5-alpha-reductase: 2013-01-13

2013年1月19日星期六

Analysis of synaptic growth and function in Drosophila with an extended larval stage.

Analysis of synaptic growth and function in Drosophila with an extended larval stage.

J Neurosci. 2012 Oct 3;32(40):13776-86

Authors: Miller DL, Ballard SL, Ganetzky B

Abstract
The Drosophila larval neuromuscular junction (NMJ) is a powerful system for the genetic and molecular analysis of neuronal excitability, synaptic transmission, and synaptic development. However, its use for studying age-dependent processes, such as maintenance of neuronal viability and synaptic stability, are temporally limited by the onset of pupariation and metamorphosis. Here we characterize larval NMJ growth, growth regulation, structure, and function in a developmental variant with an extended third instar (ETI). RNAi-knockdown of the prothoracicotropic hormone receptor, torso, in the ring gland of developing larvae leaves the timing of first and second instar molts largely unchanged, but triples duration of the third instar from 3 to 9.5 d (McBrayer et al., 2007; Rewitz et al., 2009). During this ETI period, NMJs undergo additional growth (adding >50 boutons/NMJ), and this growth remains under the control of the canonical regulators Highwire and the TGF?/BMP pathway. NMJ growth during the ETI period occurs via addition of new branches, satellite boutons, and interstitial boutons, and continues even after muscle growth levels off. Throughout the ETI, organization of synapses and active zones remains normal, and synaptic transmission is unchanged. These results establish the ETI larval system as a viable model for studying motor neuron diseases and for investigating time-dependent effects of perturbations that impair mechanisms of neuroprotection, synaptic maintenance, and response to neural injury.

PMID: 23035089 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

The microRNA miR-7 regulates Tramtrack69 in a developmental switch in Drosophila follicle cells.

The microRNA miR-7 regulates Tramtrack69 in a developmental switch in Drosophila follicle cells.

Development. 2013 Jan 16;

Authors: Huang YC, Smith L, Poulton J, Deng WM

Abstract
Development in multicellular organisms includes both small incremental changes and major switches of cell differentiation and proliferation status. During Drosophila oogenesis, the follicular epithelial cells undergo two major developmental switches that cause global changes in the cell-cycle program. One, the switch from the endoreplication cycle to a gene-amplification phase, during which special genomic regions undergo repeated site-specific replication, is attributed to Notch downregulation, ecdysone signaling activation and upregulation of the zinc-finger protein Tramtrack69 (Ttk69). Here, we report that the microRNA miR-7 exerts an additional layer of regulation in this developmental switch by regulating Ttk69 transcripts. miR-7 recognizes the 3_ UTR of ttk69 transcripts and regulates Ttk69 expression in a dose-dependent manner. Overexpression of miR-7 effectively blocks the switch from the endocycle to gene amplification through its regulation of ttk69. miR-7 and Ttk69 also coordinate other cell differentiation events, such as vitelline membrane protein expression, that lead to the formation of the mature egg. Our studies reveal the important role miR-7 plays in developmental decision-making in association with signal-transduction pathways.

PMID: 23325762 [PubMed - as supplied by publisher]

dovitinib dna-pk coxinhibitors

Rhynchophylline attenuates LPS-induced pro-inflammatory responses through down-regulation of MAPK/NF-?B signaling pathways in primary microglia.

Rhynchophylline attenuates LPS-induced pro-inflammatory responses through down-regulation of MAPK/NF-?B signaling pathways in primary microglia.

Phytother Res. 2012 Oct;26(10):1528-33

Authors: Song Y, Qu R, Zhu S, Zhang R, Ma S

Abstract
Excessive activation of microglial cells has been implicated in various types of neuroinflammation. Suppression of microglial activation would have therapeutic benefits, leading to the alleviation of the progression of neurodegeneration. In this study, the inhibitory effects of rhynchophylline (RIN), a tetracyclic oxindole alkaloid component isolated from Uncaria rhynchophylla (Miq.) Jacks., on the production of pro-inflammatory mediators were investigated in lipopolysaccharide (LPS)-stimulated microglia. The results showed that RIN markedly reduced the production of nitric oxide (NO), prostaglandins E(2) (PGE(2) ), monocyte chemoattractant protein (MCP-1), tumor necrosis factor-? (TNF-?) and interleukin-1? (IL-1?) in LPS-activated microglia. The mRNA expression levels of iNOS and COX-2 were also depressed by RIN in a concentration-dependent manner. Further studies revealed that RIN blocked I?B? phosphorylation and degradation, inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs). In summary, these data suggest that RIN suppresses inflammatory responses of microglia and may act as a potential therapeutic agent for various neurodegenerative diseases involving neuroinflammation.

PMID: 22322985 [PubMed - indexed for MEDLINE]

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

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]

ecdysone chir-258 dovitinib

2013年1月18日星期五

Obesity and risk of recurrence or death after adjuvant endocrine therapy with letrozole or tamoxifen in the breast international group 1-98 trial.

Obesity and risk of recurrence or death after adjuvant endocrine therapy with letrozole or tamoxifen in the breast international group 1-98 trial.

