Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The following review aims to provide contemporary information on therapeutic nuclear medicine procedures in paediatric malignancies. Neuroblastoma is the most common paediatric extra cranial solid cancer characterized by meta-iodobenzylguanidine (mIBG) avidity in >/=90% of patients. There exists approximately a 30-year experience with I-131-mIBG treatment. Ongoing efforts include a more standardized approach including dosimetric data for patient selection and treatment guidance of I-131-mIBG therapy. Neuroendocrine tumours (NETs) are very rare neoplasms in the paediatric population accounting for <1% of all paediatric malignancies. These neoplasms are characterized by the presence of neuroamine uptake mechanisms and/or peptide receptors at the cell membrane. These features constitute the basis of the clinical use of peptide receptor radionuclide therapy (PRRNT) using radiolabeled somatostatin analogues. Osteosarcoma is the most common primary bone tumour in children usually treated with chemotherapy and surgery. In palliative situations bone seeking radionuclide therapies (strontium-89 [Sr-89], rhenium-186 hydroxyethylene diphosphonate [Rh-186 HEDP] and Samarium-153-ethylene diamine tetramethylene phosphonic acid [Sm-153-EDTMP]) may be offered to patients with painful metastatic osteosarcoma or in case of recurrent bone sites inaccessible to local therapies (surgery, external irradiation). Thyroid cancer is a rare childhood malignancy with an approximate incidence of 0.54 per 100000 per year but is the most frequent tumour of endocrine glands in children and adolescents. Management includes radioiodine therapy but there are some distinct differences in comparison to adult thyroid cancer management.
Q J Nucl Med Mol Imaging 2010 Aug
PMID:Therapeutic nuclear medicine in pediatric malignancy. 2082 9

Osteosarcoma is the most frequent primary malignant bone tumor among the children. The advent of neoadjuvant chemotherapy significantly improved the prognosis of patients with osteosarcoma in the 1980s, but it has since plateaued in the past decades. Recently, one of the most researched areas in sarcoma treatment is tyrosine kinases. Here, we describe research on a serine/threonine kinase, cyclin G-associated kinase (GAK), which has not been reported in osteosarcoma previously. In this study, a lentiviral based human shRNA library was utilized to screen for kinases in KHOS and U-2OS osteosarcoma cells. The expression of GAK was examined in osteosarcoma and the effect on cell proliferation was analyzed by GAK siRNA knockdown. The level of GAK expression and its correlation to prognosis was analyzed in osteosarcoma tissue microarray. The effect of GAK depletion on insulin-like growth factor and epidermal growth factor receptor-mediated signal transduction was analyzed by Western blot. We observed that GAK was overexpressed in both osteosarcoma cell lines and tissue samples when compared with human osteoblasts. GAK knockdown by siRNA decreased cell proliferation in both drug-sensitive and multidrug-resistant osteosarcoma cell lines. Immunohistochemistry of osteosarcoma tissue microarray revealed that overexpression of GAK was associated with poor prognosis. Finally, knockdown of GAK resulted in alterations of receptor trafficking and several downstream proteins. In conclusion, our results suggest that osteosarcoma cell proliferation and survival are dependent on GAK. These findings may lead to the development of new therapeutic options for osteosarcoma.
Mol Cancer Ther 2010 Dec
PMID:Cyclin G-associated kinase is necessary for osteosarcoma cell proliferation and receptor trafficking. 2088 Dec 69

Osteosarcoma is a genetically complex malignancy, predominantly afflicting the adolescent population and associated still with relatively poor long-term outcomes. Although there has been some improvement in the understanding of osteosarcoma biology, this has not yet translated particularly well into therapeutic advances. By using a whole-genome tiling path array for comparative genomic hybridization analysis, we sought to evaluate DNA copy number changes in 22 osteosarcoma tumor samples. Regions of most frequent gains or losses generated by Genomic Identification of Significant Targets in Cancer analysis were evaluated for genes of interest. Correlation of the copy number data with preexisting expression data for these genes yielded not only targets known to be important in osteosarcoma but also novel targets, notably cyclin E1. Fluorescence in situ hybridization and immunohistochemical analysis confirmed the findings. Overexpression of cyclin E1 has potential prognostic and therapeutic implications that are discussed herein.
J Mol Diagn 2011 May
PMID:Cyclin E1 is amplified and overexpressed in osteosarcoma. 2145 81

