5-alpha-reductase: 2012-12-16

2012年12月22日星期六

A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma.

A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma.

Sci Transl Med. 2012 Jun 6;4(137):137ra75

Authors: Sivanand S, Pe�a-Llopis S, Zhao H, Kucejova B, Spence P, Pavia-Jimenez A, Yamasaki T, McBride DJ, Gillen J, Wolff NC, Morlock L, Lotan Y, Raj GV, Sagalowsky A, Margulis V, Cadeddu JA, Ross MT, Bentley DR, Kabbani W, Xie XJ, Kapur P, Williams NS, Brugarolas J

Abstract
Most anticancer drugs entering clinical trials fail to achieve approval from the U.S. Food and Drug Administration. Drug development is hampered by the lack of preclinical models with therapeutic predictive value. Herein, we report the development and validation of a tumorgraft model of renal cell carcinoma (RCC) and its application to the evaluation of an experimental drug. Tumor samples from 94 patients were implanted in the kidneys of mice without additives or disaggregation. Tumors from 35 of these patients formed tumorgrafts, and 16 stable lines were established. Samples from metastatic sites engrafted at higher frequency than those from primary tumors, and stable engraftment of primary tumors in mice correlated with decreased patient survival. Tumorgrafts retained the histology, gene expression, DNA copy number alterations, and more than 90% of the protein-coding gene mutations of the corresponding tumors. As determined by the induction of hypercalcemia in tumorgraft-bearing mice, tumorgrafts retained the ability to induce paraneoplastic syndromes. In studies simulating drug exposures in patients, RCC tumorgraft growth was inhibited by sunitinib and sirolimus (the active metabolite of temsirolimus in humans), but not by erlotinib, which was used as a control. Dovitinib, a drug in clinical development, showed greater activity than sunitinib and sirolimus. The routine incorporation of models recapitulating the molecular genetics and drug sensitivities of human tumors into preclinical programs has the potential to improve oncology drug development.

PMID: 22674553 [PubMed - indexed for MEDLINE]

dna-pk coxinhibitors c-met inhibitors

Induction of P-glycoprotein and Bcrp at the rat blood-brain barrier following a subchronic morphine treatment is mediated through NMDA/COX-2 activation.

Induction of P-glycoprotein and Bcrp at the rat blood-brain barrier following a subchronic morphine treatment is mediated through NMDA/COX-2 activation.

J Neurochem. 2012 Nov;123(4):491-503

Authors: Yousif S, Chaves C, Potin S, Margaill I, Scherrmann JM, Decl�ves X

Abstract
Subchronic morphine treatment induces P-glycoprotein (P-gp) up-regulation at the blood-brain barrier. This study investigates the rate and extent to which P-gp and breast cancer-resistance protein (Bcrp) increase at the rat blood-brain barrier following subchronic morphine treatment. Rats were given increasing doses of morphine (10-40 mg/kg) or saline i.p. twice daily for 5 days. The brain cortex large vessels and microvessels were then mechanical isolated 6, 9, 12, 24, and 36 h after the last injection. The gene and protein expression of P-gp and Bcrp in morphine-treated and control rats were compared by qRT-PCR and western blotting. The levels of Mdr1a and Bcrp mRNAs were not significantly modified 6 h post morphine, but the Mdr1a mRNA increased 1.4-fold and Bcrp mRNA 2.4-fold at 24 h. P-gp and Bcrp protein expression in brain microvessels was unchanged 6 h post morphine and increased 1.5-fold at 24 h. This effect was more pronounced in large vessels than in microvessels. However, extracellular morphine concentrations of 0.01-10 ?M did not modify the expressions of the MDR1 and BCRP genes in hCMEC/D3 human endothelial brain cells in vitro. MK-801 (NMDA antagonist) and meloxicam (cyclo-oxygenase-2 inhibitor) given after morphine treatment completely blocked P-gp and Bcrp up-regulation. Interestingly, misoprostol and iloprost, two well-known agonists of prostaglandin E2 receptors induced both MDR1 and BCRP mRNA levels in hCMEC/D3. Thus, morphine does not directly stimulate P-gp and Bcrp expression by the brain endothelium, but glutamate released during morphine withdrawal may do so by activating the NMDA/cyclo-oxygenase-2 cascade.

PMID: 22845665 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

Improvement of pest resistance in transgenic tobacco plants expressing dsRNA of an insect-associated gene EcR.

Improvement of pest resistance in transgenic tobacco plants expressing dsRNA of an insect-associated gene EcR.