J Clin Oncol. 2012 Nov 10;30(32):3967-75

Authors: Ewertz M, Gray KP, Regan MM, Ejlertsen B, Price KN, Th�rlimann B, Bonnefoi H, Forbes JF, Paridaens RJ, Rabaglio M, Gelber RD, Colleoni M, L�ng I, Smith IE, Coates AS, Goldhirsch A, Mouridsen HT

Abstract
PURPOSE: To examine the association of baseline body mass index (BMI) with the risk of recurrence or death in postmenopausal women with early-stage breast cancer receiving adjuvant tamoxifen or letrozole in the Breast International Group (BIG) 1-98 trial at 8.7 years of median follow-up.
PATIENTS AND METHODS: This report analyzes 4,760 patients with breast cancer randomly assigned to 5 years of monotherapy with letrozole or tamoxifen in the BIG 1-98 trial with available information on BMI at randomization. Multivariable Cox modeling assessed the association of BMI with disease-free survival, overall survival (OS), breast cancer-free interval, and distant recurrence-free interval and tested for treatment-by-BMI interaction. Median follow-up was 8.7 years.
RESULTS: Seventeen percent of patients have died. Obese patients (BMI ? 30 kg/m(2)) had slightly poorer OS (hazard ratio [HR] = 1.19; 95% CI, 0.99 to 1.44) than patients with normal BMI (< 25 kg/m(2)), whereas no trend in OS was observed in overweight (BMI 25 to < 30 kg/m(2)) versus normal-weight patients (HR = 1.02; 95% CI, 0.86 to 1.20). Treatment-by-BMI interactions were not statistically significant. The HRs for OS comparing obese versus normal BMI were HR = 1.22 (95% CI, 0.93 to 1.60) and HR = 1.18 (95% CI, 0.91 to 1.52) in the letrozole and tamoxifen groups, respectively.
CONCLUSION: There was no evidence that the benefit of letrozole over tamoxifen differed according to patients' BMI.

PMID: 23045588 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Evidence for therapeutic drug monitoring of targeted anticancer therapies.

Evidence for therapeutic drug monitoring of targeted anticancer therapies.

J Clin Oncol. 2012 Nov 10;30(32):4017-25

Authors: Gao B, Yeap S, Clements A, Balakrishnar B, Wong M, Gurney H

Abstract
Therapeutic drug monitoring (TDM) provides valuable guidance for dose adjustment of antibiotics, immunosuppressives, antiepileptics, and other drugs, but its use for traditional anticancer therapies has been limited. Perhaps the most important obstacle is the impractical requirement of multiple blood samples to adequately define systemic exposure of drugs that have a short elimination half-life and are given by intermittent intravenous injections. However, the newer targeted anticancer therapies have different pharmacokinetic (PK) and dosing characteristics compared with traditional cytotoxic drugs, making it possible to estimate the steady-state drug exposure with a single trough-level measurement. Recent evidence indicates that certain PK parameters, including trough levels, are correlated with clinical outcomes for many of these agents, including imatinib, sunitinib, rituximab, and cetuximab. Although the current evidence is insufficient to mandate TDM in routine practice, a concerted investigation should be encouraged to determine whether the steady-state trough measurements of targeted agents will have a practical place in the clinical care of patients with cancer.

PMID: 22927532 [PubMed - indexed for MEDLINE]

zm-447439 rad001 ecdysone

An autonomous chromatin/DNA-PK mechanism for localized DNA damage signaling in mammalian cells.

An autonomous chromatin/DNA-PK mechanism for localized DNA damage signaling in mammalian cells.

Nucleic Acids Res. 2013 Jan 15;

Authors: Mu�oz DP, Kawahara M, Yannone SM

Abstract
Rapid phosphorylation of histone variant H2AX proximal to DNA breaks is an initiating event and a hallmark of eukaryotic DNA damage responses. Three mammalian kinases are known to phosphorylate H2AX in response to DNA damage. However, the mechanism(s) for damage-localized phosphorylation remains incompletely understood. The DNA-dependent protein kinase (DNA-PK) is the most abundant H2AX-modifying kinases and uniquely activated by binding DNA termini. Here, we have developed a novel approach to examine enzyme activity and substrate properties by executing biochemical assays on intact cellular structures. We apply this approach to examine the mechanisms of localized protein modification in chromatin within fixed cells. DNA-PK retains substrate specificity and independently generates break-localized ?H2AX foci in chromatin. In situ DNA-PK activity recapitulates localization and intensity of in vivo H2AX phosphorylation and requires no active cellular processes. Nuclease treatments or addition of exogenous DNA resulted in genome-wide H2AX phosphorylation, showing that DNA termini dictated the locality of H2AX phosphorylation in situ. DNA-PK also reconstituted focal phosphorylation of structural maintenance of chromatin protein 1, but not activating transcription factor 2. Allosteric regulation of DNA-PK by DNA termini protruding from chromatin constitutes an autonomous mechanism for break-localized protein phosphorylation that generates sub-nuclear foci. We discuss generalized implications of this mechanism in localizing mammalian DNA damage responses.

PMID: 23325849 [PubMed - as supplied by publisher]

rad001 ecdysone chir-258

ATP Mediates NADPH Oxidase/ROS Generation and COX-2/PGE(2) Expression in A549 Cells: Role of P2 Receptor-Dependent STAT3 Activation.

ATP Mediates NADPH Oxidase/ROS Generation and COX-2/PGE(2) Expression in A549 Cells: Role of P2 Receptor-Dependent STAT3 Activation.

