5-alpha-reductase: 2013-04-21

2013年4月27日星期六

Sorafenib and Everolimus in Advanced Clear Cell Renal Carcinoma: A Phase I/II Trial of the SCRI Oncology Research Consortium.

Sorafenib and Everolimus in Advanced Clear Cell Renal Carcinoma: A Phase I/II Trial of the SCRI Oncology Research Consortium.

Cancer Invest. 2013 Apr 24;

Authors: Hainsworth JD, Waterhouse DM, Penley WC, Shipley DL, Thompson DS, Webb CD, Anthony Greco F

Abstract
Purpose: To evaluate the feasibility and efficacy of sorafenib and everolimus in renal cell carcinoma (RCC). Methods: Patients with advanced RCC and ?1 previous targeted therapy were treated. Results: Maximum tolerated doses were sorafenib 200�mg PO BID, everolimus 35�mg PO once weekly. Dose-limiting toxicity was hand-foot syndrome. The response rate was 13%; median PFS was 5.45 months (95% CI: 3.8-7.6). Skin toxicity, fatigue, hypertension, proteinuria, and mucositis (usually Grade 2) were common. Conclusions: Fifty percent doses of sorafenib and everolimus were required when these drugs were combined. No increase in efficacy was suggested; toxicity was modestly increased.

PMID: 23614653 [PubMed - as supplied by publisher]

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Going beyond EGFR.

Going beyond EGFR.

Ann Oncol. 2012 Sep;23 Suppl 10:x197-203

Authors: Zimmermann S, Peters S

Abstract
a substantial proportion of non-small-cell lung cancer (NSCLC), and adenocarcinoma in particular, depends on a so-called 'driver mutation' for their malignant phenotype. This genetic alteration induces and sustains tumorigenesis, and targeting of its protein product can result in growth inhibition, tumor response and increased patient survival. NSCLC can thus be subdivided into clinically relevant molecular subsets. Mutations in EGFR best illustrate the therapeutic relevance of molecular classification. This article reviews the scope of presently known driving molecular alterations, including ROS1, BRAF, KRAS, HER2 and PIK3CA, with a special emphasis on aLK rearrangements, and outlines their potential therapeutic applications.

PMID: 22987962 [PubMed - indexed for MEDLINE]

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Image-based high-throughput screening for inhibitors of angiogenesis.

Image-based high-throughput screening for inhibitors of angiogenesis.

Methods Mol Biol. 2013;931:139-51

Authors: Evensen L, Link W, Lorens JB

Abstract
Automated multicolor fluorescence microscopy facilitates high-throughput quantitation of cellular parameters of complex, organotypic systems. In vitro co-cultured vascular cells form capillary-like networks that model facets of angiogenesis, making it an attractive alternative for anti-angiogenic drug discovery. We have adapted this angiogenesis assay system to a high-throughput format to enable automated image-based high-throughput screening of live primary human vascular cell co-cultures with chemical libraries for anti-angiogenic drug discovery. Protocols are described for setup of a fluorescence-based co-culture assay, live cell image acquisition, image analysis of morphological parameters, and screening data handling.

PMID: 23027002 [PubMed - indexed for MEDLINE]

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Impact of the integrin signaling adaptor protein NEDD9 on prognosis and metastatic behavior of human lung cancer.

Impact of the integrin signaling adaptor protein NEDD9 on prognosis and metastatic behavior of human lung cancer.

Clin Cancer Res. 2012 Nov 15;18(22):6326-38

Authors: Kondo S, Iwata S, Yamada T, Inoue Y, Ichihara H, Kichikawa Y, Katayose T, Souta-Kuribara A, Yamazaki H, Hosono O, Kawasaki H, Tanaka H, Hayashi Y, Sakamoto M, Kamiya K, Dang NH, Morimoto C

Abstract
PURPOSE: In a substantial population of non-small cell lung cancer (NSCLC), expression and activation of EGF receptor (EGFR) have been reported and is regarded as a novel molecular target. A growing body of evidence has shown the signaling crosstalk between EGFR and integrins in cellular migration and invasion. NEDD9 is an integrin signaling adaptor protein composed of multiple domains serving as substrate for a variety of tyrosine kinases. In the present study, we aimed at elucidating a role of NEDD9 in the signaling crosstalk between EGFR and integrins.
EXPERIMENTAL DESIGN: Using NSCLC cell lines, we conducted immunoblotting and cellular migration/invasion assay in vitro. Next, we analyzed metastasis assays in vivo by the use of xenograft transplantation model. Finally, we retrospectively evaluated clinical samples and records of patients with NSCLCs.
RESULTS: We showed that tyrosine phosphorylation of NEDD9 was reduced by the inhibition of EGFR in NSCLC cell lines. Overexpression of constitutively active EGFR caused tyrosine phosphorylation of NEDD9 in the absence of integrin stimulation. By gene transfer and gene knockdown, we showed that NEDD9 plays a pivotal role in cell migration and invasion of those cells in vitro. Furthermore, overexpression of NEDD9 promoted lung metastasis of an NSCLC cell line in NOD/Shi-scid, IL-2R?(null) mice (NOG) mice. Finally, univariate and multivariate Cox model analysis of NSCLC clinical specimens revealed a strong correlation between NEDD9 expression and recurrence-free survival as well as overall survival.
CONCLUSION: Our data thus suggest that NEDD9 is a promising biomarker for the prognosis of NSCLCs and its expression can promote NSCLC metastasis.

PMID: 23037767 [PubMed - indexed for MEDLINE]

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Sorafenib and Everolimus in Advanced Clear Cell Renal Carcinoma: A Phase I/II Trial of the SCRI Oncology Research Consortium.

Sorafenib and Everolimus in Advanced Clear Cell Renal Carcinoma: A Phase I/II Trial of the SCRI Oncology Research Consortium.

Cancer Invest. 2013 Apr 24;

Authors: Hainsworth JD, Waterhouse DM, Penley WC, Shipley DL, Thompson DS, Webb CD, Anthony Greco F

PMID: 23614653 [PubMed - as supplied by publisher]

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2013年4月26日星期五

Phase I study of oral gemcitabine prodrug (LY2334737) in Japanese patients with advanced solid tumors.