PLoS One. 2012;7(6):e38572

Authors: Zhu JQ, Liu S, Ma Y, Zhang JQ, Qi HS, Wei ZJ, Yao Q, Zhang WQ, Li S

Abstract
The adoption of pest-resistant transgenic plants to reduce yield loss and pesticide utilization has been successful in the past three decades. Recently, transgenic plant expressing double-stranded RNA (dsRNA) targeting pest genes emerges as a promising strategy for improving pest resistance in crops. The steroid hormone, 20-hydroxyecdysone (20E), predominately controls insect molting via its nuclear receptor complex, EcR-USP. Here we report that pest resistance is improved in transgenic tobacco plants expressing dsRNA of EcR from the cotton bollworm, Helicoverpa armigera, a serious lepidopteran pest for a variety of crops. When H. armigera larvae were fed with the whole transgenic tobacco plants expressing EcR dsRNA, resistance to H. armigera was significantly improved in transgenic plants. Meanwhile, when H. armigera larvae were fed with leaves of transgenic tobacco plants expressing EcR dsRNA, its EcR mRNA level was dramatically decreased causing molting defects and larval lethality. In addition, the transgenic tobacco plants expressing H. armigera EcR dsRNA were also resistant to another lepidopteran pest, the beet armyworm, Spodoptera exigua, due to the high similarity in the nucleotide sequences of their EcR genes. This study provides additional evidence that transgenic plant expressing dsRNA targeting insect-associated genes is able to improve pest resistance.

PMID: 22685585 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

New insights into the roles of ATM and DNA-PKcs in the cellular response to oxidative stress.

New insights into the roles of ATM and DNA-PKcs in the cellular response to oxidative stress.

Cancer Lett. 2012 Dec 31;327(1-2):103-10

Authors: Chen BP, Li M, Asaithamby A

Abstract
Reactive oxygen species (ROS) are induced by a variety of endogenous and exogenous sources. At pathologically high levels, ROS cause damage to biological molecules, including DNA. The damage sustained by DNA likely plays a key role in the pathogenesis of aging and carcinogenesis. Extensive research has established in detail the mechanism of cellular response to oxidative stress. Attention is now focused on identifying the molecular contributions of the key DNA damage response kinases ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and ATM- and Rad3-related (ATR) in the oxidative stress response. In this review, we will provide an update of the current evidence regarding the involvement of these related DNA damage response kinases in oxidative DNA lesion repair and signaling responses. The growing understanding of the involvement of ATM, DNA-PKcs, and ATR in the oxidative stress response will offer new possibilities for the treatment of ROS-related diseases.

PMID: 22155347 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

2012年12月21日星期五

[Management of adverse events associated with molecular targeted agents].

[Management of adverse events associated with molecular targeted agents].

Hinyokika Kiyo. 2012 Nov;58(11):633

Authors: Fujisawa M, Sugimura Y

Abstract
In Japan, sorafenib and sunitinib, potential molecular targeted agents for advanced renal cell carcinoma, were approved in 2008. Currently, a total of four agents, including everolimus and temsirolimus in addition to these two agents, have been introduced into clinical practice. It would be comparatively easy to determine the indication of these molecular targeted agents because of several clinical guidelines developed based on the outcomes of reliable randomized clinical trials ; however, any adverse events associated with the use of these agents, need to be managed carefully according to each case. Furthermore, it seems difficult to properly manage adverse events encountered during treatment using these agents due to the following reasons : there are several adverse events which have not been experienced by urologists before, and there are marked differences in the incidence as well as severity of adverse events associated with these agents between the Western and Japanese populations. It is particularly important to try to achieve a maximal therapeutic benefit from treatment with molecular targeted agents through optimal management for adverse events associated with these agents. In this symposium, accordingly, five experts, well informed of the use of these agents, provided practical information on the management of adverse events associated with each agent.

PMID: 23254791 [PubMed - in process]

rad001 ecdysone

Lochmolins A-G, new sesquiterpenoids from the soft coral Sinularia lochmodes.

Lochmolins A-G, new sesquiterpenoids from the soft coral Sinularia lochmodes.

Mar Drugs. 2012 Jul;10(7):1572-81

Authors: Tseng YJ, Shen KP, Lin HL, Huang CY, Dai CF, Sheu JH

Abstract
Seven new sesquiterpenoids, lochmolins A-G (1-7), were isolated from a Taiwanese soft coral Sinularia lochmodes. The structures of these metabolites were elucidated by extensive spectroscopic study. Compounds 1-4 were found to inhibit the accumulation of the LPS-induced pro-inflammatory COX-2 protein in RAW264.7 macrophage cells.

PMID: 22851927 [PubMed - indexed for MEDLINE]

zm-447439 rad001 ecdysone

Improvement of pest resistance in transgenic tobacco plants expressing dsRNA of an insect-associated gene EcR.

Improvement of pest resistance in transgenic tobacco plants expressing dsRNA of an insect-associated gene EcR.

PLoS One. 2012;7(6):e38572

Authors: Zhu JQ, Liu S, Ma Y, Zhang JQ, Qi HS, Wei ZJ, Yao Q, Zhang WQ, Li S

PMID: 22685585 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

[Management of side effects of everolimus treatment for metastatic renal cell carcinoma].

[Management of side effects of everolimus treatment for metastatic renal cell carcinoma].

Hinyokika Kiyo. 2012 Nov;58(11):647-50

Authors: Mikami K, Hongo F, Miki T

Abstract
Treatment with everolimus is known to prolong progression-free survival in patients with renal cell carcinoma resistant against tyrosine-kinase inhibitor therapy. The side effects must be known for more effective use of this drug. Information of side effects was collected from a randomized controlled study, the early post-marketing phase vigilance and from our own experience. Interstitial lung disease (ILD) was a potentially severe side effect. Incidence of ILD was relatively large compared with that of other target therapy agents. Infections, thrombocytopenia, stomatitis and others were experienced as other side effects. However, there were few uncontrollable side effects. Management of side effects of everolimus can be improved by obtaining sufficient knowledge.