PLoS One. 2013;8(1):e54125

Authors: Cheng SE, Lee IT, Lin CC, Wu WL, Hsiao LD, Yang CM

Abstract
BACKGROUND: Up-regulation of cyclooxygenase (COX)-2 and its metabolite prostaglandin E(2) (PGE(2)) are frequently implicated in lung inflammation. Extracellular nucleotides, such as ATP have been shown to act via activation of P2 purinoceptors, leading to COX-2 expression in various inflammatory diseases, such as lung inflammation. However, the mechanisms underlying ATP-induced COX-2 expression and PGE(2) release remain unclear.
PRINCIPAL FINDINGS: Here, we showed that ATP?S induced COX-2 expression in A549 cells revealed by western blot and real-time PCR. Pretreatment with the inhibitors of P2 receptor (PPADS and suramin), PKC (G�6983, G�6976, Ro318220, and Rottlerin), ROS (Edaravone), NADPH oxidase [diphenyleneiodonium chloride (DPI) and apocynin], Jak2 (AG490), and STAT3 [cucurbitacin E (CBE)] and transfection with siRNAs of PKC?, PKC?, PKC?, p47(phox), Jak2, STAT3, and cPLA(2) markedly reduced ATP?S-induced COX-2 expression and PGE(2) production. In addition, pretreatment with the inhibitors of P2 receptor attenuated PKCs translocation from the cytosol to the membrane in response to ATP?S. Moreover, ATP?S-induced ROS generation and p47(phox) translocation was also reduced by pretreatment with the inhibitors of P2 receptor, PKC, and NADPH oxidase. On the other hand, ATP?S stimulated Jak2 and STAT3 activation which were inhibited by pretreatment with PPADS, suramin, G�6983, G�6976, Ro318220, GF109203X, Rottlerin, Edaravone, DPI, and apocynin in A549 cells.
SIGNIFICANCE: Taken together, these results showed that ATP?S induced COX-2 expression and PGE(2) production via a P2 receptor/PKC/NADPH oxidase/ROS/Jak2/STAT3/cPLA(2) signaling pathway in A549 cells. Increased understanding of signal transduction mechanisms underlying COX-2 gene regulation will create opportunities for the development of anti-inflammation therapeutic strategies.

PMID: 23326583 [PubMed - in process]

chir-258 dovitinib dna-pk

Cyclooxygenase-2 Generates the Endogenous Mutagen trans-4-Hydroxy-2-nonenal in Enterococcus faecalis-infected Macrophages.

Cyclooxygenase-2 Generates the Endogenous Mutagen trans-4-Hydroxy-2-nonenal in Enterococcus faecalis-infected Macrophages.

Cancer Prev Res (Phila). 2013 Jan 15;

Authors: Wang X, Allen T, Yang Y, Moore DR, Huycke MM

Abstract
Infection of macrophages by the human intestinal commensal Enterococcus faecalis generates DNA damage and chromosomal instability in mammalian cells through bystander effects. These effects are characterized by clastogenesis and damage to mitotic spindles in target cells and are mediated, in part, by trans-4-hydroxy-2-nonenal (4-HNE). In this study we investigated the role of cyclooxygenase (COX) and lipoxygenase (LOX) in producing this reactive aldehyde using E. faecalis-infected macrophages and interleukin-10 knockout mice colonized with this commensal. 4-HNE production by E. faecalis-infected macrophages was significantly reduced by COX and LOX inhibitors. The infection of macrophages led to decreased Cox1 and Alox5 expression while COX-2 and 4-HNE increased. Silencing Alox5 and Cox1 with gene-specific siRNAs had no effect on 4-HNE production. In contrast, silencing Cox2 significantly decreased 4-HNE production by E. faecalis-infected macrophages. Depleting intracellular glutathione increased 4-HNE production by these cells. Next, to confirm COX-2 as a source for 4-HNE, we assayed the products generated by recombinant human COX-2 and found 4-HNE in a concentration-dependent manner using arachidonic acid as a substrate. Finally, tissue macrophages in colon biopsies from interleukin-10 knockout mice colonized with E. faecalis were positive for COX-2 by immunohistochemical staining. This was associated with increased staining for 4-HNE-protein adducts in surrounding stroma. These data show that E. faecalis, a human intestinal commensal, can trigger macrophages to produce 4-HNE through COX-2. Importantly, it reinforces the concept of COX-2 as a procarcinogenic enzyme capable of damaging DNA in target cells through bystander effects that contribute to colorectal carcinogenesis.

PMID: 23321929 [PubMed - as supplied by publisher]

chir-258 dovitinib dna-pk

2013年1月17日星期四

Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors.

Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors.

Cancer Discov. 2012 Mar;2(3):270-87

Authors: Sennino B, Ishiguro-Oonuma T, Wei Y, Naylor RM, Williamson CW, Bhagwandin V, Tabruyn SP, You WK, Chapman HA, Christensen JG, Aftab DT, McDonald DM

Abstract
Invasion and metastasis increase after the inhibition of VEGF signaling in some preclinical tumor models. In the present study we asked whether selective VEGF inhibition is sufficient to increase invasion and metastasis and whether selective c-Met inhibition is sufficient to block this effect. Treatment of pancreatic neuroendocrine tumors in RIP-Tag2 mice with a neutralizing anti-VEGF antibody reduced tumor burden but increased tumor hypoxia, hypoxia-inducible factor-1?, and c-Met activation and also increased invasion and metastasis. However, invasion and metastasis were reduced by concurrent inhibition of c-Met by PF-04217903 or PF-02341066 (crizotinib). A similar benefit was found in orthotopic Panc-1 pancreatic carcinomas treated with sunitinib plus PF-04217903 and in RIP-Tag2 tumors treated with XL184 (cabozantinib), which simultaneously blocks VEGF and c-Met signaling. These findings document that invasion and metastasis are promoted by selective inhibition of VEGF signaling and can be reduced by the concurrent inhibition of c-Met. SIGNIFICANCE: This report examines the mechanism of increased tumor aggressiveness after anti-VEGF therapy and presents evidence for roles of vascular pruning, hypoxia, and c-Met activation. The results show that simultaneous inhibition of c-Met and VEGF signaling not only slows tumor growth but also reduces invasion and metastasis.

