5-alpha-reductase: 2012-07-08

2012年7月14日星期六

Effect of intravitreal bevacizumab on retrobulbar blood flow in injected and uninjected fellow eyes of patients with neovascular age-related macular degeneration.

Effect of intravitreal bevacizumab on retrobulbar blood flow in injected and uninjected fellow eyes of patients with neovascular age-related macular degeneration.

Retina. 2012 May;32(5):967-71

Authors: Hosseini H, Lotfi M, Esfahani MH, Nassiri N, Khalili MR, Razeghinejad MR, Nouri-Mahdavi K

Abstract
BACKGROUND: To determine the effect of intravitreal administration of bevacizumab (1.25 mg/0.05 mL) on retrobulbar circulation of the injected and the fellow (uninjected) eyes in patients with neovascular age-related macular degeneration.
METHODS: In this prospective study, the retrobulbar hemodynamics of 43 patients with neovascular age-related macular degeneration was examined by color Doppler ultrasonography. Peak systolic velocity, end-diastolic velocity, and resistive index values in the central retinal artery and short posterior ciliary artery in both injected and uninjected fellow eyes were measured at baseline and 7 days after a single intravitreal injection of bevacizumab.
RESULTS: At baseline, the peak systolic velocity, end-diastolic velocity, and the resistive index in the central retinal artery and short posterior ciliary artery of the injected eye were not significantly different compared with the fellow uninjected eye (P > 0.05 for all). However, intravitreal bevacizumab induced a significant reduction in the peak systolic velocity and end-diastolic velocity and a significant rise in the resistive index of the central retinal artery and short posterior ciliary artery of the injected eye (P ? 0.006 for all). Peak systolic velocity and end-diastolic velocity decreased in the central retinal artery (P = 0.023 and P = 0.030) and the short posterior ciliary artery (P = 0.001 and P < 0.000) in the uninjected eye while the resistive index did not significantly change in central retinal artery (P = 0.114) and short posterior ciliary artery (P = 0.082) of the fellow eyes.
CONCLUSION: Intravitreal injection of bevacizumab significantly affects ocular hemodynamic parameters of both the injected and the uninjected fellow eyes with neovascular age-related macular degeneration.

PMID: 22146127 [PubMed - indexed for MEDLINE]

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?A-crystallin in the pathogenesis and intervention of experimental murine corneal neovascularization.

?A-crystallin in the pathogenesis and intervention of experimental murine corneal neovascularization.

Exp Eye Res. 2012 May;98:44-51

Authors: Zhu W, Qi X, Ren S, Jia C, Song Z, Wang Y

Abstract
This study was to determine the potential roles of lens crystallins in the pathogenesis of corneal neovascularization (CorNV) and implications in therapy of CorNV-related diseases. Suture- or chemical burn-induced CorNV in different strains of mice were used. Changes of gene expression patterns were analyzed by microarray, and the results of interesting genes were confirmed by real-time quantitative PCR and Western blot. Mice deficient in ?A-crystallin gene were used to evaluate the role of ?A-crystallin in the development of CorNV. In some animals, exogenous ?A-crystallin proteins were injected around time of CorNV induction. CorNV was assessed by slit-lamp, flat-mounts and histology. In BALB/C mice, the expression of ?-, ?-, and ?-crystallins were up-regulated at day 5 and returned to baseline level at day 10 of suture-induced CorNV, but remained up-regulated from day 6 to day 14 of chemical burn-induced CorNV. In chemical burn-induced CorNV in C57BL/6J mice, however, they were down-regulated at day 6. Corneal crystallins were down-regulated in both CorNV models at all time points in both BALB/c and C57BL/6J mice. Comparison of CorNV development in ?A-crystallin-deficient mice and that in wild-type mice revealed no significant difference. Subconjunctival injection of ?A-crystallin significantly attenuated suture-induced CorNV, and the inhibitory activity might be implemented by the increased expression of�soluble VEGFR-1. In conclusion, the expression patterns of lens crystallins were time- and strain-dependent but different from that of corneal crystallins in mouse CorNV models. Exogenous ?A-crystallin protein attenuated CorNV, potentially by increasing the expression of soluble VEGFR-1.