PMID: 23254794 [PubMed - in process]

dna-pk coxinhibitors c-met inhibitors

2012年12月20日星期四

The effects of piroxicam and deracoxib on canine mammary tumour cell line.

The effects of piroxicam and deracoxib on canine mammary tumour cell line.

ScientificWorldJournal. 2012;2012:976740

Authors: Ust�n Alkan F, Ust�ner O, Bak?rel T, C?nar S, Erten G, Deniz G

Abstract
Cyclooxygenase (COX) inhibitors, already widely used for the treatment of pain and inflammation, are considered as promising compounds for the prevention and treatment of neoplasia. The aim of our study was to determine the direct antiproliferative effects of nonsteroidal anti-inflammatory drugs (NSAIDs), piroxicam and deracoxib, at a variety of concentrations as both single and combined treatments on canine mammary carcinoma cell line CMT-U27 and to understand the mechanisms of cell death. MTT assay was performed to determine cell viability, and flow cytometric analyses were performed to evaluate apoptosis and cell cycle alterations. Significant decrease in cell viability was observed at high concentrations of piroxicam and deracoxib in both single and combined treatments after 72?h incubation. Combined treatment produced a significantly greater inhibition than that caused by either agent alone. Also apoptotic cell number was increased by both drugs at the cytotoxic concentrations. However, concomitant treatment of cells with piroxicam and deracoxib resulted in significant induction of apoptosis at lower concentrations and accumulation of cells in the G(0)/G(1) phase. Significant cytotoxic effects exhibited by the combination of piroxicam and deracoxib against canine mammary carcinoma cells in vitro suggest an attractive approach for the treatment of canine mammary carcinoma.

PMID: 23251109 [PubMed - in process]

dna-pk coxinhibitors c-met inhibitors

DNA-PK is a DNA sensor for IRF-3-dependent innate immunity.

DNA-PK is a DNA sensor for IRF-3-dependent innate immunity.

elife. 2012;1:e00047

Authors: Ferguson BJ, Mansur DS, Peters NE, Ren H, Smith GL

Abstract
Innate immunity is the first immunological defence against pathogens. During virus infection detection of nucleic acids is crucial for the inflammatory response. Here we identify DNA-dependent protein kinase (DNA-PK) as a DNA sensor that activates innate immunity. We show that DNA-PK acts as a pattern recognition receptor, binding cytoplasmic DNA and triggering the transcription of type I interferon (IFN), cytokine and chemokine genes in a manner dependent on IFN regulatory factor 3 (IRF-3), TANK-binding kinase 1 (TBK1) and stimulator of interferon genes (STING). Both cells and mice lacking DNA-PKcs show attenuated cytokine responses to both DNA and DNA viruses but not to RNA or RNA virus infection. DNA-PK has well-established functions in the DNA repair and V(D)J recombination, hence loss of DNA-PK leads to severe combined immunodeficiency (SCID). However, we now define a novel anti-microbial function for DNA-PK, a finding with implications for host defence, vaccine development and autoimmunity.DOI:http://dx.doi.org/10.7554/eLife.00047.001.

PMID: 23251783 [PubMed - in process]

chir-258 dovitinib dna-pk

Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.

Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.

J Transl Med. 2012 Dec 10;10(1):245

Authors: Chen ZY, Shi M, Peng LX, Wei W, Li XJ, Guo ZX, Li SH, Zhong C, Qian CN, Guo RP

Abstract
ABSTRACT: BACKGROUND: Dovitinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptors and platelet-derived growth factor receptor beta. Dovitinib is currently in clinical trials for the treatment of hepatocellular carcinoma (HCC). METHOD: In this study, we used five HCC cell lines and five endothelial cell lines to validate molecular and cellular targets of dovitinib. RESULTS: Tumor growth and pulmonary metastasis were significantly suppressed in an orthotopic HCC model. Immunoblotting revealed that among known dovitinib targets, only PDGFR-beta was expressed in two HCC cell lines, while four of five endothelial lines expressed PDGFR-beta, FGFR-1, and VEGFR-2. Dovitinib inhibited endothelial cell proliferation and motility at 0.04 mumol/L, a pharmacologically relevant concentration; it was unable to inhibit the proliferation or motility of HCC cells at the same concentration. Immunohistochemical analyses showed that dovitinib significantly decreased the microvessel density of xenograft tumors, inhibiting proliferation and inducing apoptosis in HCC cells. CONCLUSION: Our findings indicate that dovitinib inhibits HCC growth and metastasis preferentially through an antiangiogenic mechanism, not through direct targeting of HCC cells.

PMID: 23228017 [PubMed - as supplied by publisher]

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C-Met inhibitor MK-8003 radiosensitizes c-Met-expressing non-small-cell lung cancer cells with radiation-induced c-Met-expression.