PMID: 22585997 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

Anti-VEGF therapy revived by c-Met inhibition, but is c-Met the answer?

Anti-VEGF therapy revived by c-Met inhibition, but is c-Met the answer?

Cancer Discov. 2012 Mar;2(3):211-3

Authors: Lynn KD, Brekken RA

Abstract
A new study by Sennino and colleagues demonstrates that selective VEGF inhibition via the use of an anti-VEGF antibody is sufficient to increase invasion and metastasis in a c-Met-dependent manner. Anti-VEGF therapy induced tumor hypoxia, hypoxia-inducible factor 1?, and c-Met activation in the RIP-Tag2 model of neuroendocrine pancreatic cancer. Selective c-Met inhibition was sufficient to block these effects, providing a potential mechanism for and solution to overcome increased invasion in the face of anti-VEGF therapy.

PMID: 22585992 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors

Cyclooxygenase-2 Generates the Endogenous Mutagen trans-4-Hydroxy-2-nonenal in Enterococcus faecalis-infected Macrophages.

Cyclooxygenase-2 Generates the Endogenous Mutagen trans-4-Hydroxy-2-nonenal in Enterococcus faecalis-infected Macrophages.

Cancer Prev Res (Phila). 2013 Jan 15;

Authors: Wang X, Allen T, Yang Y, Moore DR, Huycke MM

PMID: 23321929 [PubMed - as supplied by publisher]

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]

c-met inhibitors zm-447439 rad001

2013年1月16日星期三

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]

dna-pk coxinhibitors c-met inhibitors

Hemimegalencephaly: foetal tauopathy with mTOR hyperactivation and neuronal lipidosis.

Hemimegalencephaly: foetal tauopathy with mTOR hyperactivation and neuronal lipidosis.

Folia Neuropathol. 2012;50(4):330-45

Authors: Sarnat H, Flores-Sarnat L, Crino P, Hader W, Bello-Espinosa L

Abstract
Background: Hemimegalencephaly (HME) is a hamartomatous malformation of one cerebral hemisphere. As this is a disorder of cellular growth and lineage, we sought evidence of an early ontogenetic disturbance of microtubular assembly or function. Material and methods: Three male infants with HME had brain resections for refractory epilepsy. One died postoperatively at 2.5 months and an autopsy was performed. Two were isolated cases and one has Proteus syndrome. The phosphorylated form of the microtubule-associated protein tau was studied, transmission electron microscopy (EM) was performed, and activation of the mTOR pathway was defined. Results: The hippocampus and neocortex of HME exhibited cytoarchitectural abnormalities and intense tau immunoreactivity. The post-mortem non-HME hemisphere exhibited sparse dysmorphic tau-reactive cortical neurones, intense only in the cingulate gyrus, a few isolated dysmorphic white matter neurons and none in subcortical structures. Numerous enlarged and dysmorphic cells exhibited P-4E-BP1 and phosphoribosomal P-S6 immunoreactivity, indicating mTOR activation. Control brains were negative for tau expression and mTOR activation. EM in each case showed abundant lipid in neurones and astrocytic end-feet on capillaries, and well-preserved mitochondria; oil red O in frozen sections and semi-thin sections also showed lipid storage by light microscopy. Conclusions: Because HME tissue exhibited enhanced levels of phosphorylated tau protein and evidence of mTOR hyperactivation, we propose that the pathogenesis of HME may involve an early defect in microtubules, likely related to the AKT3 gene. Lipidosis of neurones and glia suggests metabolic impairment of yet undetermined type and relation to tauopathy in HME. Perinatal treatment of HME with everolimus theoretically is plausible.

PMID: 23319189 [PubMed - in process]

zm-447439 rad001 ecdysone

Disposition and metabolism of 14C-dovitinib (TKI258), an inhibitor of FGFR and VEGFR, after oral administration in patients with advanced solid tumors.

Disposition and metabolism of 14C-dovitinib (TKI258), an inhibitor of FGFR and VEGFR, after oral administration in patients with advanced solid tumors.

Cancer Chemother Pharmacol. 2012 Nov;70(5):653-63

Authors: Dubbelman AC, Upthagrove A, Beijnen JH, Marchetti S, Tan E, Krone K, Anand S, Schellens JH

Abstract
PURPOSE: This study investigated the metabolism and excretion of dovitinib (TKI258), a tyrosine kinase inhibitor that inhibits fibroblast, vascular endothelial, and platelet-derived growth factor receptors, in patients with advanced solid tumors.
METHODS: Four patients (cohort 1) received a single 500 mg oral dose of (14)C-dovitinib, followed by the collection of blood, urine, and feces for ?10�days. Radioactivity concentrations were measured by liquid scintillation counting and plasma concentrations of dovitinib by liquid chromatography-tandem mass spectrometry. Both techniques were applied for metabolite profiling and identification. A continuous-dosing extension phase (nonlabeled dovitinib 400�mg daily) was conducted with the 3 patients from cohort 1 and 9 additional patients from cohort 2.
RESULTS: The majority of radioactivity was recovered in feces (mean 61�%; range 52-69�%), as compared with urine (mean 16�%; range 13-21�%). Only 6-19�% of the radioactivity was recovered in feces as unchanged dovitinib, suggesting high oral absorption. (14)C-dovitinib was eliminated predominantly via oxidative metabolism, with prominent primary biotransformations including hydroxylation on the fluorobenzyl ring and N-oxidation and carbon oxidation on the methylpiperazine moiety. Dovitinib was the most prominent radioactive component in plasma. The high apparent volume of distribution (2,160 L) may indicate that dovitinib distributes extensively to tissues. Adverse events were predominantly mild to moderate, and most common events included nausea, vomiting, constipation, diarrhea, and fatigue.
CONCLUSIONS: Dovitinib was well absorbed, extensively distributed, and eliminated mainly by oxidative metabolism, followed by excretion, predominantly in feces. The adverse events were as expected for this class of drug.

