-treated organs.
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PMID:Glucocorticoids induce a near-total suppression of hyaluronan synthase mRNA in dermal fibroblasts and in osteoblasts: a molecular mechanism contributing to organ atrophy. 1086 Dec 15

Effects of gamma-tocopherol on the cell cycle and proliferation were examined in human prostate carcinoma, colorectal adenocarcinoma, and osteosarcoma cells. Many epidemiological studies have suggested an anticancer activity of vitamin E, yet mechanistic studies are sparse to date. Vitamin E consists of four tocopherols (alpha-, beta-, gamma-, delta-) and the corresponding tocotrienols. Because gamma-tocopherol is the predominant form of tocopherol found in the U.S. diet, while alpha-tocopherol is the form of vitamin E most readily found in dietary supplements, we compared physiologically relevant concentrations of these tocopherols and found a more significant growth inhibition effect for gamma- than for alpha-tocopherol. Flow cytometry analysis of gamma-tocopherol treated prostate carcinoma DU-145 cells showed decreased progression into the S-phase. This effect was associated with reduced DNA synthesis as measured by 5-bromo-2'-deoxy-uridine incorporation. Furthermore, Western-blot analysis of gamma-tocopherol treated cells showed decreased levels of cyclin D1 and cyclin E. Taken together, the results indicate that gamma-tocopherol inhibits cell cycle progression via reduction of cyclin D1 and cyclin E levels. Because gamma-tocopherol has a weaker antioxidant capacity than a-tocopherol and gamma-tocopherol more significantly inhibited cell proliferation as well as DNA synthesis than alpha-tocopherol, we suggest a non-antioxidant mechanism to be at the basis of this effect.
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PMID:Gamma-tocopherol inhibits human cancer cell cycle progression and cell proliferation by down-regulation of cyclins. 1236 34

A new system for the local delivery of chemotherapy to malignant solid tumors has been developed based on calcium phosphate (CaP) nanoparticles. The adsorption of the anti-neoplastic drug cis-diamminedichloroplatinum (cisplatin) was characterized on three types of apatitic CaP (poorly and well crystallized hydroxyapatite, and carbonated apatite). Adsorption isotherms obtained in chloride-free phosphate solutions at pH = 7.4 (24 and 37 degrees C) indicate that cisplatin adsorption increases with temperature and increases with decreasing crystallinity. Release studies in phosphate buffer saline (containing the chloride ion essential for release) showed that while the cumulative amount of released drug was the same for all apatites at 20 days (approximately 70% of the total bound), the least crystalline material released the drug more slowly. The drug release rate increased slightly with temperature. Cytotoxicity testing was conducted in a K8 clonal murine osteosarcoma cell line to verify that drug activity was retained after adsorption onto the apatite crystals. K8 cells were plated onto dried films of the apatite/cisplatin conjugates and after 24 h, viability was measured with tritiated uridine. The apatite/cisplatin formulations exhibited cytotoxic effects with a dose dependent diminishment of cell viability.
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PMID:Interactions of cisplatin with calcium phosphate nanoparticles: in vitro controlled adsorption and release. 1518 24

Leflunomide (LFM) is an inhibitor of mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that catalyzes the conversion of dihydroorotate to orotate coupled with the generation of reactive oxygen species (ROS) from mitochondria. We demonstrate here that LFM causes an unrestrained proliferation of mitochondria both in human osteosarcoma cell line 143B cells and rat liver derived RL-34 cells. Increases in the total mass of mitochondria per cell in LFM-treated cells were evidenced by the application of Green FM or 10-n-nonyl acridine orange to flow cytometry, an enhanced replication of mtDNA and electron microscopy. Externally added uridine improved the disturbance in cell cycle progression in LFM-treated cells, but failed to suppress such unrestrained mitochondrial proliferation. On the contrary, lapacol and 5-fluoroorotate, inhibitors of DHODH besides LFM, suppressed the biogenesis of mitochondria during the cell cycle progression. LFM, but not lapacol or 5-fluoroorotate, caused increases of the intracellular level of acetylated alpha-tubulin. These data suggest that the inhibition of DHODH may not be at least primarily related to the LFM-induced abnormal proliferation of mitochondria, and support our recent published observation that changes in the physicochemical properties of microtubules may be in someway concerned with the biogenesis of mitochondria.
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PMID:Mechanism of leflunomide-induced proliferation of mitochondria in mammalian cells. 1612 Mar 18