C-Met inhibitor MK-8003 radiosensitizes c-Met-expressing non-small-cell lung cancer cells with radiation-induced c-Met-expression.

J Thorac Oncol. 2012 Aug;7(8):1211-7

Authors: Bhardwaj V, Zhan Y, Cortez MA, Ang KK, Molkentine D, Munshi A, Raju U, Komaki R, Heymach JV, Welsh J

Abstract
INTRODUCTION: The radiation doses used to treat unresectable lung cancer are often limited by the proximity of normal tissues. Overexpression of c-Met, a receptor tyrosine kinase, occurs in about half of non-small-cell lung cancers (NSCLCs) and has been associated with resistance to radiation therapy and poor patient survival. We hypothesized that inhibiting c-Met would increase the sensitivity of NSCLC cells to radiation, enhancing the therapeutic ratio, which may potentially translate into improved local control.
METHODS: We tested the radiosensitivity of two high-c-Met-expressing NSCLC lines, EBC-1 and H1993, and two low-c-Met-expressing lines, A549 and H460, with and without the small-molecule c-Met inhibitor MK-8033. Proliferation and protein expression were measured with clonogenic survival assays and Western blotting, respectively. ?-H2AX levels were evaluated by immunofluorescence staining.
RESULTS: MK-8033 radiosensitized the high-c-Met-expressing EBC-1 and H1993 cells but not the low-c-Met-expressing cell lines A549 and H460. However, irradiation of A549 and H460 cells increased the expression of c-Met protein at 30 minutes after the irradiation. Subsequent targeting of this up-regulated c-Met by using MK-8033 followed by a second radiation dose reduced the clonogenic survival of both A549 and H460 cells. MK-8033 reduced the levels of radiation-induced phosphorylated (activated) c-Met in A549 cells.
CONCLUSIONS: These results suggest that inhibition of c-Met could be an effective strategy to radiosensitize NSCLC tumors with high basal c-Met expression or tumors that acquired resistance to radiation because of up-regulation of c-Met.

PMID: 22617250 [PubMed - indexed for MEDLINE]

zm-447439 rad001 ecdysone

2012年12月19日星期三

Improvement of pest resistance in transgenic tobacco plants expressing dsRNA of an insect-associated gene EcR.

Improvement of pest resistance in transgenic tobacco plants expressing dsRNA of an insect-associated gene EcR.

PLoS One. 2012;7(6):e38572

Authors: Zhu JQ, Liu S, Ma Y, Zhang JQ, Qi HS, Wei ZJ, Yao Q, Zhang WQ, Li S

PMID: 22685585 [PubMed - indexed for MEDLINE]

dna-pk coxinhibitors c-met inhibitors

The mTORC1 Inhibitor Everolimus Prevents and Treats E?-Myc Lymphoma by Restoring Oncogene-Induced Senescence.

The mTORC1 Inhibitor Everolimus Prevents and Treats E?-Myc Lymphoma by Restoring Oncogene-Induced Senescence.

Cancer Discov. 2012 Dec 14;

Authors: Wall M, Poortinga G, Stanley KL, Lindemann RK, Bots M, Chan CJ, Bywater MJ, Kinross KM, Astle MV, Waldeck K, Hannan KM, Shortt J, Smyth MJ, Lowe SW, Hannan RD, Pearson RB, Johnstone RW, McArthur GA

Abstract
MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in E?-Myc mice occur in almost all cases of Burkitt lymphoma as well as in other B-cell lymphoproliferative disorders. Deregulated expression of MYC results in increased mTOR complex 1 (mTORC1) signaling. As tumors with mTORC1 activation are sensitive to mTORC1 inhibition, we used everolimus, a potent and specific mTORC1 inhibitor, to test the requirement for mTORC1 in the initiation and maintenance of E?-Myc lymphoma. Everolimus selectively cleared premalignant B cells from the bone marrow and spleen, restored a normal pattern of B-cell differentiation, and strongly protected against lymphoma development. Established E?-Myc lymphoma also regressed after everolimus therapy. Therapeutic response correlated with a cellular senescence phenotype and induction of p53 activity. Therefore, mTORC1-dependent evasion of senescence is critical for cellular transformation and tumor maintenance by MYC in B lymphocytes.

PMID: 23242809 [PubMed - as supplied by publisher]

coxinhibitors c-met inhibitors zm-447439

Rash to the mTOR Inhibitor Everolimus: Systematic Review and Meta-Analysis.

Rash to the mTOR Inhibitor Everolimus: Systematic Review and Meta-Analysis.