PMID: 22465406 [PubMed - indexed for MEDLINE]

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2012年7月13日星期五

DNA methyl transferase I acts as a negative regulator of allergic skin inflammation.

DNA methyl transferase I acts as a negative regulator of allergic skin inflammation.

Mol Immunol. 2012 Jul 9;53(1-2):1-14

Authors: Kim Y, Kim K, Park D, Lee E, Lee H, Lee YS, Choe J, Kim YM, Jeoung D

Abstract
The role of DNA methyl transferase I (DNMT1) in allergic inflammation was investigated. Antigen stimulation decreased expression of DNMT1 in rat basophilic leukemia cells (RBL2H3). The down regulation of DNMT1 induced expression of histone deacetylase 3 (HDAC3). HDAC3 was necessary for allergic skin inflammation, such as such as triphasic cutaneous reaction and passive cutaneous anaphylaxis. The down regulation of DNMT1 resulted from activation of PKC and rac1 which were necessary for proteasome-dependent ubiquitination of DNMT1 by antigen stimulation. N-acetyl-L-cysteine, an inhibitor of reactive oxygen species production, exerted negative effects on allergic skin inflammation. Antigen stimulation led to increased expression of Tip60, a histone acetyl transferase. Wild type, but not mutant form, Tip60 decreased expression of DNMT1 while increasing expression of HDAC3, suggesting role for acetylation in ubiquitin-dependent proteasomal degradation of DNMT1. In vivo down regulation of DNMT1 increased ear thickness, typical of allergic skin inflammation, induced vascular leakage and promoted angiogenesis in BALB/c mouse. The down regulation of DNMT1 enhanced angiogenic potential of rat aortic endothelial cells (RAEC) accompanied by activation of VEGR-2 and induced interaction between VEGR-2 and syk in RAEC. The enhanced angiogenic potential of RAEC was associated with the induction of VEGF by down regulation of DNMT1 in RBL2H3 cells. The down regulation of DNMT1 induced leukocytes-endothelial cell interaction and expression of various adhesion molecules. Aspirin exerted a negative effect on allergic skin inflammation by indirect regulation on DNMT1 via Tip60. Taken together, these results suggest novel role for DNMT1 in allergic skin inflammation.

PMID: 22784989 [PubMed - as supplied by publisher]

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IL8 and serum soluble TRAIL levels following anti-VEGF monoclonal antibody treatment in patients with metastatic colon cancer.

IL8 and serum soluble TRAIL levels following anti-VEGF monoclonal antibody treatment in patients with metastatic colon cancer.