PMID: 23010851 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

MET Is Required for the Maximal Action of 20-Hydroxyecdysone during Bombyx Metamorphosis.

MET Is Required for the Maximal Action of 20-Hydroxyecdysone during Bombyx Metamorphosis.

PLoS One. 2012;7(12):e53256

Authors: Guo E, He Q, Liu S, Tian L, Sheng Z, Peng Q, Guan J, Shi M, Li K, Gilbert LI, Wang J, Cao Y, Li S

Abstract
Little is known about how the putative juvenile hormone (JH) receptor, the bHLH-PAS transcription factor MET, is involved in 20-hydroxyecdysone (20E; the molting hormone) action. Here we report that two MET proteins found in the silkworm, Bombyx mori, participate in 20E signal transduction. Met is 20E responsive and its expression peaks during molting and pupation, when the 20E titer is high. As found with results from RNAi knockdown of EcR-USP (the ecdysone receptor genes), RNAi knockdown of Met at the early wandering stage disrupts the 20E-triggered transcriptional cascade, preventing tissue remodeling (including autophagy, apoptosis and destruction of larval tissues and generation of adult structures) and causing lethality during the larval-pupal transition. MET physically interacts with EcR-USP. Moreover, MET, EcR-USP and the 20E-response element (EcRE) form a protein-DNA complex, implying that MET might modulate 20E-induced gene transcription by interacting with EcR-USP. In conclusion, the 20E induction of MET is required for the maximal action of 20E during Bombyx metamorphosis.

PMID: 23300902 [PubMed - in process]

dna-pk coxinhibitors c-met inhibitors

2013年1月15日星期二

Aspirin attenuates spontaneous recurrent seizures and inhibits hippocampal neuronal loss, mossy fiber sprouting and aberrant neurogenesis following pilocarpine-induced status epilepticus in rats.

Aspirin attenuates spontaneous recurrent seizures and inhibits hippocampal neuronal loss, mossy fiber sprouting and aberrant neurogenesis following pilocarpine-induced status epilepticus in rats.

Brain Res. 2012 Aug 21;1469:103-13

Authors: Ma L, Cui XL, Wang Y, Li XW, Yang F, Wei D, Jiang W

Abstract
Accumulating data suggest that inflammation may contribute to epileptogenesis in experimental models as well as in humans. However, whether anti-inflammatory treatments can prevent epileptogenesis still remains controversial. Here, we examined the anti-epileptogenic effect and possible mechanisms of aspirin, a non-selective Cyclooxygenase (COX) inhibitor, in a rat model of lithium-pilocarpine-induced status epilepticus (SE). Epileptic rats were treated with aspirin (20mg/kg) at 0h, 3h, or 24h after the termination of SE, followed by once daily treatment for the subsequent 20 days. We found that aspirin treatment significantly reduced the frequency and duration of spontaneous recurrent seizures during the chronic epileptic phase. Hippocampal neuronal loss five weeks after SE was also attenuated in the CA1, CA3 and hilus following aspirin administration. Furthermore, the aberrant migration of newly generated granule cells and the formation of hilar basal dendrites were prevented by aspirin. Treatment with aspirin starting at 3h or 24h after SE also suppressed the development of mossy fiber sprouting. These findings suggest the possibility of a relative broad time-window for aspirin intervention in the epileptogenic process after injury. Aspirin may serve as a potential adjunctive therapy for individuals susceptible to chronic epilepsy.

PMID: 22765917 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

Should duration of dual antiplatelet therapy depend on the type and/or potency of implanted stent? A pre-specified analysis from the PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY (PRODIGY).

Should duration of dual antiplatelet therapy depend on the type and/or potency of implanted stent? A pre-specified analysis from the PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY (PRODIGY).

Eur Heart J. 2013 Jan 12;

Authors: Valgimigli M, Borghesi M, Tebaldi M, Vranckx P, Parrinello G, Ferrari R, for the PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY (PRODIGY) Investigators

Abstract
AimsThe purpose of this pre-specified analysis of the PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY (PRODIGY) was to assess device-specific outcomes relative to different duration of dual antiplatelet therapy (DAPT) after Everolimus- (EES), Paclitaxel (PES), Zotarolimus- (ZES-S) eluting, or bare metal stents (BMS).Methods and resultsWe randomized 2013 patients to BMS, ZES-S, PES, or EES implantation. At 30 days, each stent group underwent up to 6 or 24 months clopidogrel therapy. The primary endpoint, which was a composite of death, myocardial infarction, or cerebrovascular accident, did not differ in patients receiving BMS [HR: 0.89 (95%CI: 0.54-1.45)], PES [HR: 0.74 (95%CI: 0.43-1.25)], or EES [HR: 0.63 (95%CI: 0.33-1.21)] implantation across DAPT groups, whereas it was significantly higher in ZES-S patients undergoing long when compared with short-term DAPT therapy (HR: 2.85, P = 0.0018), with positive interaction testing (P-value = 0.004). At the 6-month landmark analysis, heterogeneity across stent types persisted for the primary study endpoint and other secondary clinical outcomes, whereas patients receiving PES showed a significantly higher rate of definite, probable and definite, probable, possible stent thrombosis in the short DAPT regimen. No association in absolute or relative terms was noted between stent potency in inhibiting intimal hyperplasia and greater vulnerability to shorter DAPT therapy.ConclusionOur study suggests that optimal duration of DAPT may be stent-specific and it does not support a clear association between stent potency and vulnerability to shorter DAPT therapy.Trial Registration clinicaltrials.gov Identifier: NCT00611286. http://clinicaltrials.gov/ct2/show/NCT00611286?term=prodigy&rank=2.