Am J Clin Oncol. 2012 Dec 13;

Authors: Ramirez-Fort MK, Case EC, Rosen AC, Cerci FB, Wu S, Lacouture ME

Abstract
BACKGROUND:: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for treatment of renal cell carcinoma, subependymal giant cell astrocytoma, breast cancer, and progressive neuroendocrine tumors of pancreatic origin. Its use may be hindered because of adverse events, including rash. The reported incidence and risk of a rash to everolimus varies widely and has not been closely investigated. Therefore, we conducted a systematic review and meta-analysis of the literature to determine the incidence and risk of developing a rash. METHODS:: We searched PubMed and Web of Science databases and abstracts presented at the American Society of Clinical Oncology from 1998 to December 2011 using the keyword "everolimus" to identify relevant clinical trials. Eligible studies included prospective phase II and III clinical trials of cancer patients on 10 mg of everolimus daily with available data on incidence of rash. The summary incidence and relative risk (RR) of rash were calculated using either the random-effects or fixed-effects model, depending on the heterogeneity of the constituent studies. RESULTS:: A total of 2242 patients with various malignancies from 13 clinical trials were included in the analysis. The summary incidences of all-grade and high-grade rash in patients on everolimus were 28.6% [95% confidence interval (CI), 20.8-38.0] and 1.0% (95% CI, 0.6-1.8), respectively. Everolimus was associated with a statistically significant increased risk of all-grade rash (RR=3.853, 95% CI, 2.470-6.013, P=0.000), but the RR for high-grade rash (RR=2.997, 95% CI, 0.633-14.185) was not statistically significant, with a P value of 0.166. CONCLUSIONS:: Everolimus is associated with a significant risk of developing a rash. Management of rash to everolimus is critical to prevent dose modifications and decreased quality of life, both of which can negatively affect overall clinical outcomes.

PMID: 23241507 [PubMed - as supplied by publisher]

coxinhibitors c-met inhibitors zm-447439

Rash to the mTOR Inhibitor Everolimus: Systematic Review and Meta-Analysis.

Rash to the mTOR Inhibitor Everolimus: Systematic Review and Meta-Analysis.

Am J Clin Oncol. 2012 Dec 13;

Authors: Ramirez-Fort MK, Case EC, Rosen AC, Cerci FB, Wu S, Lacouture ME

PMID: 23241507 [PubMed - as supplied by publisher]

zm-447439 rad001 ecdysone

2012年12月18日星期二

Inhibition of dendritic cell maturation by the tumor microenvironment correlates with the survival of colorectal cancer patients following bevacizumab treatment.

Inhibition of dendritic cell maturation by the tumor microenvironment correlates with the survival of colorectal cancer patients following bevacizumab treatment.

Mol Cancer Ther. 2012 Aug;11(8):1829-37

Authors: Michielsen AJ, Noonan S, Martin P, Tosetto M, Marry J, Biniecka M, Maguire AA, Hyland JM, Sheahan KD, O'Donoghue DP, Mulcahy HE, Fennelly D, Ryan EJ, O'Sullivan JN

Abstract
Development of bevacizumab has improved survival in colorectal cancer, however, currently there are no biomarkers that predict response to bevacizumab and it is unknown how it influences the immune system in colorectal cancer patients. Dendritic cells are important for the induction of an antitumor immune response; however tumors are capable of disabling dendritic cells and escaping immune surveillance. The aim of this study was to assess the numbers of CD11c+ cells infiltrating tumor tissue and to examine the effects of tumor conditioned media (TCM) and bevacizumab conditioned media (BCM) on dendritic cell maturation and correlate our findings with patient survival. colorectal cancer explant tissues were cultured with or without bevacizumab, to generate BCM and TCM, which were used to treat dendritic cells. CD80, CD86, CD83, CD54, HLA-DR, and CD1d expression was measured by flow cytometry. Interleukin (IL)-10 and IL-12p70 were measured by ELISA. The Cox proportional hazards model was used to associate survival with dendritic cell inhibition. TCM and BCM inhibited lipopolysaccharide (LPS)-induced dendritic cell maturation and IL-12p70 secretion (P < 0.0001), while increasing IL-10 secretion (P = 0.0033 and 0.0220, respectively). Inhibition of LPS-induced CD1d (P = 0.021, HR = 1.096) and CD83 (P = 0.017, HR = 1.083) by TCM and inhibition of CD1d (P = 0.017, HR = 1.067), CD83 (P = 0.032, HR = 1.035), and IL-12p70 (P = 0.037, HR = 1.036) by BCM was associated with poor survival in colorectal cancer patients. CD11c expression was elevated in tumor tissue compared with normal tissue (P < 0.001), but this did not correlate with survival. In conclusion, TCM and BCM inhibit dendritic cells, and this inhibition correlates with survival of colorectal cancer patients receiving bevacizumab.

PMID: 22675042 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma.

A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma.

Sci Transl Med. 2012 Jun 6;4(137):137ra75

PMID: 22674553 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

Antiplatelet therapy use and the risk of venous thromboembolic events in the Raloxifene Use for the Heart (RUTH) trial.

Antiplatelet therapy use and the risk of venous thromboembolic events in the Raloxifene Use for the Heart (RUTH) trial.