Although rare, osteosarcoma is an aggressive cancer that often metastasizes to the lungs. Toward the goal of developing new treatment options for osteosarcoma, we show that the cyclin-dependent kinase (CDK) inhibitor SCH 727965 (SCH) induces the apoptosis of several osteosarcoma cell lines including those resistant to doxorubicin and dasatinib. Cell lines prepared in our laboratory from patients who had received adjuvant chemotherapy and explants derived from a human osteosarcoma xenograft in mice were also responsive to SCH. Apoptosis occurred at low nanomolar concentrations of SCH, as did CDK inhibition, and was p53-independent. SCH activated the mitochondrial pathway of apoptosis as evidenced by caspase-9 cleavage and accumulation of cytoplasmic cytochrome c. Amounts of the apoptotic proteins Bax and Bim increased in mitochondria, whereas amounts of the antiapoptotic proteins Mcl-1 and Bcl-x(L) declined. Osteosarcoma cells apoptosed when codepleted of CDK1 and CDK2 but not when depleted of other CDK combinations. We suggest that SCH triggers the apoptosis of osteosarcoma cells by inactivating CDK1 and CDK2 and that SCH may be useful for treatment of drug-resistant osteosarcomas. SCH also induced the apoptosis of other sarcoma types but not of normal quiescent osteoblasts or fibroblasts.
Mol Cancer Ther 2011 Jun
PMID:The cyclin-dependent kinase inhibitor SCH 727965 (dinacliclib) induces the apoptosis of osteosarcoma cells. 2149 Mar 7

Osteosarcoma, the most common primary bone tumor, occurs most frequently in adolescents. Chromosomal aneuploidy is common in osteosarcoma cells, suggesting underlying chromosomal instability. Telomeres, located at chromosome ends, are essential for genomic stability; several studies have suggested that germline telomere length (TL) is associated with cancer risk. We hypothesized that TL and/or common genetic variation in telomere biology genes may be associated with risk of osteosarcoma. We investigated TL in peripheral blood DNA and 713 single nucleotide polymorphisms (SNPs) from 39 telomere biology genes in 98 osteosarcoma cases and 69 orthopedic controls. For the genotyping component, we added 1363 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer ScreeningTrial. Short TL was not associated with osteosarcoma risk overall (OR 1.39, P=0.67), although there was a statistically significant association in females (OR 4.35, 95% Cl 1.20-15.74, P=0.03). Genotype analyses identified seven SNPs in TERF1 significantly associated with osteosarcoma risk after Bonferroni correction by gene. These SNPs were highly linked and associated with a reduced risk of osteosarcoma (OR 0.48-0.53, P=0.0001-0.0006). We also investigated associations between TL and telomere gene SNPs in osteosarcoma cases and orthopedic controls. Several SNPs were associated with TL prior to Bonferroni correction; one SNP in NOLA2 and one in MEN1 were marginally non-significant after correction (P(adj)=0.057 and 0.066, respectively). This pilot-study suggests that females with short telomeres may be at increased risk of osteosarcoma, and that SNPs in TERF1 are inversely associated with osteosarcoma risk.
Int J Mol Epidemiol Genet 2011 Jan 01
PMID:Telomere length and variation in telomere biology genes in individuals with osteosarcoma. 2153 98

Osteosarcoma, which is the most common primary bone tumor, occurs most frequently in adolescents. A number of studies have indicated that plumbagin (PL) (5-hydroxy-2-methyl-1, 4-naphthoquinone), a compound found in the plants of the Plumbaginaceae and Droseraceae families, possesses anticancer activity. However, its anticancer effects and mechanisms against osteosarcoma have not been explored. To determine the anticancer effect of PL on osteosarcoma cell lines MG-63 and U2OS, cell viability, apoptosis, cell cycle distribution, caspase-3 and caspase-9 activity and intracellular reactive oxygen species (ROS) generation were measured, and Western blot analyses were performed. PL significantly inhibited the growth of osteosarcoma cells, particularly U2OS cells. PL up-regulated the expression of p53 in U2OS cells and p21 in the two osteosarcoma cell lines causing cell cycle arrest by decreasing the expression of murine double minute 2 (MDM2)/cyclin B1 and cyclin D1. Furthermore, PL altered the ratio of Bax/Bcl-2, and may have triggered the mitochondrial apoptotic pathway, resulting in caspase-3 and caspase-9 activation. We also found that PL induced the generation of ROS in osteosarcoma cell lines. To conclude, PL exerted anticancer activity on osteosarcoma cells by inducing pro-apoptotic signaling and modulating the intracellular ROS that causes induction of apoptosis. These effects may relate to the p53 status.
Mol Med Rep 2012 Jan
PMID:Plumbagin induces apoptosis via the p53 pathway and generation of reactive oxygen species in human osteosarcoma cells. 2199 62