PMID: 23315904 [PubMed - as supplied by publisher]

dna-pk coxinhibitors c-met inhibitors

Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial.

Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial.

Lancet. 2013 Jan 10;

Authors: Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, Sauter M, Nonomura N, Brakemeier S, de Vries PJ, Whittemore VH, Chen D, Sahmoud T, Shah G, Lincy J, Lebwohl D, Budde K

Abstract
BACKGROUND: Angiomyolipomas are slow-growing tumours associated with constitutive activation of mammalian target of rapamycin (mTOR), and are common in patients with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis. The insidious growth of these tumours predisposes patients to serious complications including retroperitoneal haemorrhage and impaired renal function. Everolimus, a rapamycin derivative, inhibits the mTOR pathway by acting on the mTOR complex 1. We compared the angiomyolipoma response rate on everolimus with placebo in patients with tuberous sclerosis or sporadic lymphanioleiomyomatosis-associated angiomyolipomata. METHODS: In this double-blind, placebo-controlled, phase 3 trial, patients aged 18 years or older with at least one angiomyolipoma 3 cm or larger in its longest diameter (defined by radiological assessment) and a definite diagnosis of tuberous sclerosis or sporadic lymphangioleiomyomatosis were randomly assigned, in a 2:1 fashion with the use of an interactive web response system, to receive oral everolimus 10 mg per day or placebo. The primary efficacy endpoint was the proportion of patients with confirmed angiomyolipoma response of at least a 50% reduction in total volume of target angiomyolipomas relative to baseline. This study is registered with ClinicalTrials.gov number NCT00790400. RESULTS: 118 patients (median age 31�0 years; IQR 18�0-61�0) from 24 centres in 11 countries were randomly assigned to receive everolimus (n=79) or placebo (n=39). At the data cutoff, double-blind treatment was ongoing for 98 patients; two main reasons for discontination were disease progression (nine placebo patients) followed by adverse events (two everolimus patients; four placebo patients). The angiomyolipoma response rate was 42% (33 of 79 [95% CI 31-53%]) for everolimus and 0% (0 of 39 [0-9%]) for placebo (response rate difference 42% [24-58%]; one-sided Cochran-Mantel-Haenszel test p<0�0001). The most common adverse events in the everolimus and placebo groups were stomatitis (48% [38 of 79], 8% [3 of 39], respectively), nasopharyngitis (24% [19 of 79] and 31% [12 of 39]), and acne-like skin lesions (22% [17 of 79] and 5% [2 of 39]). INTERPRETATION: Everolimus reduced angiomyolipoma volume with an acceptable safety profile, suggesting it could be a potential treatment for angiomyolipomas associated with tuberous sclerosis. FUNDING: Novartis Pharmaceuticals.

PMID: 23312829 [PubMed - as supplied by publisher]

chir-258 dovitinib dna-pk

Expression of angiogenic markers in the peripheral blood of patients with advanced breast cancer treated with weekly docetaxel.

Expression of angiogenic markers in the peripheral blood of patients with advanced breast cancer treated with weekly docetaxel.

Anticancer Res. 2012 Oct;32(10):4569-80

Authors: Korantzis I, Kalogeras KT, Papaxoinis G, Kotoula V, Koutras A, Soupos N, Papakostas P, Dionysopoulos D, Samantas E, Christodoulou C, Linardou H, Pectasides D, Fountzilas G

Abstract
BACKGROUND: Metronomic chemotherapy targets the inhibition of tumor growth primarily through antiangiogenic mechanisms. The aim of the present study was to investigate the antiangiogenic properties of weekly metronomic docetaxel administration in patients with metastatic breast cancer.
PATIENTS AND METHODS: In total, 157 patients with metastatic breast cancer received docetaxel at 35 mg/m(2) on a weekly basis as first-line treatment. Blood samples were collected before and during treatment. Plasma protein levels and peripheral blood mRNA expression of human epidermal growth factor-2 (HER2), interleukin-8 (IL8) and transforming growth factor beta-1 (TGF-?1) were measured by enzyme-linked immunosorbent assays (ELISA) and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), respectively in 127 patients and 39 healthy controls.
RESULTS: Sixty-one patients (38%) achieved an objective response (4% complete and 33% partial responses), 52 (33%) had stable disease, and in 27 patients (17%) the disease progressed. At a median follow-up of 33.5 months, 118 patients (74%) demonstrated disease progression and 94 (59%) had died. The median overall survival (OS) was 27.7 months, while the median progression-free survival (PFS) was 8.8 months. Median baseline plasma HER2 protein levels were significantly higher in patients than in controls (Mann-Whitney test, p=0.033). In addition, the median relative quantification (RQ) values for blood IL8 mRNA were significantly lower in patients (p<0.001) compared to healthy controls, while the median RQ values for TGF-?1 mRNA were significantly higher (p<0.001). Furthermore, plasma HER2 protein levels (Wilcoxon signed ranked test, p<0.001), as well as blood IL8 mRNA (p=0.026) and TGF-?1 mRNA levels (p=0.016) decreased significantly upon treatment. Univariate Cox regression analysis showed that high baseline plasma protein levels of IL8 were of adverse prognostic significance for OS (Wald's p=0.031), while high blood HER2 mRNA levels were marginally associated with longer OS (p=0.060). In multivariate analysis, plasma IL8 protein lost its prognostic significance, while high blood HER2 mRNA levels were associated with significantly improved OS (Wald's p=0.022).
CONCLUSION: Our study demonstrated a potential in vivo antiangiogenic activity of weekly docetaxel. Some interesting observations were made regarding the prognostic role of baseline plasma IL8 protein levels and blood HER2 mRNA levels, however, further research is required in order to validate these findings in larger cohorts, and to fully understand the angiogenic processes and optimize treatment strategies.