J Womens Health (Larchmt). 2010 Aug;19(8):1459-65

Authors: Duvernoy CS, Yeo AA, Wong M, Cox DA, Kim HM

Abstract
BACKGROUND: Raloxifene use in postmenopausal women with osteoporosis increases the risk of venous thromboembolic events (VTE) 2-fold compared with placebo. Platelet activation is involved in the pathophysiology of arterial thromboses more than venous thromboses, but aspirin may reduce VTE risk associated with estrogen use. This analysis examines the effects of concomitant antiplatelet therapy on VTE risk in raloxifene-treated women.
METHODS: In the Raloxifene Use for the Heart (RUTH) trial, 10,101 postmenopausal women from 177 sites in 26 countries at increased risk of coronary heart disease (CHD) (primary prevention cohort) or with CHD (secondary prevention cohort) were randomized to placebo or raloxifene 60 mg/day and followed for a median 5.6 years. Reports of clinical symptoms of VTE were assessed. Concomitant use of antiplatelet agents (aspirin, clopidogrel, ticlopidine, dipyridamole) was allowed. Cox proportional hazard models, with use of warfarin, presence of fracture, and hospitalization as covariates, were used to estimate hazard ratios (HR) with 95% confidence intervals (CI).
RESULTS: Overall, raloxifene use was associated with an increased VTE risk (HR 1.44, 95% CI 1.06-1.95) vs. placebo. Most women (72%) reported using aspirin, and 14.2% reported using nonaspirin antiplatelet agents during the study period. Users of antiplatelet agents were older, more likely to have CHD, and more likely to be hyperlipidemic. They had a higher VTE risk than nonusers. No difference in VTE risk was observed in women who used raloxifene alone vs. those who used raloxifene with antiplatelet agents during the study. The increase in VTE risk with raloxifene compared with placebo was not different between women who used antiplatelet agents at baseline (HR 1.44, 95% CI 0.98, 2.10) and those who did not use antiplatelet agents (HR 1.37, 95% CI 0.83, 2.27) (interaction p = 0.88). Similar conclusions were noted for aspirin and nonaspirin antiplatelet use.
CONCLUSIONS: In RUTH, postmenopausal women treated with raloxifene had an increased risk of VTE compared with placebo. Concomitant use of aspirin or nonaspirin antiplatelet agents along with raloxifene did not change VTE risk.

PMID: 20626269 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia.

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia.

Biol Chem. 2012 Dec 14;

Authors: Wrann S, Kaufmann MR, Wirthner R, Stiehl DP, Wenger RH

Abstract
Abstract The histone variant 2AX (H2AX) is phosphorylated at Ser139 by the PI3K-like kinase family members ATM, ATR and DNA-PK. Genotoxic stress such as tumor radio- and chemotherapy is considered to be the main inducer of phosphorylated H2AX (?H2AX) which forms distinct foci at sites of DNA damage where DNA repair factors accumulate. ?H2AX accumulation under severe hypoxic/anoxic (0.02% oxygen) conditions has recently been reported to follow replication fork stalling in the absence of detectable DNA damage. In this study, we found HIF dependent accumulation of ?H2AX in several cancer cell lines and mouse embryonic fibroblasts exposed to physiologically relevant chronic hypoxia (0.2% oxygen) which did not induce detectable levels of DNA strand breaks. The hypoxic accumulation of ?H2AX was delayed by RNAi mediated knockdown of HIF-1? or HIF-2? and further decreased when both HIF-?s were absent. Conversely, basal phosphorylation of H2AX was increased in cells with constitutively stabilized HIF-2?. These results suggest that both HIF-1 and HIF-2 are involved in ?H2AX accumulation by tumor hypoxia which might increase the cancer cell's capacity to repair DNA damage, contributing to tumor therapy resistance.

PMID: 23241668 [PubMed - as supplied by publisher]

dna-pk coxinhibitors c-met inhibitors

Signal Transduction Pathways (MAPKs, NF-?B, and C/EBP) Regulating COX-2 Expression in Nasal Fibroblasts from Asthma Patients with Aspirin Intolerance.

Signal Transduction Pathways (MAPKs, NF-?B, and C/EBP) Regulating COX-2 Expression in Nasal Fibroblasts from Asthma Patients with Aspirin Intolerance.

PLoS One. 2012;7(12):e51281

Authors: Garcia-Garcia FJ, Mullol J, Perez-Gonzalez M, Pujols L, Alobid I, Roca-Ferrer J, Picado C

Abstract
BACKGROUND: Recent studies have revealed that cyclooxygenase-2 (COX-2) expression is down-regulated in aspirin-induced asthma (AIA). Various signal pathways (MAPKs, NF-?B and C/EBP) are involved in COX-2 regulation.
OBJECTIVE: To investigate the regulation of COX-2 expression through MAP-kinase pathway activation and nuclear factor translocation in aspirin-induced asthma (AIA).
METHODS: Fibroblasts were isolated from specimens of nasal mucosa (NM, N?=?5) and nasal polyps (NP, N?=?5). After IL-1? (1 ng/ml) incubation, COX-2 and phosphorylated forms of ERK, JNK and p38 MAPK were measured by Western blot. MAPK's role in IL-1?-induced COX-2 expression was assessed by treating cells with ERK (PD98059), JNK (SP600125) and p38 MAPK (SB203580) inhibitors (0.1-10 �M) prior to IL-1? exposure. NF-?B and C/EBP nuclear translocation was measured by Western blot and TransAM� after IL-1? (10 ng/ml) exposure.
RESULTS: No differences were observed in the MAPK phosphorylation time-course between NM and NP-AIA fibroblasts. The p38 MAPK inhibitor at 10 �M significantly reduced IL-1?-induced COX-2 expression in NM fibroblasts (85%). In NP-AIA fibroblasts the COX-2 inhibition (65%) at 1 and 10 �M was not statistically significant compared to non-treated cells. ERK and JNK inhibitors had no significant effect in either the NM or NP-AIA cultures. The effect of IL-1? on NF-?B and C/EBP subunits' nuclear translocation was similar between NM and NP-AIA fibroblasts.
CONCLUSIONS: These results suggest that p38 MAPK is the only MAPK involved in IL-1?-induced COX-2 expression. NM and NP-AIA fibroblasts have similar MAPK phosphorylation dynamics and nuclear factor translocation (NF-?B and C/EBP). COX-2 downregulation observed in AIA patients appears not to be caused by differences in MAPK dynamics or transcription factor translocation.