Clin Lab. 2012;58(5-6):501-5

Authors: Kargi A, Yalcin AD, Erin N, Savas B, Polat HH, Gorczynski RM

Abstract
BACKGROUND: Colorectal cancer is the third most common human cancer and the third leading cause of cancer related death. BevacizumAb is a humanized monoclonal antibody developed against vascular endothelial growth factor (VEGF) for the treatment of metastatic cancers. Our goal was to evaluate the possibility of using serum sTRAIL and IL8 as markers of treatment efficacy and prognosis in patients with metastatic colon cancer.
METHODS: The study was conducted in Denizli between November 10, 2009 and September 20, 2010. 25 patients (6 female, 19 male) with metastatic colon cancer whose mean age was 58.7 years, were selected and included in the study. All patients received therapy with BevacizumAb. All patients were followed in the Oncology Clinic of Denizli State Hospital and were evaluated by clinical status, sTRAIL and IL8 levels were measured by ELISA in the sera of 25 BevacizumAb treated metastatic colon cancer patients and 20 healthy age-gender matched controls. Measurements were taken before and after treatment.
RESULTS: The serum sTRAIL concentrations in patients before therapy were similar to those of healthy age-gender matched controls, namely 1.23 +/- 0.06 ng/mL and 1.21 +/- 0.04 ng/mL, respectively. After BevacizumAb treatment, sTRAIL ratios were increased significantly in 11 of 25 patients. 14 patients showed progressive disease with median overall survival of only 8.1 +/- 0.4 months. These 14 patients were the same ones who showed no increase in sTRAIL levels after BevacizumAb treatment. We explored evidence for a correlation between sTRAIL levels and overall survival rates and observed that elevated sTRAIL levels after the BevacizumAb treatment were significantly associated with increased median overall survival up to 22.6 months. Serum IL8 levels were decreased in all patients who received BevacizumAb therapy.
CONCLUSIONS: In BevacizumAb therapy, serum IL8 levels were decreased in all patients, and thus, changes in such levels were not correlated with disease outcome. Our data suggest measurement of changes in sTRAIL following BevacizumAb treatment may have prognostic value in metastatic colon cancer patients.

PMID: 22783581 [PubMed - in process]

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Predicting chemosensitivity in osteosarcoma prior to chemotherapy: An investigational study of biomarkers with immunohistochemistry.

Predicting chemosensitivity in osteosarcoma prior to chemotherapy: An investigational study of biomarkers with immunohistochemistry.

Oncol Lett. 2012 May;3(5):1011-1016

Authors: Chen Y, Yang Y, Yuan Z, Wang C, Shi Y

Abstract
Osteosarcoma has one of the worst prognoses in adolescents; only 20-60% of patients have high rates of histological necrosis with intensive neoadjuvant chemotherapy. In this study, we investigated the prognostic values of hypoxia-inducible factor 1 ? (HIF-1?), apurinic endonuclease 1 (APE1), vascular endothelial growth factor (VEGF) and cycloogenase-2 (COX-2) protein expression and their predictive value of tumor necrosis rate and prognosis, as well as their interrelationships. Formalin-fixed paraffin-embedded tissue samples were obtained from 49 patients with osteosarcoma. Immunohistochemistry assays were performed in pre-chemotherapy samples to determine HIF-1?, VEGF, APE1 and COX-2 protein expression levels and hematoxylin and eosin staining was performed in post-operative samples to determine the tumor necrosis rate. Univariate and multivariate analyses were used to assess the impact of protein expression on prognosis. HIF-1? was significantly correlated with every protein we tested: VEGF (P=0.032), APE1 (P<0.001) and COX-2 (P<0.001). HIF-1? protein expression had a significant impact on disease-free survival (P=0.006). Expression of HIF-1? had a sensitivity of 64.7% and a specificity of 71.9% for a poor pathological response (<90% tumor necrosis) versus a good pathological response (?90% tumor necrosis). In conclusion, expression of HIF-1? is a predictor of tumor response to neoadjuvant chemotherapy and outcome in osteosarcoma, and correlates with VEGF, APE1 and COX-2.

PMID: 22783382 [PubMed - as supplied by publisher]

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2012年7月12日星期四

Predicting chemosensitivity in osteosarcoma prior to chemotherapy: An investigational study of biomarkers with immunohistochemistry.

Predicting chemosensitivity in osteosarcoma prior to chemotherapy: An investigational study of biomarkers with immunohistochemistry.

Oncol Lett. 2012 May;3(5):1011-1016

Authors: Chen Y, Yang Y, Yuan Z, Wang C, Shi Y

PMID: 22783382 [PubMed - as supplied by publisher]

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The urokinase receptor (CD87) represents a central mediator of growth factor-induced endothelial cell migration.

The urokinase receptor (CD87) represents a central mediator of growth factor-induced endothelial cell migration.