Phase I study of oral gemcitabine prodrug (LY2334737) in Japanese patients with advanced solid tumors.

Cancer Chemother Pharmacol. 2013 Apr 25;

Authors: Yamamoto N, Nokihara H, Yamada Y, Uenaka K, Sekiguchi R, Makiuchi T, Slapak CA, Benhadji KA, Tamura T

Abstract
PURPOSE: LY2334737 is an oral gemcitabine prodrug. This Phase I study assessed the safety and tolerability of LY2334737 in Japanese patients with solid tumors and evaluated pharmacokinetics (PK), pharmacodynamics, and antitumor activity. METHODS: Patients with advanced/metastatic solid tumors received escalating doses of LY2334737 once daily for 14�days, followed by a 7-day drug-free period. Cycles were repeated until discontinuation criteria were met. RESULTS: Of 13 patients treated, 3 received 20�mg/day, 6 received 30�mg/day, 4 received 40�mg/day. On the 40�mg dose, 3 patients experienced dose-limiting toxicities (DLTs): hepatic toxicities (e.g., Grade [G]3/4 transaminase and G1-3 bilirubin elevation) and G4 thrombocytopenia; all 3 showed features of disseminated intravascular coagulation. One additional DLT occurred on the 30�mg dose (G3 transaminase elevation). Exploratory pharmacogenetic analyses identified a genetic variation in the CES2 gene potentially associated with these DLTs. PK data showed no clear relationship between the AUC of gemcitabine and its incorporation into leukocyte DNA; 2 of the 3 DLT patients had high incorporation. Two patients (30�mg/day) achieved stable disease with progression-free survival lasting 135 and 155�days. CONCLUSIONS: LY2334737 was tolerated by Japanese patients up to 30�mg/day. The toxicities observed at the 40�mg dose may require the development of alternative dosing schedules.

PMID: 23616084 [PubMed - as supplied by publisher]

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The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors - Is there more to come?

The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors - Is there more to come?

Eur J Cancer. 2013 Apr 16;

Authors: Gr�nwald V, Merseburger AS

Abstract
The field of renal cell carcinoma (RCC) treatment has changed dramatically during recent years. Sunitinib, sorafenib and pazopanib were the first generation of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) to have significant clinical activity in metastatic clear cell RCC. These TKI share inhibition of VEGFR family members, but differ in their ability to block other cellular kinases. Axitinib and tivozanib are 2nd generation TKIs, which show high specificity for VEGFR inhibition and exert a favourable toxicity profile. Both agents have succeeded in pivotal clinical trials, which were the first studies to compare two distinct TKIs. Progression free survival (PFS) shows an advantage for the 2nd generation TKIs, but also curbs enthusiasm for limitless PFS expectations with a PFS plateau of 13-14months in 1st line treatment. More recently, novel targets have gained attention in RCC, such as the mesenchymal epithelial transition factor also known as the MET receptor and the fibroblast growth factor receptor (FGFR). These receptors are included into the inhibitory profiles of third generation TKIs such as cabozantinib or dovitinib, which showed promising activity in early clinical trials. Randomised controlled trials explore the role of these agents, and whether the expansion of targets inhibited may lead to more effective treatments in RCC.

PMID: 23601669 [PubMed - as supplied by publisher]

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Potential Role of mTORC2 as a Therapeutic Target in Clear Cell Carcinoma of the Ovary.

Potential Role of mTORC2 as a Therapeutic Target in Clear Cell Carcinoma of the Ovary.

Mol Cancer Ther. 2013 Apr 24;

Authors: Hisamatsu T, Mabuchi S, Matsumoto Y, Kawano M, Sasano T, Takahashi R, Sawada K, Ito K, Kurachi H, Schilder RJ, Testa JR, Kimura T

Abstract
The goal of this study was to examine the role of mTORC2 as a therapeutic target in ovarian clear cell carcinoma (CCC), which is regarded as an aggressive, chemoresistant histological subtype. Using tissue microarrays of 98 primary ovarian cancers (52 CCCs and 46 serous adenocarcinomas (SACs)), activation of mTORC2 was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTORC2-targeting therapy, as well as the role of mTORC2 signaling as a mechanism for acquired resistance to the mTORC1 inhibitor RAD001 in ovarian CCC, were examined using two pairs of RAD001-sensitive parental (RMG2 and HAC2) and RAD001-resistant CCC cell lines (RMG2-RR and HAC2-RR). mTORC2 was more frequently activated in CCCs than in SACs (71.2% vs. 45.7%). Simultaneous inhibition of mTORC1 and mTORC2 by AZD8055 markedly inhibited the proliferation of both RAD001-sensitive and RAD001-resistant cells in vitro. Treatment with RAD001 induced mTORC2-mediated AKT activation in RAD001-sensitive CCC cells. Moreover, increased activation of mTORC2-AKT signaling was observed in RAD001-resistant CCC cells compared to the respective parental cells. Inhibition of mTORC2 during RAD001 treatment enhanced the anti-tumor effect of RAD001 and prevented CCC cells from acquiring resistance to RAD001. In conclusion, mTORC2 is frequently activated, and can be a promising therapeutic target, in ovarian CCCs. Moreover, mTORC2-targeted therapy may be efficacious in a front-line setting as well as for second-line treatment of recurrent disease developing after RAD001-treatment.

PMID: 23615631 [PubMed - as supplied by publisher]

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Upright T waves in lead aVR are associated with cardiac death or hospitalization for heart failure in patients with a prior myocardial infarction.

Upright T waves in lead aVR are associated with cardiac death or hospitalization for heart failure in patients with a prior myocardial infarction.