PMID: 23240010 [PubMed - in process]

dovitinib dna-pk coxinhibitors

2012年12月17日星期一

Predicting everolimus treatment efficacy in patients with advanced endometrial carcinoma: a GINECO group study.

Predicting everolimus treatment efficacy in patients with advanced endometrial carcinoma: a GINECO group study.

Target Oncol. 2012 Dec 13;

Authors: Tr�dan O, Treilleux I, Wang Q, Gane N, Pissaloux D, Bonnin N, Petit T, Cretin J, Bonichon-Lamichhane N, Priou F, Lavau-Denes S, Mari V, Freyer G, Lebrun D, Alexandre J, Ray-Coquard I

Abstract
This study aimed to determine whether the expression of various tumor biomarkers of the mTOR pathway predicts tumor response to everolimus in metastatic recurrent endometrial cancer. Tumor blocks from 44 patients of a phase II clinical trial receiving everolimus until progression or toxicity were collected and evaluated at 3 and 6�months for response. Thirty-six blocks were available for analysis of ER, PR, HER2, LKB1, PI3K, PTEN, pAKT, 4E-BP1, p4E-BP1, and S6RP expression by immunohistochemistry, PTEN deletion by FISH, and mutational status of K-RAS, PIK3CA, PTEN, and AKT1 genes. Twelve of 34 evaluable patients had partial response or stable disease (PR, SD) and 22 had progressive disease (PD). Immunohistochemistry showed that no protein expression could predict response to everolimus. Neither could loss of PTEN expression or PTEN deletion or PTEN mutation predict patient outcome. Thirty-one samples were assessable for K-RAS mutations (ten for PR+SD and 21 for PD). There are only four patients with K-RAS mutations and none of them responded to treatment. Median progression-free survival (PFS) and overall survival (OS) were longer in patients without K-RAS mutations (PFS 3.12?�?1.7�months versus 1.05?�?0.4�months, p?<?0.001; OS 9.28?�?2.0�months versus 2.30?�?1.4�months, p?=?0.034). In conclusion, the level of expression of proteins of the PI3K/mTOR pathway tested in this study cannot predict response to everolimus. However, endometrial cancer patients with K-RAS mutations do not seem to derive benefit from everolimus treatment.

PMID: 23238879 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib

Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.

Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.

J Transl Med. 2012 Dec 10;10(1):245

Authors: Chen ZY, Shi M, Peng LX, Wei W, Li XJ, Guo ZX, Li SH, Zhong C, Qian CN, Guo RP

PMID: 23228017 [PubMed - as supplied by publisher]

dovitinib dna-pk coxinhibitors

Everolimus dual effects of an area vasculosa angiogenesis and lymphangiogenesis.

Everolimus dual effects of an area vasculosa angiogenesis and lymphangiogenesis.

In Vivo. 2013 Jan;27(1):61-6

Authors: Ceausu RA, Cimpean AM, Dimova I, Hlushchuk R, Djonov V, Gaje PN, Raica M

Abstract
Recently approved as treatment for astrocytoma, kidney and pancreatic cancer, everolimus acts on tumor cells by inhibiting tumor cell growth and proliferation, as well as by inhibition of angiogenic activity by both direct effects on vascular cell proliferation and indirect effects on growth factor production. The effects of everolimus on early stages of normal vasculogenesis, angiogenesis and lymphangiogenesis are not yet available. We found increased development of intravascular pillars by using area vasculosa of the chick chorioallantoic membrane treated with everolimus. An active lymphangiogenic response was highlighted by the expression of Prospero homeobox protein 1 (Prox1) and podoplanin, together with vascular endothelial growth factor receptor C (Vegf-C) and vascular endothelial growth factor receptor 3 (Vegfr-3) expression on day 4 in the treated group. These findings suggest a potential role of everolimus in the activation of lymphangiogenesis.

PMID: 23239853 [PubMed - in process]

dovitinib dna-pk coxinhibitors

Everolimus dual effects of an area vasculosa angiogenesis and lymphangiogenesis.

Everolimus dual effects of an area vasculosa angiogenesis and lymphangiogenesis.