Thromb Haemost. 2012 Jul 10;108(2):357-366

Authors: Poettler M, Unseld M, Mihaly-Bison J, Uhrin P, Koban F, Binder B, Zielinski C, Prager GW

Abstract
Angiogenesis, the sprouting of blood vessels form pre-existing vasculature after injury or in neoplastic diseases, is initiated by growth factor-induced endothelial cell migration. Recently, the major angiogenic growth factor VEGF165 has become the target of therapeutic interventions. However, this approach has been clinically proven to be of limited efficacy, which might be due to the fact that tumour angiogenesis is not only induced by VEGF, but also by a variety of other growth factors. Thus, the identification of a common downstream mediator of growth-factor-induced endothelial cell migration is mandatory to effectively interfere with (tumour-) angiogenesis. We found that the urokinase-type plasminogen activator (uPA)-system, which affects proteolytic as well as adhesive capacities, represents an essential regulatory mechanism in growth factor-induced endothelial cell migration and invasion. This mechanism was not limited to VEGF165, but mediated pro-angiogenic endothelial cell behaviour induced by various growth factors. Thus, VEGF165, VEGF-E, FGF-2, EGF as well as HGF induced a PI3k-dependent activation of pro-uPA when bound to uPAR, which led to an increase in cell surface fibrinolytic activity. As a consequence, uPAR became internalised and redistributed via LDLR-proteins. Interference with these events led to a reduced migratory response of endothelial cells towards VEGF in vitro as well as endothelial cell invasion in vivo. These data give first evidence that the uPA-system, which represents the only level-of-evidence-1 cancer biomarker system for prognosis and/or prediction in node negative breast cancer, might directly affect (tumour-) angiogenesis.

PMID: 22782499 [PubMed - as supplied by publisher]

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2012年7月11日星期三

Ruthenium-106 brachytherapy and intravitreal bevacizumab for retinal capillary hemangioma.

Ruthenium-106 brachytherapy and intravitreal bevacizumab for retinal capillary hemangioma.

Int Ophthalmol. 2012 Feb;32(1):71-5

Authors: Russo V, Stella A, Barone A, Scott IU, Noci ND

Abstract
The purpose of this study is to report a case of retinal capillary hemangioma treated with ruthenium-106 brachytherapy combined with intravitreal bevacizumab. A 58-year-old woman presented with blurred vision in her left eye for 15 days. Best-corrected visual acuity (BCVA) was counting fingers at 3 m in her left eye. Examination showed a peripheral endophytic retinal capillary hemangioma, with associated macular edema and diffuse hard exudates in a macular star pattern. B-scan ultrasonography revealed a solid, highly reflective retinal tumor measuring 7.1 � 7.5 mm in basal dimension and 3.5 mm in thickness. The hemangioma and macular edema were treated with ruthenium-106 brachytherapy (500 Gy) followed 1 month later with an intravitreal injection of 1.25 mg (0.05 ml) bevacizumab. After 10 months of follow-up, examination demonstrated involution of the hemangioma, resolution of the macular edema, less hard exudates, and improvement of BCVA to 20/25. Ruthenium-106 brachytherapy combined with intravitreal bevacizumab was associated with significant involution of the choroidal hemangioma with resolution of the macular edema and improvement in visual acuity.

PMID: 22271068 [PubMed - indexed for MEDLINE]

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Prospective Study of Bevacizumab Plus Temozolomide in Patients With Advanced Neuroendocrine Tumors.

Prospective Study of Bevacizumab Plus Temozolomide in Patients With Advanced Neuroendocrine Tumors.

J Clin Oncol. 2012 Jul 9;

Authors: Chan JA, Stuart K, Earle CC, Clark JW, Bhargava P, Miksad R, Blaszkowsky L, Enzinger PC, Meyerhardt JA, Zheng H, Fuchs CS, Kulke MH