PMID: 23060588 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

A review of oral toxicity associated with mTOR inhibitor therapy in cancer patients.

A review of oral toxicity associated with mTOR inhibitor therapy in cancer patients.

Oral Oncol. 2013 Jan 8;

Authors: Martins F, de Oliveira MA, Wang Q, Sonis S, Gallottini M, George S, Treister N

Abstract
Aphthous-like stomatitis has been identified as one of the most common dose-limiting toxicities associated with mTOR inhibitor therapy in cancer patients. The objective of this study was to summarize the cumulative oral toxicities associated with mTOR inhibitors in published oncology trials with respect to dose, schedule, and need for dose modifications. A review of all oncology-related clinical trials of mTOR inhibitors was conducted and standardized data was abstracted from each study. 44 studies were included in the analysis with a total of 2822 patients treated with temsirolimus (19 studies), everolimus (20 studies), and ridaforolimus (five studies) for a wide range of malignancies. At least one adverse event (AE) occurred in 74.4% of patients. Mucositis was the most frequent AE overall (73.4%), the third most frequent severe AE (20.7%), accounting for 27.3% dose reductions and 13.1% of discontinuations, and the most frequent dose limiting toxicity (52.5%). Mucositis typically occurred during the first cycle of therapy and was graded as mild to moderate in approximately 90% of the patients; severe mucositis generally occurred at higher doses. There were no clear differences in mucositis among the three agents and in most cases lesions resolved spontaneously. Oral mucositis is a frequent complication of mTOR inhibitor therapy and a significant cause of dose reductions and discontinuations in oncology trials. Prevention and management strategies should be investigated to improve tolerability and better permit effective long-term regimens.

PMID: 23312237 [PubMed - as supplied by publisher]

dovitinib dna-pk coxinhibitors

2013年1月14日星期一

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

PMID: 22722494 [PubMed - in process]

coxinhibitors c-met inhibitors zm-447439

MET Is Required for the Maximal Action of 20-Hydroxyecdysone during Bombyx Metamorphosis.

MET Is Required for the Maximal Action of 20-Hydroxyecdysone during Bombyx Metamorphosis.

PLoS One. 2012;7(12):e53256

Authors: Guo E, He Q, Liu S, Tian L, Sheng Z, Peng Q, Guan J, Shi M, Li K, Gilbert LI, Wang J, Cao Y, Li S

PMID: 23300902 [PubMed - in process]

rad001 ecdysone chir-258

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

PMID: 22722494 [PubMed - in process]

chir-258 dovitinib dna-pk

ABO-incompatible heart transplantation in early childhood: An international multicenter study of clinical experiences and limits.

ABO-incompatible heart transplantation in early childhood: An international multicenter study of clinical experiences and limits.

J Heart Lung Transplant. 2013 Jan 7;

Authors: Urschel S, Larsen IM, Kirk R, Flett J, Burch M, Shaw N, Birnbaum J, Netz H, Pahl E, Matthews KL, Chinnock R, Johnston JK, Derkatz K, West LJ

Abstract
BACKGROUND: Intentional blood group (BG)-incompatible (ABOi) heart transplantation in childhood is emerging in many centers. Safety limits remain undetermined. In this multicenter study we have compiled experience on clinical and immunologic boundaries. METHODS: Data from six centers in Europe and North America on ABOi transplantation were collected in a standardized survey. RESULTS: Fifty-eight ABOi transplants were performed in 57 patients. Median age at transplant was 6.8 months (0.03 to 90 months); post-transplant follow-up was 37.7 months (0.46 to 117 months), accumulating 188 patient-years. Forty-seven percent of the patients received pretransplant mechanical circulatory support. Donors were either blood group A (n = 25), B (n = 18) or AB (n = 15). The median peak antibody titer to the donor BG pretransplant was 1:8 (0 to 1:64) for anti-A and 1:4 (0 to 1:32) for anti-B. Titers against the donor BG were lower post- than pretransplant in B recipients (p = 0.02), whereas third-party antibodies in BG O recipients developed normally post-transplant. Induction immunosuppression included anti-thymocyte globulin (61%), basiliximab (32%) or none (7%). All patients received calcineurin inhibitors, including 62% with mycophenolate mofetil, 10% with azathioprine, 2% with everolimus and 24% with steroids. There were 4 episodes of cellular rejection (Grade?2R) and 7 antibody-mediated rejections. Five patients underwent antibody removal post-transplant. One patient developed severe graft vasculopathy. Freedom from death or retransplantation was 100%/96%/69% at 1/5/10 years. No graft loss was attributed to BG antibodies. CONCLUSIONS: Successful ABOi heart transplantation can be performed at an older age and with higher isohemagglutinin titers than initially assumed and using similar immunosuppressive regimens as for ABO-compatible transplants. Rejection and graft vasculopathy are rare. Persistently low titers of antibodies to the donor BG post-transplant suggest elements of tolerance and/or accommodation.