In Vivo. 2013 Jan;27(1):61-6

Authors: Ceausu RA, Cimpean AM, Dimova I, Hlushchuk R, Djonov V, Gaje PN, Raica M

PMID: 23239853 [PubMed - in process]

c-met inhibitors zm-447439 rad001

2012年12月16日星期日

MTRX1011A, a humanized anti-CD4 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled study incorporating pharmacodynamic biomarker assessments.

MTRX1011A, a humanized anti-CD4 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled study incorporating pharmacodynamic biomarker assessments.

Arthritis Res Ther. 2011;13(5):R177

Authors: Scheerens H, Su Z, Irving B, Townsend MJ, Zheng Y, Stefanich E, Chindalore V, Bingham CO, Davis JC

Abstract
INTRODUCTION: The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the humanized anti-CD4 monoclonal antibody MTRX1011A in a randomized, double-blind placebo-controlled Phase 1 study in patients with rheumatoid arthritis (RA).
METHODS: In the single ascending dose (SAD) portion of the study, patients received single doses of a placebo or MTRX1011A at 0.3, 1.0, 3.5 and 7.0 mg/kg intravenously (i.v.) or 1.0 and 3.5 mg/kg subcutaneously (s.c.), followed by five weeks of evaluation. In the multi-dose (MD) portion of the study, placebo or MTRX1011A was administered weekly for eight doses at 1.5 or 3.5 mg/kg s.c., or 5 mg/kg i.v., followed by eight weeks of evaluation.
RESULTS: MTRX1011A was well tolerated in the SAD phase up to 7 mg/kg i.v. and in the MD phase up to 1.5 mg/kg s.c.. At weekly doses of 3.5 mg/kg s.c. and 5 mg/kg i.v., a moderate pruritic papular rash was observed in some MTRX1011A-treated patients, which was considered a dose-limiting toxicity for this clinical indication. No serious adverse events occurred in any cohort. Reduction in disease activity was modest. PD assessments demonstrated that MTRX1011A induced a dose-dependent down-modulation of CD4 expression on peripheral blood CD4 T cells, CD4 receptor occupancy, increases in serum sCD4-MTRX1011A complexes and up-regulation of CD69 on T cells, but was non-depleting.
CONCLUSIONS: The maximum tolerated dose of MTRX1011A was 1.5 mg/kg SC administered weekly. At this dose MTRX1011A did not achieve maximum PD activity expected to be required for reduction in disease activity.

PMID: 22029963 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

MTRX1011A, a humanized anti-CD4 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled study incorporating pharmacodynamic biomarker assessments.

Arthritis Res Ther. 2011;13(5):R177

Authors: Scheerens H, Su Z, Irving B, Townsend MJ, Zheng Y, Stefanich E, Chindalore V, Bingham CO, Davis JC

PMID: 22029963 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Cell Cycle. 2012 Jul 1;11(13):2567-77

Authors: Marxer M, Foucar CE, Man WY, Chen Y, Ma HT, Poon RY

Abstract
Aurora kinases are overexpressed in many cancers and are targets for anticancer drugs. The yeast homolog of Aurora B kinase, IPL1, was found to be a ploidy-specific lethality gene. Given that polyploidization is a common feature of many cancers, we hypothesized polyploidization also sensitizes mammalian cells to inhibition of Aurora kinases. Using two models of apparent diploid vs. tetraploid cell lines (one based on the hepatocellular carcinoma cell line Hep3B and another on untransformed mouse fibroblasts), we found that tetraploid cells were more sensitive to Aurora B inhibition than their diploid counterparts. Apoptosis could be induced in tetraploid cells by two different Aurora B inhibitors. Furthermore, tetraploid cells were sensitive to Aurora B inhibition but were not affected by Aurora A inhibition. Interestingly, the underlying mechanism was due to mitotic slippage and the subsequent excessive genome reduplication. In support of this, abolition of cytokinesis with dihydrocytochalasin B resulted in similar effects on tetraploid cells as Aurora B inhibition. These results indicate that inhibition of Aurora B or cytokinesis can promote apoptosis effectively in polyploid cancer cells.

PMID: 22722494 [PubMed - in process]

chir-258 dovitinib dna-pk

Signal Transduction Pathways (MAPKs, NF-?B, and C/EBP) Regulating COX-2 Expression in Nasal Fibroblasts from Asthma Patients with Aspirin Intolerance.

Signal Transduction Pathways (MAPKs, NF-?B, and C/EBP) Regulating COX-2 Expression in Nasal Fibroblasts from Asthma Patients with Aspirin Intolerance.

PLoS One. 2012;7(12):e51281

Authors: Garcia-Garcia FJ, Mullol J, Perez-Gonzalez M, Pujols L, Alobid I, Roca-Ferrer J, Picado C

PMID: 23240010 [PubMed - in process]

coxinhibitors c-met inhibitors zm-447439

Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.

Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.

J Transl Med. 2012 Dec 10;10(1):245

Authors: Chen ZY, Shi M, Peng LX, Wei W, Li XJ, Guo ZX, Li SH, Zhong C, Qian CN, Guo RP

PMID: 23228017 [PubMed - as supplied by publisher]

coxinhibitors c-met inhibitors zm-447439

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