Heart Vessels. 2012 Nov;27(6):548-52

Authors: Torigoe K, Tamura A, Kawano Y, Shinozaki K, Kotoku M, Kadota J

Abstract
The aim of the present study was to clarify the prognostic significance of upright T waves (amplitude > 0 mV) in lead aVR in patients with a prior myocardial infarction (MI). We retrospectively examined 167 patients with a prior MI. The primary end point was cardiac death or hospitalization for heart failure. During a follow-up period of 6.5 � 2.8 years, 34 patients developed the primary end point. A Kaplan-Meier analysis showed a lower primary event-free rate in patients with upright T waves in lead aVR than in those with nonupright T waves in lead aVR (P = 0.001). Univariate Cox proportional hazards regression analyses showed that age, gender, chronic kidney disease, anterior wall MI, upright T waves in lead aVR, left ventricular ejection fraction, loop diuretic use, and spironolactone use were significantly associated with the primary end point. A multivariate Cox proportional hazards regression analysis selected age [hazard ratio (HR) 1.10, 95% confidence interval (CI) 1.05-1.16, P < 0.001], upright T waves in lead aVR (HR 3.10, 95% CI 1.23-7.82, P = 0.017), and loop diuretic use (HR 4.61, 95% CI 1.55-13.67, P = 0.006) as independent predictors of the primary end point. In conclusion, the presence of upright T waves in lead aVR is an independent predictor of cardiac death or hospitalization for heart failure in patients with a prior MI. The analysis of T-wave amplitude in lead aVR provides useful prognostic information in patients with a prior MI.

PMID: 21969217 [PubMed - indexed for MEDLINE]

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Prolonged exposure to tyrosine kinase inhibitors or early use of everolimus in metastatic renal cell carcinoma: are the two options alike?

Prolonged exposure to tyrosine kinase inhibitors or early use of everolimus in metastatic renal cell carcinoma: are the two options alike?

Med Oncol. 2013 Jun;30(2):578

Authors: Calvani N, Morelli F, Chiuri V, Gnoni A, Scavelli C, Fedele P, Orlando L, Maiello E, Lorusso V, Cinieri S

Abstract
We retrospectively analyzed metastatic renal cell carcinoma (RCC) patients treated with 3 targeted agents. Patients started the sequence with a tyrosine kinase inhibitor (TKI), sunitinib or sorafenib, and were divided into 2 groups based on the order in which they received the other reciprocal TKI and everolimus (EVE): TKI-TKI-EVE group (n�=�19) and TKI-EVE-TKI group (n�=�14). Median progression-free survival (PFS) with first TKI was 13�months in the TKI-TKI-EVE group and 10�months in the TKI-EVE-TKI group. PFS with the second agent showed a trend in favor of the TKI-TKI-EVE sequence, with a median of 11 versus 6.5�months, whereas median PFS with the third agent was 6�months in both groups. Total PFS also showed a trend in favor of the TKI-TKI-EVE sequence with a median of 31 versus 23�months. Median overall survival (OS) was 38�months in both groups, with more patients receiving subsequent treatment in the TKI-EVE-TKI group. The subgroup of patients no long-term responders (?9�months) to first TKI showed similar outcomes irrespective of the sequence. The subgroup of long-term responders to first TKI (>9�months) who received the other TKI instead of EVE had better outcomes in terms of median PFS with the second agent (13 vs. 5.5�months; p�=�0.0271), median total PFS (39.5 vs. 23.5�months; p�=�0.0415), and median OS (46 vs. 38�months). In conclusion, no apparent advantage was observed with early use of EVE in advanced RCC, even in those patients who did not benefit long from first-line TKI, whereas long-term duration of first-line TKI seems to be predictor of second-line TKI efficacy.

PMID: 23613183 [PubMed - in process]

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2013年4月25日星期四

Changes in seasonal expression patterns of ecdysone receptor, retinoid X receptor and an A-type allatostatin in the copepod, Calanus finmarchicus, in a sea loch environment: an investigation of possible mediators of diapause.

Changes in seasonal expression patterns of ecdysone receptor, retinoid X receptor and an A-type allatostatin in the copepod, Calanus finmarchicus, in a sea loch environment: an investigation of possible mediators of diapause.

Gen Comp Endocrinol. 2013 Apr 18;

Authors: Clark KA, Brierley AS, Pond DW, Smith VJ

Abstract
The marine copepod, Calanus finmarchicus, is a crucial component of the pelagic food web in the North Atlantic and peripheral seas where it is a major player in biogeochemical cycles and the productivity of commercially important fisheries. A key stage in its life cycle is the emergence of the pre-adult, copepodite developmental stage five (CV) from a period of overwintering dormancy, known as diapause. As is the case in many insect species, diapause is also likely to be under endocrine control in C. finmarchicus. To investigate the hormonal regulation diapause behaviour of stage CV C. finmarchicus, the expression of three key genes- ecdysone receptor (EcR), retinoid X receptor (RXR) and an A-type allatostatin (A-type AST) were measured in specimens collected at monthly intervals from Loch Etive, a ca. 150 m deep sea loch on the west coast of Scotland, between June 2006 and May 2007. The full length RXR gene was cloned and sequenced from C. finmarchicus, and was found to share 49-53% total identity with equivalent proteins from other crustaceans, and >80% identity in the DNA binding domain with other crustaceans, insects and vertebrates. EcR expression was least in December when the animals are expected to be in diapause, but began to increase in January, when the animals were terminating diapause. Concomittant with the rise in EcR in January was low expression of A-type AST and high expression of RXR.

PMID: 23603431 [PubMed - as supplied by publisher]

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Prolonged exposure to tyrosine kinase inhibitors or early use of everolimus in metastatic renal cell carcinoma: are the two options alike?

Prolonged exposure to tyrosine kinase inhibitors or early use of everolimus in metastatic renal cell carcinoma: are the two options alike?

Med Oncol. 2013 Jun;30(2):578

Authors: Calvani N, Morelli F, Chiuri V, Gnoni A, Scavelli C, Fedele P, Orlando L, Maiello E, Lorusso V, Cinieri S

PMID: 23613183 [PubMed - in process]

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The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors - Is there more to come?

The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors - Is there more to come?