PMID: 23305695 [PubMed - as supplied by publisher]

zm-447439 rad001 ecdysone

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]

c-met inhibitors zm-447439 rad001

2013年1月13日星期日

Disposition and metabolism of 14C-dovitinib (TKI258), an inhibitor of FGFR and VEGFR, after oral administration in patients with advanced solid tumors.

Disposition and metabolism of 14C-dovitinib (TKI258), an inhibitor of FGFR and VEGFR, after oral administration in patients with advanced solid tumors.

Cancer Chemother Pharmacol. 2012 Nov;70(5):653-63

Authors: Dubbelman AC, Upthagrove A, Beijnen JH, Marchetti S, Tan E, Krone K, Anand S, Schellens JH

PMID: 23010851 [PubMed - indexed for MEDLINE]

zm-447439 rad001 ecdysone

Interaction between polymorphisms of DNA repair genes significantly modulated bladder cancer risk.

Interaction between polymorphisms of DNA repair genes significantly modulated bladder cancer risk.

Int J Med Sci. 2012;9(6):498-505

Authors: Zhi Y, Yu J, Liu Y, Wei Q, Yuan F, Zhou X, Song B, Chen Z, Yang J

Abstract
DNA repair is a primary defense mechanism against damage caused by exogenous and endogenous sources. We examined the associations between bladder cancer and 7 polymorphisms from 5 genes involved in the maintenance of genetic stability (MMR: MLH1-93G>A; BER: XRCC1--77T>C and Arg399Gln; NER:XPC Lys939Gln and PAT +/-; DSBR:ATM G5557A and XRCC7 G6721T) in 302 incident bladder cancer cases and 311 hospital controls. Genotyping was done using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. The homozygous variant of XRCC7 G6721T (Odds Ratio [OR]: 2.36; 95% Confidence Interval [CI]: 1.13-4.92) was associated with increased bladder cancer risk. In an analysis of combined genotypes, the combination of XRCC1Arg399Gln (Gln allele) with XRCC1-77 T/T led to an increase in risk (OR: 1.61; 95% CI: 1.10-2.36). Moreover, when the XPCLys939Gln (Gln allele) (nucleotide excision repair [NER]) was present together with XRCC7 (T allele) (double strand break repair [DSBR]), the bladder cancer risk dramatically increased (OR: 4.42; 95% CI: 1.23-15.87). Our results suggest that there are multigenic variations in the DNA repair pathway involved in bladder cancer susceptibility, despite the existence of ethnic group differences.

PMID: 22927776 [PubMed - indexed for MEDLINE]

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]

rad001 ecdysone chir-258

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

Acquired resistance to sunitinib in human renal cell carcinoma cells is mediated by constitutive activation of signal transduction pathways associated with tumour cell proliferation.

Acquired resistance to sunitinib in human renal cell carcinoma cells is mediated by constitutive activation of signal transduction pathways associated with tumour cell proliferation.

BJU Int. 2013 Jan 10;

Authors: Sakai I, Miyake H, Fujisawa M

Abstract
WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Although there have been a few studies investigating the molecular mechanism mediating the acquisition of resistance to molecular-targeted agents, including sunitinib, by renal cell carcinoma (RCC) cells, this mechanism remains largely unclear. The maintenance of protein kinase activation during sunitinib treatment may be involved in the acquisition of a phenotype resistant to sunitinib in RCC, and additional treatment with agents targeting activated protein kinases could be a promising approach for overcoming resistance to sunitinib in RCC. OBJECTIVE: To characterise the mechanism involved in the acquired resistance to sunitinib, a potential inhibitor of multiple receptor tyrosine kinases (RTKs), in renal cell carcinoma (RCC). MATERIALS AND METHODS: A parental human RCC cell line, ACHN (ACHN/P), was continuously exposed to increasing doses of sunitinib, and a cell line resistant to sunitinib (ACHN/R), showing an ?5-fold higher IC(50) (concentration that reduces the effect by 50%) than that of ACHN/P, was developed. RESULTS: ACHN/R appeared to acquire significant cross resistance to sorafenib; however, there were no significant differences in sensitivities to the Mammalian target of rapamycin inhibitors, temsirolimus and everolimus, between ACHN/P and ACHN/R. After sunitinib treatment, the expression levels of phosphorylated Akt and p44/42 mitogen-activated protein kinase in ACHN/P, but not those in ACHN/R, were significantly inhibited. RTK assay showed that treatment of ACHN/P with sunitinib resulted in the marked downregulation of several phosphorylated RTKs compared with that of ACHN/R. Additional treatment with a specific inhibitor of Akt significantly increased the sensitivity of ACHN/R to sunitinib, but not that of ACHN/P. There were no significant differences between in vivo growth patterns of ACHN/P and ACHN/R in mice before and after the administration of sunitinib; however, the proportion of cells positive for TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) staining in ACHN/P tumour was significantly greater than that in ACHN/R tumour in mice treated with sunitinib. CONCLUSION: The maintenance of protein kinase activation during sunitinib treatment may be involved in the acquisition of resistant phenotype to sunitinib in RCC cells.

PMID: 23305097 [PubMed - as supplied by publisher]

coxinhibitors c-met inhibitors zm-447439

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