Abstract
PURPOSEBoth tyrosine kinase inhibitors targeting the vascular endothelial growth factor (VEGF) receptor and bevacizumab, a monoclonal antibody targeting VEGF, have antitumor activity in neuroendocrine tumors (NETs). Temozolomide, an oral analog of dacarbazine, also has activity against NETs when administered alone or in combination with other agents. We performed a phase II study to evaluate the efficacy of temozolomide in combination with bevacizumab in patients with locally advanced or metastatic NETs. PATIENTS AND METHODSThirty-four patients (56% with carcinoid, 44% with pancreatic NETs) were treated with temozolomide 150 mg/m(2) orally per day on days 1 through 7 and days 15 through 21, together with bevacizumab at a dose of 5 mg/kg per day intravenously on days 1 and 15 of each 28-day cycle. All patients received prophylaxis against Pneumocystis carinii and varicella zoster. Patients were followed for toxicity, biochemical and radiologic response, and survival.ResultsThe combination of temozolomide and bevacizumab was associated with anticipated grade 3 to 4 toxicities, including lymphopenia (53%) and thrombocytopenia (18%). Although the overall radiographic response rate was 15% (five of 34), response rates differed between patients with pancreatic NETs (33%; five of 15) and those with carcinoid tumors (zero of 19). The median progression-free survival was 11.0 months (14.3 months for pancreatic NETs v 7.3 months for carcinoid tumors). The median overall survival was 33.3 months (41.7 months for pancreatic NETs v 18.8 months for carcinoid tumors). CONCLUSIONTemozolomide and bevacizumab can be safely administered together in patients with advanced NETs, and the combination regimen appears promising for patients with pancreatic NETs. Studies evaluating the relative contributions of these two agents to the observed antitumor activity are warranted.

PMID: 22778320 [PubMed - as supplied by publisher]

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Immunohistochemistry of angiogenesis mediators before and after pulsed dye laser treatment of angiomas.

Immunohistochemistry of angiogenesis mediators before and after pulsed dye laser treatment of angiomas.

Lasers Surg Med. 2012 Mar;44(3):205-10

Authors: Laquer VT, Dao BM, Pavlis JM, Nguyen AN, Chen TS, Harris RM, Rugg EL, Kelly KM

Abstract
BACKGROUND AND OBJECTIVE: Tissue effects of vascular lesion laser treatment are incompletely understood. Injury caused by pulsed dye laser (PDL) treatment may result in altered expression of mediators associated with angiogenesis.
MATERIALS AND METHODS: Eight human subjects had one angioma treated with PDL (7 mm, 1.5 millisecond pulse duration, 9 J/cm(2), cryogen spray cooling of 30 millisecond with a 30 millisecond delay). One week later, three biopsies were taken: normal skin, untreated angioma, angioma post-PDL. Tissue was frozen and sections processed for immunohistochemistry staining of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), matrix metalloproteinase 9 (MMP-9), and angiopoietin 2 (ANG-2). Images were graded in a blinded fashion by a board certified dermatopathologist.
RESULTS: There were no clear trends in VEGF expression in the epidermis, dermis, or endothelial cells. As compared to normal skin, angiomas demonstrated the following: bFGF was decreased in the epidermis; MMP-9 was decreased or unchanged in the epidermis and increased in the endothelial cells; ANG-2 was increased in the endothelial cells. When comparing normal skin to angiomas?+?PDL, bFGF was decreased in the epidermis and increased in the dermis; MMP-9 was decreased or unchanged in the epidermis; ANG-2 was again increased in the endothelial cells. Comparison of staining in angioma to angioma?+?PDL samples revealed increased dermal bFGF expression.
CONCLUSION: Alterations in angiogenesis mediators were noted after PDL. Angiogenesis mediator changes associated with PDL treatment differed from those previously reported for incisional biopsies. This pilot study can guide future work on laser-induced alterations in vascular lesions and such information may ultimately be used to optimize treatment outcomes.

PMID: 22302773 [PubMed - indexed for MEDLINE]

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2012年7月10日星期二

Meta analysis on the relationship between gene polymorphisms of vascular endothelial growth factor and retinal prognosis risk of prematurity.

Meta analysis on the relationship between gene polymorphisms of vascular endothelial growth factor and retinal prognosis risk of prematurity.