Eur J Cancer. 2013 Apr 16;

Authors: Gr�nwald V, Merseburger AS

PMID: 23601669 [PubMed - as supplied by publisher]

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Everolimus as second- or third-line treatment of advanced endometrial cancer: ENDORAD, a phase II trial of GINECO.

Everolimus as second- or third-line treatment of advanced endometrial cancer: ENDORAD, a phase II trial of GINECO.

Br J Cancer. 2013 Apr 23;

Authors: Ray-Coquard I, Favier L, Weber B, Roemer-Becuwe C, Bougnoux P, Fabbro M, Floquet A, Joly F, Plantade A, Paraiso D, Pujade-Lauraine E

Abstract
Background:Patients with recurrent/metastatic endometrial cancer that progresses after chemotherapy have limited treatment options and poor outcomes. Preclinical data suggest the oral mammalian target of rapamycin inhibitor everolimus may provide clinical benefit in these patients.Methods:In this multicenter, open-label, phase 2 study, patients with advanced or metastatic endometrial cancer refractory to one or two previous chemotherapy regimens received everolimus 10?mg per day until progression or unacceptable toxicity. Primary end point was the non-progressive disease rate at 3 months. Secondary end points included duration of response, progression-free, and overall survival (OS), and safety.Results:Forty-four patients were enrolled (median age, 65 years); 66% received one previous chemotherapy regimen. The 3-month non-progressive disease rate was 36% (95% confidence interval 22-52%), including two patients (5%) with partial response (PR). At 6 months, two additional patients experienced PR. Median duration of response was 3.1 months. Median progression-free and OS were 2.8 months and 8.1 months, respectively. The most common adverse events were anaemia (100%), fatigue (93%), hypercholesterolaemia (81%), and lymphopenia (81%).Conclusion:Everolimus demonstrated efficacy and acceptable tolerability in patients with chemotherapy-refractory advanced or metastatic endometrial cancer. These results support the further development of phosphatidylinositol 3-kinase-targeted therapies in endometrial cancer.British Journal of Cancer advance online publication, 23 April 2013; doi:10.1038/bjc.2013.183 www.bjcancer.com.

PMID: 23612453 [PubMed - as supplied by publisher]

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Novel therapeutic targets in non-small cell lung cancer.

Novel therapeutic targets in non-small cell lung cancer.

Curr Opin Pharmacol. 2013 Apr 19;

Authors: Alamgeer M, Ganju V, Neil Watkins D

Abstract
Oncogenic driver mutations frequently occur in lung cancer and play role in carcinogenesis. These mutations are usually associated with distinct clinical and histological features and are attractive targets for anticancer therapy. Recently, several molecularly distinct phenotypes of NSCLC based on specific and mutually exclusive genetic derangements have been described. Few targets like epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements have successfully been targeted with EGFR tyrosine kinase inhibitors (TKIs) and crizotinib, respectively. Many more inhibitors of specific driver mutations involving genes like ROS, c-MET, FGFR, mTOR, IGFR and RET are currently under development. However, efforts to target some mutated genes like K-RAS have been unsuccessful. Moreover, the emerging challenge of acquired resistance to initially effective therapy is becoming another major concern. In this review recent data on novel molecular targets and their future prospects are discussed.

PMID: 23608109 [PubMed - as supplied by publisher]

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2013年4月24日星期三

Specific Adverse Events Predict Survival Benefit in Patients Treated With Tamoxifen or Aromatase Inhibitors: An International Tamoxifen Exemestane Adjuvant Multinational Trial Analysis.

Specific Adverse Events Predict Survival Benefit in Patients Treated With Tamoxifen or Aromatase Inhibitors: An International Tamoxifen Exemestane Adjuvant Multinational Trial Analysis.

J Clin Oncol. 2013 Apr 22;

Authors: Fontein DB, Seynaeve C, Hadji P, Hille ET, van de Water W, Putter H, Kranenbarg EM, Hasenburg A, Paridaens RJ, Vannetzel JM, Markopoulos C, Hozumi Y, Bartlett JM, Jones SE, Rea DW, Nortier JW, van de Velde CJ

Abstract
PURPOSESpecific adverse events (AEs) associated with endocrine therapy and related to depletion or blocking of circulating estrogens may be related to treatment efficacy. We investigated the relationship between survival outcomes and specific AEs including vasomotor symptoms (VMSs), musculoskeletal adverse events (MSAEs), and vulvovaginal symptoms (VVSs) in postmenopausal patients with breast cancer participating in the international Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. PATIENTS AND METHODSPrimary efficacy end points were disease-free survival (DFS), overall survival (OS), and distant metastases (DM). VMSs, MSAEs, and VVSs arising in the first year of endocrine treatment were considered. Patients who did not start or who discontinued their allocated therapy and/or had an event (recurrence/death) within 1 year after randomization were excluded. Landmark analyses and time-dependent multivariate Cox proportional hazards models assessed survival differences up to 5 years from the start of treatment. RESULTS: VMSs, 0.731 [95% CI, 0.618 to 0.866]; MSAEs, 0.826 [95% CI, 0.694 to 0.982]; VVSs, 0.769 [95% CI, 0.585 to 1.01]; multivariate HR for OS: VMSs, 0.583 [95% CI, 0.424 to 0.803]; MSAEs, 0.811 [95% CI, 0.654 to 1.005]; VVSs, 0.570 [95% CI, 0.391 to 0.831]) and fewer DM (VMSs, 0.813 [95% CI, 0.664 to 0.996]; MSAEs, 0.749 [95% CI, 0.601 to 0.934]; VVSs, 0.687 [95% CI, 0.436 to 1.085]) than patients not reporting these symptoms. Increasing numbers of specific AEs were also associated with better survival outcomes. Outcomes were unrelated to treatment allocation. CONCLUSIONCertain specific AEs are associated with superior survival outcomes and may therefore be useful in predicting treatment responses in patients with breast cancer treated with endocrine therapy.

PMID: 23610112 [PubMed - as supplied by publisher]

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The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors - Is there more to come?

The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors - Is there more to come?