The aim of this study was to investigate cellular response to several ruthenium(III), chromium(III) and rhodium(III) compounds carrying bidentate beta-diketonato ligands: [(acac)--acetylacetonate ligand, (tfac)--trifluoroacetylacetonate ligand]. Cell sensitivity studies were performed on several cell lines (A2780, cisplatin-sensitive and -resistant U2-OS and U2-OS/Pt, HeLa, B16) using growth-inhibition assay. Effect of intracellular GSH depletion on cell sensitivity to the agents was analyzed in A2780 cells. Flow cytometry was used to assess apoptosis by Annexin-V-FITC/PI staining, and to analyze induction of caspase-3 activity. Possible DNA binding/damaging affinity was investigated, by inductively coupled mass spectrometry, and by 14C-thymidine / 3H-uridine incorporation assay. Cell sensitivity studies showed that the pattern of sensitivity to Ru(tfac)3 complex of the two cisplatin-sensitive/-resistant osteosarcoma cell lines, U2-OS and U2-OS/Pt, was similar to that of A2780 cells (72 h exposure), with the IC50 being around 40 microM. The growth-inhibitory effect of Ru(acac)3 ranged over 100 microM, while Cr(III) and Rh(III) complexes were completely devoid of antitumor action in vitro. Ru(tfac)3 exhibited strong potential for apoptosis induction on A2780 cells (up to 40%) and caused cell cycle arrest in the S phase as well as decrease of the percent of G1 and G2 cells. Ru(acac)3-induced apoptosis was slightly higher than 10%, whereas activation of caspase-3 in HeLa cells was moderate. DNA binding study revealed that only Cr(acac)3 was capable of binding DNA, while Cr(III) and Ru(III) compounds possess potential to inhibit DNA/RNA synthesis. In conclusion, only Ru(III) complexes showed potential for antitumor action.
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PMID:Cellular sensitivity to beta-diketonato complexes of ruthenium(III), chromium(III) and rhodium(III). 1694 68

The DNA of all organisms is constantly damaged by oxidation. Among the array of damage products is 5-hydroxymethyluracil, derived from oxidation of the thymine methyl group. Previous studies have established that HmU can be a sensitive and valuable marker of DNA damage. More recently, the corresponding deoxynucleoside, 5-hydroxymethyl-2'-deoxyuridine (HmdU), has proven to be valuable for the introduction of controlled amounts of a single type of damage lesion into the DNA of replicating cells, which is subsequently repaired by the base excision repair pathway. Complicating the study of HmU formation and repair, however, is the known chemical reactivity of the hydroxymethyl group of HmU under conditions used to hydrolyze DNA. In the work reported here, this chemical property has been exploited by creating conditions that convert HmU to the corresponding methoxymethyluracil (MmU) derivative that can be further derivatized to the 3,5-bis-(trifluoromethyl)benzyl analogue. This derivatized compound can be detected by gas chromatography-negative chemical ionization-mass spectrometry (GC-NCI-MS) with good sensitivity. Using isotopically enriched exogenous HmdU and human osteosarcoma cells (U2OS) in culture, we demonstrate that this method allows for the measurement of HmU in DNA formed from the incorporation of exogenous HmdU. We further demonstrate that the addition of isotopically enriched uridine to the culture medium allows for the simultaneous measurement of DNA replication and repair kinetics. This sensitive and facile method should prove valuable for studies on DNA oxidation damage and repair in living cells.
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PMID:Measurement of the incorporation and repair of exogenous 5-hydroxymethyl-2'-deoxyuridine in human cells in culture using gas chromatography-negative chemical ionization-mass spectrometry. 1791 83

Gunn rats, deficient in the enzyme uridine diphosphate glucuronyl transferase, were used to investigate the effects of unconjugated hyperbilirubinemia in cisplatin nephrotoxicity. The effect of bilirubin on the antineoplastic activity of cisplatin in osteosarcoma cell lines was also determined. The in vivo model involved three groups of rats (n=6 rats/group): homozygous Gunn rats (j/j), heterozygous Gunn rats (j/+), and congenic Wistar rats. On day 0, all rats were given 4 mg/kg cisplatin intraperitoneally. Blood was sampled on days 0, 3, and 5 for bilirubin, BUN, and creatinine and kidneys were taken on day 5. Cell culture was performed in four canine osteosarcoma cell lines using the average concentrations of bilirubin for homozygous Gunn rats at day 0 and 3. Bilirubin was added to cell lines alone and with cisplatin. Cell viability was assessed using the CellTiter Blue assay. Serum bilirubin levels were highly elevated in Gunn j/j, moderately elevated in Gunn j/+, and undetectable in Wistar rats at day 0. Bilirubin provided a nephroprotective effect, with significantly lower BUN and creatinine in Gunn j/j when compared with Wistar rats at day 5. Histological grading demonstrated preservation of the S3 segment in Gunn j/j when compared with Wistar rats (P<0.05). Bilirubin had no significant effect on the antineoplastic effect of cisplatin at either concentration in the four cell lines (P<0.001). Hyperbilirubinemia in the Gunn rat provided marked preservation of renal function and histology in a cisplatin nephrotoxicity model. Exogenous bilirubin did not interfere with the antineoplastic activity of cisplatin in vitro.
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PMID:Hyperbilirubinemia's protective effect against cisplatin nephrotoxicity in the Gunn rat. 1841 16


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