Osteosarcoma (OS) is the most common primary malignant neoplasm in children and adolescents. Epirubicin is one of the chemotherapeutic agents currently used for the treatment of OS; however, the efficacy of chemotherapy is hampered by the acquired drug resistance of OS. Cerulenin, an inhibitor of fatty acid synthase, has been defined as a candidate tumor suppressor. In this study, we explored the combined effect of cerulenin plus the chemotherapy drug, epirubicin, on human OS U2-OS cells in vitro and in vivo. We demonstrated that cerulenin plus epirubicin induced synergistic growth inhibition and enhanced apoptosis in U2-OS cells. We also demonstrated that cerulenin plus epirubicin synergistically suppressed tumor growth in subcutaneously xenografted U2-OS cells in athymic nude mice. Our results indicate that cerulenin enhances the anti-OS effects of epirubicin in vivo and in vitro.
Mol Med Rep 2012 Feb
PMID:Enhanced antitumor activity of epirubicin combined with cerulenin in osteosarcoma. 2205 53

The development of a sensitive, specific, and non-invasive approach for cancer detection will facilitate early detection and, hence, improve the outcome of individuals with known cancer predispositions. Proteomic profiling of blood emerges to be a logical choice of such non-invasive or minimal invasive detection. However, plasma biomarker discovery of pediatric cancers lags behind that of adult cancers, suggesting more efforts are needed in this area. In this study, we used surface-enhanced laser desorption/ionization-time of flight mass spectrometry to profile plasma proteome in osteosarcoma patients. Osteosarcoma is a bone cancer that affects many children and young adults. We have shown that the plasma proteome contains a unique cancer signature that can distinguish patients with osteosarcoma from those with a benign bone disease. To improve cancer biomarker discovery in plasma, we have also shown that depletion of two highly abundant plasma proteins increases the detection sensitivity of lower-abundance proteins. The combination of depletion and proteomic profiling may increase the chance of identifying tumor-derived proteins within the plasma of pediatric cancer patients.
Methods Mol Biol 2012
PMID:Plasma proteomic profiling of pediatric osteosarcoma. 2208 17

Osteosarcoma is the most frequent, nonhematopoietic, primary malignant tumor of bone. Histopathologically, osteosarcoma is characterized by complex mixtures of different cell types with bone formation. The role of environmental factors in the formation of such a complicated tissue structure as osteosarcoma remains to be elucidated. Here, a newly established murine osteosarcoma model was used to clarify the roles of environmental factors such as fibroblast growth factor-2 (Fgf2) or leukemia-inhibitory factor (Lif) in the maintenance of osteosarcoma cells in an immature state. These factors were highly expressed in tumor environmental stromal cells, rather than in osteosarcoma cells, and they potently suppressed osteogenic differentiation of osteosarcoma cells in vitro and in vivo. Further investigation revealed that the hyperactivation of extracellular signal-regulated kinase (Erk)1/2 induced by these factors affected in the process of osteosarcoma differentiation. In addition, Fgf2 enhanced both proliferation and migratory activity of osteosarcoma cells and modulated the sensitivity of cells to an anticancer drug. The results of the present study suggest that the histology of osteosarcoma tumors which consist of immature tumor cells and pathologic bone formations could be generated dependent on the distribution of such environmental factors. The combined blockade of the signaling pathways of several growth factors, including Fgf2, might be useful in controlling the aggressiveness of osteosarcoma.
Mol Cancer Res 2012 Mar
PMID:Fibroblast growth factor-2 is an important factor that maintains cellular immaturity and contributes to aggressiveness of osteosarcoma. 2222 19

Osteosarcoma, a common malignancy primarily affecting children, generally has a poor prognosis. Novel diagnostic, prognostic and therapeutic markers are required to ameliorate the negative outcomes of this disease. We investigated two potential markers, WNT-5a and ROR2, which are hypothesized to dysregulate WNT signaling pathways to promote tumorigenesis in other types of cancer. We investigated WNT-5a and ROR2 expression using immunohistochemistry in 42 osteosarcoma and 12 osteochondroma specimens, and compared the expression of these proteins with one another as well as with clinicopathological parameters. WNT-5a was detected in 34/42 (81.0%) cases and ROR2 was detected in 31/42 (73.8%) cases, significantly higher than in osteochondroma (16.7 and 25.0%, respectively; both P<0.05). Expression of these proteins was positively correlated (r=0.552, P<0.05). Furthermore, expression of WNT-5a and ROR2 was both correlated with Enneking surgical stage and tumor metastasis (P<0.05), but not with patient gender, age or pathological type. Thus, WNT-5a and ROR2 were more highly expressed in more severe disease states, and therefore may play a coordinated role in the occurrence and progression of osteosarcoma.
Mol Med Rep 2012 Apr
PMID:Expression of WNT-5a and ROR2 correlates with disease severity in osteosarcoma. 2229 3


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