Eur J Cancer. 2013 Apr 16;

Authors: Gr�nwald V, Merseburger AS

PMID: 23601669 [PubMed - as supplied by publisher]

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Activation of liver X receptors suppresses inflammatory gene expressions and transcriptional corepressor clearance in rheumatoid arthritis fibroblast like synoviocytes.

Activation of liver X receptors suppresses inflammatory gene expressions and transcriptional corepressor clearance in rheumatoid arthritis fibroblast like synoviocytes.

J Clin Immunol. 2013 Jan;33(1):190-9

Authors: Yoon CH, Kwon YJ, Lee SW, Park YB, Lee SK, Park MC

Abstract
OBJECTIVES: Liver X receptors (LXR) are nuclear receptors that play important roles in lipid metabolism and transport. LXR also suppress inflammatory responses in macrophages through a unique mechanism of transrepression. This study was performed to investigate whether the synthetic LXR agonist GW3965 can modulate the inflammatory status of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and to identify the mechanism for their effect.
METHODS: RA FLS were treated with 0.1 and 1 ?M of GW3965, a synthetic LXR agonist. The mRNA expressions of pro-inflammatory mediators were measured using quantitative real-time PCR. Apoptotic cell death of RA FLS was assessed using TUNEL assay and determination of caspase-3 activity by a colorimetric assay. The levels of transcriptional corepressors including NCoR and SMRT were determined using western blot analyses.
RESULTS: Treatment of RA FLS with GW3965 induced dose-dependent reductions in mRNA expression of pro-inflammatory mediators (IL-1?, IL-6, MMP-9, CCL-2, CCL-7, and COX-2). However, treatment with GW3965 at the concentration selected for this study had no effect on apoptosis of RA FLS. Decreased productions of NCoR and SMRT by LPS stimulation was attenuated by GW3965 treatment.
CONCLUSIONS: GW3965 treatment suppressed mRNA expressions of pro-inflammatory mediators from RA FLS and inhibited the clearance of transcriptional corepressors. These data suggest that LXR activation can be used as a therapeutic approach to reduce the synovial inflammation in RA.

PMID: 22990668 [PubMed - indexed for MEDLINE]

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Image-based high-throughput screening for inhibitors of angiogenesis.

Image-based high-throughput screening for inhibitors of angiogenesis.

Methods Mol Biol. 2013;931:139-51

Authors: Evensen L, Link W, Lorens JB

PMID: 23027002 [PubMed - indexed for MEDLINE]

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2013年4月23日星期二

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Transfusion. 2012 Nov;52(11):2406-13

Authors: Avanzi MP, Chen A, He W, Mitchell WB

Abstract
BACKGROUND: Large-scale in vitro production of platelets (PLTs) from cord blood stem cells is one goal of stem cell research. One step toward this goal will be to produce polyploid megakaryocytes capable of releasing high numbers of PLTs. Megakaryocyte polyploidization requires distinct cytoskeletal and cellular mechanisms, including actin polymerization, myosin activation, microtubule formation, and increased DNA production. In this study we variably combined inhibition of these principal mechanisms of cytokinesis with the goal of driving polyploidization in megakaryocytes.
STUDY DESIGN AND METHODS: Megakaryocytes were derived from umbilical cord blood and cultured with reagents that inhibit distinct mechanisms of cytokinesis: Rho-Rock inhibitor (RRI), Src inhibitor (SI), nicotinamide (NIC), aurora B inhibitor (ABI), and myosin light chain kinase inhibitor (MLCKI). Combinations of reagents were used to determine their interactions and to maximize megakaryocyte ploidy.
RESULTS: Treatment with RRI, NIC, SI, and ABI, but not with MLCKI, increased the final ploidy and RRI was the most effective single reagent. RRI and MLCKI, both inhibitors of MLC activation, resulted in opposite ploidy outcomes. Combinations of reagents also increased ploidy and the use of NIC, SI, and ABI was as effective as RRI alone. Addition of MLCKI to NIC, SI, and ABI reached the highest level of polyploidization.
CONCLUSION: Megakaryocyte polyploidization results from modulation of a combination of distinct cytokinesis pathways. Reagents targeting distinct cytoskeletal pathways produced additive effects in final megakaryocyte ploidy. The RRI, however, showed no additive effect but produced a high final ploidy due to overlapping inhibition of multiple cytokinesis pathways.

PMID: 22612069 [PubMed - indexed for MEDLINE]

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The impact of statin and macrolide use on early survival in patients with pneumococcal pneumonia.

The impact of statin and macrolide use on early survival in patients with pneumococcal pneumonia.

Am J Med Sci. 2013 Mar;345(3):173-7

Authors: Doshi SM, Kulkarni PA, Liao JM, Rueda AM, Musher DM

Abstract
BACKGROUND: Mortality in pneumococcal pneumonia remains high despite early antibiotic eradication of bacteria. Most deaths occur within the first week, the time of peak inflammatory responses. Statins and macrolides have broad immunosuppressive activity; their impact, separately and together, on survival in patients with pneumococcal pneumonia was evaluated.
METHODS: All patients with pneumococcal pneumonia seen at a single medical center from 2000 through 2010 were included in this retrospective cohort study. A multivariate-adjusted Cox proportional hazard model was used to evaluate survival.
RESULTS: Of 347 patients with pneumococcal pneumonia, 90 (26%) were taking a statin at presentation and 126 (36%) were started on treatment with a macrolide. Thirty-two (9%) statin users were treated with a macrolide. Statin users were older than non-statin users, with a higher prevalence of diabetes, coronary artery disease and chronic kidney disease and a lower prevalence of alcohol consumption and liver disease. Statin users had higher mean Pneumonia Patient Outcomes Research Team scores. Patients treated with a macrolide were not different from those who received other antibiotics. The risk of mortality among statin users was reduced at 7, 14, 20 and 30 days after admission. Mortality was not reduced in patients treated with a macrolide or with a macrolide plus a statin compared with those who did not receive a macrolide.
CONCLUSIONS: Patients who are receiving statins at the time of admission for pneumococcal pneumonia have better clinical outcomes than those who are not. Treatment with a macrolide does not appear to confer a survival benefit.