Int J Ophthalmol. 2012;5(3):397-400

Authors: Zhai J, Jiang QH, Liu CX, Tian ZR, Sun YP

Abstract
AIM: To explore the relationship between gene polymorphisms of vascular endothelial growth factor (VEGF) and retinopathy of prematurity (ROP).
METHODS: Literature materials related to gene polymorphisms of VEGF and ROP in PubMed, EMBASE, Cochrane and CBM database were retrieved. These materials were screened according to inclusion and exclusion standards. Patients diagnosed with ROP in clinic were regarded as control group and ROP patients who were in treatment were regarded as observation group. The indexes in two groups were matched except birth weight (BW), gender and gestational weeks. Meta5.1 was used to analyze the relationship between gene polymorphisms of VEGF and ROP.
RESULTS: Four random control tests (RCT) were included in this research, including 2611 patients. Meta analysis results showed that VEGF affected ROP, having statistical significance. The combined ratio was 0.44 (95%CI, 0.07, 0.80), 0.42 (95%CI, 0.09, 0.74) and 0.75 (95%CI, 0.02, 1.49), respectively. Carrying +405 allele might increase the premature infants' risk of having ROP.
CONCLUSION: ROP may be related to its carrying of +405 allele. Large-scale, multi-factor RCT researches are still needed in order to identify the relation between VEGF and ROP.

PMID: 22773996 [PubMed - in process]

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RAF265, a dual BRAF and VEGFR2 inhibitor, prevents osteoclast formation and resorption. Therapeutic implications.

RAF265, a dual BRAF and VEGFR2 inhibitor, prevents osteoclast formation and resorption. Therapeutic implications.

Invest New Drugs. 2012 Jul 7;

Authors: Garcia-Gomez A, Ocio EM, Pandiella A, San Miguel JF, Garayoa M

Abstract
Introduction The RAS/RAF/MEK/ERK signaling pathway plays an important role in osteoclast (OC) differentiation and survival mediated by macrophage-colony stimulating factor (M-CSF). Also, vascular endothelial growth factor (VEGF) may greatly influence OC formation and resorption through VEGFR1 and VEGFR2. RAF265 is a novel, orally bioavailable dual inhibitor of RAF kinase and VEGFR2. Methods Effect of RAF265 on osteoclastogenesis from peripheral blood mononuclear cells (PBMCs) and OC resorption on calcium-coated wells was assessed by appropriate in vitro assays. Immunoblotting, real-time RT-PCR and flow cytometry were used to evaluate RAF265 mechanism of action. Results RAF265 significantly impaired in vitro differentiation of PBMCs to OCs induced by receptor activator of NF-kB ligand (RANKL) and M-CSF (IC(50)???160 nM). In parallel, RAF265 exerted a potent inhibition of OC resorptive capacity (IC(50)???20 nM). RAF265 treatment led to ERK inhibition and diminished expression of c-fos and NFATc1 (nuclear factor of activated T cells, calcineurin-dependent 1), which would likely account for inhibition of osteoclastogenesis. The reduced gene expression of aVb3 integrin, CCR1, cathepsin K, carbonic anhydrase II, matrix metalloproteinase 9, urokinase and tissue-type plasminogen activators, vacuolar H(+)-ATPase subunit (ATP6V1A) and Rab7 GTPase would probably mediate RAF265 hindered resorption. RAF265 inhibitory effect on VEGFR2 (noticeable at 10-50 nM) was also found to be implicated in the potent inhibition of this agent on OC function. Conclusions We have found a new therapeutic application for RAF265 as an inhibitory agent of osteoclastogenesis and OC function, which might be useful for the treatment of skeletal disorders associated with increased bone resorption.

PMID: 22773056 [PubMed - as supplied by publisher]

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2012年7月9日星期一

VEGF upregulates VEGF receptor-2 on human outer root sheath cells and stimulates proliferation through ERK pathway.