PMID: 23111390 [PubMed - indexed for MEDLINE]

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Clinical Outcome Following Stringent Discontinuation of Dual Anti-Platelet Therapy After 12 Months in Real-World Patients Treated With Second-Generation Zotarolimus-Eluting Resolute and Everolimus-Eluting Xience V Stents: Two-Year Follow-up of the Randomized TWENTE Trial.

Clinical Outcome Following Stringent Discontinuation of Dual Anti-Platelet Therapy After 12 Months in Real-World Patients Treated With Second-Generation Zotarolimus-Eluting Resolute and Everolimus-Eluting Xience V Stents: Two-Year Follow-up of the Randomized TWENTE Trial.

J Am Coll Cardiol. 2013 Apr 16;

Authors: Tandjung K, Sen H, Kai Lam M, Basalus MW, Louwerenburg JH, Stoel MG, van Houwelingen KG, de Man FH, Linssen GC, Sa�d SA, Nienhuis MB, L�wik MM, Verhorst PM, van der Palen J, von Birgelen C

Abstract
OBJECTIVES: The aim of this study was to assess safety and efficacy of the implantation of Resolute zotarolimus-eluting stents (ZES) and Xience V everolimus-eluting stents (EES) following strict discontinuation of dual anti-platelet therapy (DAPT) after 12 months. BACKGROUND: Only limited long-term follow-up data are available from head-to-head comparisons of second-generation drug-eluting stents (DES). METHODS: The randomized TWENTE (the real-world endeavor Resolute versus Xience V drug-eluting stent study in Twente) is an investigator-initiated study performed in a population with many complex patients and lesions, and only limited exclusion criteria. Patients were 1:1 randomly assigned to ZES (n=697) or EES (n=694). RESULTS: Two-year follow-up information on all patients were available. The rate of DAPT continuation beyond 12 months was very low (5.4%). The primary endpoint target-vessel failure (TVF), a composite of cardiac death, target-vessel-related myocardial infarction, and target-vessel revascularization did not differ between ZES and EES (10.8% vs. 11.6, p=0.65), despite fewer target-lesion revascularizations in EES (2.6% vs. 4.9%, p=0.03). The patient-oriented composite endpoint was similar (16.4% vs. 17.1%, p=0.75). Two-year definite-or-probable stent thrombosis rates were 1.2% and 1.4% (p=0.63), respectively. Very late definite-or-probable stent thrombosis occurred only in 2 patients of each study arm (0.3% vs. 0.3%, p=1.00). CONCLUSION: After 2 years of follow-up and stringent discontinuation of DAPT beyond 12 months, Resolute ZES and Xience V EES showed similar results in terms of safety and efficacy for treating patients with a majority of complex lesions and off-label indications for DES. http://www.clinicaltrials.gov. Unique identifier: NCT01066650.

PMID: 23602769 [PubMed - as supplied by publisher]

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Secreted phospholipase A2-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding.

Secreted phospholipase A2-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding.

J Neuroinflammation. 2012;9:154

Authors: Mart�n R, Cordova C, Nieto ML

Abstract
BACKGROUND: Activation of microglia, the primary component of the innate immune response in the brain, is a hallmark of neuroinflammation in neurodegenerative disorders, including Alzheimer's disease (AD) and other pathological conditions such as stroke or CNS infection. In response to a variety of insults, microglial cells produce high levels of inflammatory cytokines that are often involved in neuronal injury, and play an important role in the recognition, engulfment, and clearance of apoptotic cells and/or invading microbes. Secreted phospholipase A2-IIA (sPLA2-IIA), an enzyme that interacts with cells involved in the systemic immune/inflammatory response, has been found up-regulated in the cerebrospinal fluid and brain of AD patients. However, despite several approaches, its functions in mediating CNS inflammation remain unknown. In the present study, the role of sPLA2-IIA was examined by investigating its direct effects on microglial cells.
METHODS: Primary and immortalized microglial cells were stimulated by sPLA2-IIA in order to characterize the cytokine-like actions of the phospholipase. The hallmarks of activated microglia analyzed include: mitogenic response, phagocytic capabilities and induction of inflammatory mediators. In addition, we studied several of the potential molecular mechanisms involved in those events.
RESULTS: The direct exposure of microglial cells to sPLA2-IIA stimulated, in a time- and dose-dependent manner, their phagocytic and proliferative capabilities. sPLA2-IIA also triggered the synthesis of the inflammatory proteins COX-2 and TNF?. In addition, EGFR phosphorylation and shedding of the membrane-anchored heparin-binding EGF-like growth factor (pro-HB-EGF) ectodomain, as well as a rapid activation/phosphorylation of the classical survival proteins ERK, P70S6K and rS6 were induced upon sPLA2-IIA treatment. We further demonstrated that the presence of an EGFR inhibitor (AG1478), a matrix metalloproteinase inhibitor (GM6001), an ADAM inhibitor (TAPI-1), and a HB-EGF neutralizing antibody abrogated the phenotype of activated microglia induced by the sPLA2-IIA.
CONCLUSION: These results support the hypothesis that sPLA2-IIA may act as a potent modulator of microglial functions through its ability to induce EGFR transactivation and HB-EGF release. Accordingly, pharmacological modulation of EGFR might be a useful tool for treating neuroinflammatory diseases characterized by sPLA2-IIA accumulation.

PMID: 22747893 [PubMed - indexed for MEDLINE]

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Everolimus With Reduced Tacrolimus in Liver Transplantation.

Everolimus With Reduced Tacrolimus in Liver Transplantation.

Am J Transplant. 2013 Apr 19;

Authors: De Simone P, Beckebaum S, Koneru B, Fung J, Saliba F

PMID: 23601137 [PubMed - as supplied by publisher]

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2013年4月22日星期一

Pathophysiology of regression of synovial cysts of the lumbar spine: the 'anti-inflammatory hypothesis'.

Pathophysiology of regression of synovial cysts of the lumbar spine: the 'anti-inflammatory hypothesis'.

Med Hypotheses. 2012 Dec;79(6):813-8

Authors: Mattei TA, Goulart CR, McCall TD

Abstract
The term 'synovial cysts' of the lumbar spine refers to cysts that arise from the zygapophyseal joint capsule of the lumbar spine. Although several cases of regression of lumbar spine synovial cysts after oral anti-inflammatory therapy as well as local steroid injection have already been reported in the literature, no study up to now has addressed the role of 'inflammation suppression' in the regression of such lesions. In fact most of the previous studies have regarded 'spontaneous rupture' as well as 'instability resolution' as the most probable explanations for such phenomenon. In this article the authors review the current experimental data about the role of cytokines and inflammation in the development of synovial cysts of the lumbar spine. Additionally with basis on both our clinical experience of regression of a synovial cyst after conservative treatment with a non-steroidal anti-inflammatory drug (Cox-2 inhibitor) as well as on the experimental data supporting the multi-factorial effects of such drugs on the lumbar facet joints, the authors hypothesize that inhibition of inflammation might play a significant role in the pathophysiology of lumbar spine synovial cysts' regression.

PMID: 23021571 [PubMed - indexed for MEDLINE]

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Cytotoxic Activity of Tivantinib (ARQ 197) Is Not Due Solely to c-MET Inhibition.

Cytotoxic Activity of Tivantinib (ARQ 197) Is Not Due Solely to c-MET Inhibition.

Cancer Res. 2013 Apr 18;

Authors: Katayama R, Aoyama A, Yamori T, Qi J, Oh-Hara T, Song Y, Engelman JA, Fujita N

Abstract
The receptor tyrosine kinase c-MET is the high-affinity receptor for the hepatocyte growth factor (HGF). The HGF/c-MET axis is often dysregulated in tumors. c-MET activation can be caused by MET gene amplification, activating mutations, and auto- or paracrine mechanisms. Thus, c-MET inhibitors are under development as anticancer drugs. Tivantinib (ARQ 197) was reported as a small-molecule c-MET inhibitor and early clinical studies suggest antitumor activity. To assess whether the antitumor activity of tivantinib was due to inhibition of c-MET, we compared the activity of tivantinib with other c-MET inhibitors in both c-MET-addicted and nonaddicted cancer cells. As expected, other c-MET inhibitors, crizotinib and PHA-665752, suppressed the growth of c-MET-addicted cancers, but not the growth of cancers that are not addicted to c-MET. In contrast, tivantinib inhibited cell viability with similar potency in both c-MET-addicted and nonaddicted cells. These results suggest that tivantinib exhibits its antitumor activity in a manner independent of c-MET status. Tivantinib treatment induced a G2-M cell-cycle arrest in EBC1 cells similarly to vincristine treatment, whereas PHA-665752 or crizotinib treatment markedly induced G0-G1 cell-cycle arrest. To identify the additional molecular target of tivantinib, we conducted COMPARE analysis, an in silico screening of a database of drug sensitivities across 39 cancer cell lines (JFCR39), and identified microtubule as a target of tivantinib. Tivantinib-treated cells showed typical microtubule disruption similar to vincristine and inhibited microtubule assembly in vitro. These results suggest that tivantinib inhibits microtubule polymerization in addition to inhibiting c-MET. Cancer Res; 1-10. �2013 AACR.

PMID: 23598276 [PubMed - as supplied by publisher]

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Ubiquitin-like protein MNSF? covalently binds to Bcl-G and enhances lipopolysaccharide/interferon ?-induced apoptosis in macrophages.

Ubiquitin-like protein MNSF? covalently binds to Bcl-G and enhances lipopolysaccharide/interferon ?-induced apoptosis in macrophages.

FEBS J. 2013 Mar;280(5):1281-93

Authors: Watanabe J, Nakagawa M, Watanabe N, Nakamura M

Abstract
Monoclonal non-specific suppressor factor ? (MNSF?) is a ubiquitously expressed member of the ubiquitin-like family that is involved in various biological functions. Previous studies have demonstrated that MNSF? covalently binds to intracellular pro-apoptotic protein Bcl-G and regulates the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) cascade in the mouse macrophage cell line Raw264.7. In this study, we demonstrate that MNSF? promotes lipopolysaccharide (LPS)/interferon ? (IFN?)-induced apoptosis of Raw264.7 macrophages. In Raw264.7 cells treated with MNSF? small interfering RNA (siRNA), LPS/IFN?- or NO donor S-nitrosoglutathione-induced apoptosis was inhibited. siRNA-mediated knockdown of MNSF? did not affect inducible nitric-oxide synthase (iNOS) expression in LPS/IFN?-stimulated Raw264.7 cells. Conversely, co-transfection with MNSF? and Bcl-G greatly enhanced LPS/IFN?- induced apoptosis in Raw264.7 cells, accompanied by increased expression of p53 and decreased Cox-2 activity. Unlike co-transfection with wild-type MNSF?, co-transfection of a mutant MNSF? (G74A) and Bcl-G did not result in enhancement of LPS/IFN?-induced apoptosis. Co-over-expression of MNSF? and Bcl-G reduced S-nitrosoglutathione-induced ERK1/2 phosphorylation. Furthermore, electrophoretic mobility shift assay experiments revealed that MNSF? down-regulates the ERK/activator protein 1 (AP-1) signaling cascade which leads to Cox-2 activation. We also observed that MNSF?-Bcl-G promotes LPS/IFN?-induced apoptosis of mouse peritoneal macrophages, together with a decrease in Cox-2 expression. Taken together, our data indicate an apoptosis-enhancing effect of MNSF?-Bcl-G is due in part to down-regulation of Cox-2 activation in macrophages.

PMID: 23298187 [PubMed - indexed for MEDLINE]

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Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Transfusion. 2012 Nov;52(11):2406-13

Authors: Avanzi MP, Chen A, He W, Mitchell WB

PMID: 22612069 [PubMed - indexed for MEDLINE]

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Effects of in vivo exposure to UV filters (4-MBC, OMC, BP-3, 4-HB, OC, OD-PABA) on endocrine signaling genes in the insect Chironomus riparius.