VEGF upregulates VEGF receptor-2 on human outer root sheath cells and stimulates proliferation through ERK pathway.

Mol Biol Rep. 2012 Jun 16;

Authors: Li W, Lu ZF, Man XY, Li CM, Zhou J, Chen JQ, Yang XH, Wu XJ, Cai SQ, Zheng M

Abstract
Vascular endothelial growth factor (VEGF) is a key regulator of physiological and pathological angiogenesis. The biological effects of VEGF are mediated by receptor tyrosine kinases. VEGF receptor-2, the primary receptor for VEGF, is thought to mediate most functional effects. In this study, we examined the expression and roles of VEGF receptor-2 on human outer root sheath cells (ORS). The expression of VEGFR-2 was determined at mRNA and protein levels by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Localization of VEGFR-2 in ORS cells was detected by immunofluorescence. The effect of VEGF on ORS cell proliferation was determined by MTT assays. Our data showed the expression of VEGFR-2 on ORS cells at both mRNA and protein levels. Immunostaining for VEGFR-2 demonstrated strong signal on cultured ORS cells. Exogenous VEGF(165) stimulated proliferation of ORS cells and upregulated expression of VEGFR-2 in a dose-dependent manner. Moreover, VEGF(165) induced phosphorylation of VEGFR-2, PLC-γ1, PKC-α, MEK, and p44/42 MAPK (ERK1/2) in a time-dependent manner. Taken together, human ORS cells express functional VEGF receptor-2 and exogenous VEGF(165) upregulates expression of VEGFR-2 and stimulates proliferation of ORS cells via VEGFR-2 mediated ERK signaling pathway.

PMID: 22707147 [PubMed - as supplied by publisher]

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Clinical efficacy and safety of bevacizumab monotherapy in patients with metastatic melanoma: predictive importance of induced early hypertension.

Clinical efficacy and safety of bevacizumab monotherapy in patients with metastatic melanoma: predictive importance of induced early hypertension.

PLoS One. 2012;7(6):e38364

Authors: Schuster C, Eikesdal HP, Puntervoll H, Geisler J, Geisler S, Heinrich D, Molven A, LÃ¸nning PE, Akslen LA, Straume O

Abstract
BACKGROUND: VEGF driven angiogenesis plays a key role in cancer progression. We determined the clinical efficacy of bevacizumab monotherapy in patients with metastatic melanoma.
METHODS AND FINDINGS: Thirty-five patients with metastatic melanoma in progression were enrolled in this phase II, single arm clinical trial. Each patient received bevacizumab monotherapy 10 mg/kg q14 d until intolerable toxicity or disease progression occurred. Clinical efficacy was evaluated as objective response, disease control (DC), and survival. We observed one complete (3%) and 5 partial (14%) responses. In addition, 5 patients experienced stable disease >6 months (14%) while 24 patients had progressive disease (PD, 69%), corresponding to a total DC at 6 months in 11 out of 35 patients (31%). Median progression free survival (PFS) was 2.14 months and median overall survival (OS) was 9 months (1.12-49). Seven of the 11 patients experiencing DC developed early hypertension (<2 months) compared to 3/24 of patients with PD (Pâ€Š=â€Š0.001), and hypertension was associated with PFS (Pâ€Š=â€Š0.005) and OS (Pâ€Š=â€Š0.013).
CONCLUSION: Bevacizumab monotherapy demonstrated promising clinical efficacy in patients with metastatic melanoma with disease control in 31% of the patients. Induced early hypertension was a marker for clinical efficacy of bevacizumab.
TRIAL REGISTRATION: ClinicalTrials.gov NCT00139360.

PMID: 22719881 [PubMed - in process]

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2012年7月8日星期日

Thalidomide attenuates mammary cancer associated-inflammation, angiogenesis and tumor growth in mice.

Thalidomide attenuates mammary cancer associated-inflammation, angiogenesis and tumor growth in mice.