Effects of in vivo exposure to UV filters (4-MBC, OMC, BP-3, 4-HB, OC, OD-PABA) on endocrine signaling genes in the insect Chironomus riparius.

Sci Total Environ. 2013 Apr 13;456-457C:120-126

Authors: Oz�ez I, Mart�nez-Guitarte JL, Morcillo G

Abstract
There is increasing evidence indicating that several UV filters might have endocrine disruptive effects. Numerous studies have evaluated hormonal effects in vertebrates, mainly reporting estrogenic and androgenic activities in mammals and fishes. There is only limited knowledge about potential endocrine activity in invertebrate hormonal systems. In this work, the effects on endocrine signaling genes of six frequently used UV filters were investigated in Chironomus riparius, a reference organism in aquatic toxicology. The UV filters studied were: octyl-p-methoxycinnamate (OMC) also called 2-ethylhexyl-4-methoxycinnamate (EHMC); 4-methylbenzylidene camphor (4-MBC); benzophenone-3 (BP-3); 4-hidroxybenzophenone (4-HB); octocrylene (OC); and octyldimethyl-p-aminobenzoate (OD-PABA). After in vivo exposure at different dosages, expression levels of the genes coding for the ecdysone receptor (EcR), the ultraspiracle (usp, ortholog of the RXR) and the estrogen-related receptor (ERR) were quantified by Real Time PCR. The EcR gene was significantly upregulated by 4-MBC, OMC/EHMC and OD-PABA, with a dose-related response following 24h exposure. In contrast, the benzophenones, BP-3 and 4-HB, as well as OC did not alter this gene at the same exposure conditions. The transcription profiles of the usp and ERR genes were not significantly affected, except for BP-3 that inhibited the usp gene at the highest concentration. To our knowledge, this is the first experimental evidence in invertebrates of a direct effect of UV filters on endocrine-related genes, and is consistent with the known effects on vertebrate hormonal receptor genes. The capability of 4-MBC, OMC/EHMC and OD-PABA to stimulate the expression of the ecdysone receptor, a key transcription factor for the ecdysone-genomic response in arthropods, suggests the possibility of a broad and long-term effect on this hormonal pathway. These findings strengthen the need for further research about the ecotoxicological implications of chronic exposure to these compounds in aquatic invertebrates.

PMID: 23591065 [PubMed - as supplied by publisher]

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2013年4月21日星期日

Therapeutic Targeting of CPT-11 Induced Diarrhea: A Case For Prophylaxis.

Therapeutic Targeting of CPT-11 Induced Diarrhea: A Case For Prophylaxis.

Curr Drug Targets. 2013 Apr 15;

Authors: Swami U, Goel S, Mani S

Abstract
CPT-11 (irinotecan), a DNA topoisomerase I inhibitor is one of the main treatments for colorectal cancer. The main dose limiting toxicities are neutropenia and late onset diarrhea. Though neutropenia is manageable, CPT-11 induced diarrhea is frequently severe, resulting in hospitalizations, dose reductions or omissions leading to ineffective treatment administration. Many potential agents have been tested in preclinical and clinical studies to prevent or ameliorate CPT-11 induced late onset diarrhea. It is predicted that prophylaxis of CPT-11 induced diarrhea will reduce sub-therapeutic dosing as well as hospitalizations and will eventually lead to dose escalations resulting in better response rates. This article reviews various experimental agents and strategies employed to prevent this debilitating toxicity. Covered topics include schedule/dose modification, intestinal alkalization, structural/chemical modification, genetic testing, anti-diarrheal therapies, transporter (ABCB1, ABCC2, BCRP2) inhibitors, enzyme (?-glucuronidase, UGT1A1, CYP3A4, carboxylesterase, COX-2) inducers and inhibitors, probiotics, antibiotics, adsorbing agents, cytokine and growth factor activators and inhibitors and other miscellaneous agents.

PMID: 23597015 [PubMed - as supplied by publisher]

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Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells.

Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells.

Mol Cancer Ther. 2013 Feb 26;

Authors: Konecny GE, Kolarova T, O'Brien NA, Winterhoff B, Yang G, Qi J, Qi Z, Venkatesan N, Ayala R, Luo T, Finn RS, Kristof J, Galderisi C, Graus Porta D, Anderson L, Shi MM, Yovine A, Slamon DJ

Abstract
The recent identification of activating fibroblast growth factor receptor 2 (FGFR2) mutations in endometrial cancer (EC) has generated an opportunity for a novel target-based therapy. Here we explore the therapeutic potential of two FGFR inhibitors, the multi-kinase inhibitor dovitinib (TKI258) and the more selective FGFR inhibitor NVP-BGJ398 for the treatment of EC. We examined the effects of both inhibitors on tumor cell growth, FGFR2 signaling, cell cycle and apoptosis using a panel of 20 molecularly characterized human EC cell lines. Anchorage independent growth was studied using soft agar assays. In vivo studies were conducted using EC xenograft models. Cell lines with activating FGFR2 mutations (S252W, N550K) were more sensitive to dovitinib or NVP-BGJ398 when compared to their FGFR2 wild-type counterparts (p=0.073 and p=0.021, respectively). Both agents inhibited FGFR2 signaling, induced cell cycle arrest and significantly increased apoptosis in FGFR2 mutant lines. In vitro, dovitinib and NVP-BGJ398 were both potent at inhibiting cell growth of FGFR2 mutant EC cells but the activity of dovitinib was less restricted to FGFR2 mutant lines when compared to NVP-BGJ398. In vivo, dovitinib and NVP-BGJ398 significantly inhibited the growth of FGFR2 mutated EC xenograft models. In addition, dovitinib showed significant antitumor activity in FGFR2 wild-type EC xenograft models including complete tumor regressions in a long term in vivo study. Dovitinib and NVP-BGJ398 warrant further clinical evaluation in patients with FGFR2 mutated EC. Dovitinib may have antitumor activity in EC beyond FGFR2 mutated cases and may permit greater flexibility in patient selection.

PMID: 23443805 [PubMed - as supplied by publisher]

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