Biomed Pharmacother. 2012 May 29;

Authors: Souza CM, Carvalho LF, Vieira TD, Silva AC, Lopes MT, Ferreira MA, Andrade SP, Cassali GD

Abstract
Thalidomide has proven to exert anti-inflammatory, anti-proliferative and anti-angiogenic activities in both neoplastic and non-neoplastic conditions. We investigated the effects of this compound on key components (blood vessel formation, inflammatory cell recruitment/activation, cytokine production) of 4T1 mammary tumor in mice. In addition, tumor growth and lung metastasis were evaluated. 4T1 cells were injected subcutaneously into Balb/c mice. After tumor engraftment (5days), thalidomide (150mg/kg) was administered to the treated group for 7days. Tumors of control (saline) and treated groups were sized regularly, removed 12days after inoculation and processed for biochemical and immunohistological parameters to assess neovascularization, inflammation and proliferative activity. Daily oral dose of thalidomide was able to reduce in 46% the tumor volume. The number of metastasis in the lungs was less in the thalidomide-treated group compared with the control animals. Assessment of tumor vascularization revealed a significant decrease in blood vessels formation by thalidomide. Likewise, the expression of FGF-1 showed weaker cytoplasmic positivity in the group treated with thalidomide compared with the control group. The levels of two cytokines, VEGF (pro-angiogenic) and TNF-Î± (pro-inflammatory) were decreased in tumor samples of thalidomide-treated group compared with the control group. Accumulation of neutrophils or macrophages in the 4T1 tumor measured by the activities of inflammatory enzymes, myeloperoxidase (MPO) for neutrophils and N-acetyl-Î²-D-glucosaminidase (NAG) for macrophages was inhibited by the treatment. By targeting key components of 4T1 tumor simultaneously, thalidomide was effective in attenuating tumor growth and metastasis. This approach, suppression of inflammation and angiogenesis may provide further insights for both prevention and treatment of cancer.

PMID: 22705333 [PubMed - as supplied by publisher]

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mTOR Is Essential for the Proteotoxic Stress Response, HSF1 Activation and Heat Shock Protein Synthesis.

mTOR Is Essential for the Proteotoxic Stress Response, HSF1 Activation and Heat Shock Protein Synthesis.

PLoS One. 2012;7(6):e39679

Authors: Chou SD, Prince T, Gong J, Calderwood SK

Abstract
The target of rapamycin (TOR) is a high molecular weight protein kinase that regulates many processes in cells in response to mitogens and variations in nutrient availability. Here we have shown that mTOR in human tissue culture cells plays a key role in responses to proteotoxic stress and that reduction in mTOR levels by RNA interference leads to increase sensitivity to heat shock. This effect was accompanied by a drastic reduction in ability to synthesize heat shock proteins (HSP), including Hsp70, Hsp90 and Hsp110. As HSP transcription is regulated by heat shock transcription factor 1 (HSF1), we examined whether mTOR could directly phosphorylate this factor. Indeed, we determined that mTOR could directly phosphorylate HSF1 on serine 326, a key residue in transcriptional activation. HSF1 was phosphorylated on S326 immediately after heat shock and was triggered by other cell stressors including proteasome inhibitors and sodium arsenite. Null mutation of S326 to alanine led to loss of ability to activate an HSF1-regulated promoter-reporter construct, indicating a direct role for mTOR and S326 in transcriptional regulation of HSP genes during stress. As mTOR is known to exist in at least two intracellular complexes, mTORC1 and mTOR2 we examined which complex might interact with HSF1. Indeed mTORC1 inhibitor rapamycin prevented HSF1-S326 phosphorylation, suggesting that this complex is involved in HSF1 regulation in stress. Our experiments therefore suggest a key role for mTORC1 in transcriptional responses to proteotoxic stress.

PMID: 22768106 [PubMed - in process]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22768106?dopt=Abstract

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First-line chemotherapy with planned sequential administration of cisplatin/gemcitabine followed by docetaxel in elderly 'unfrail' patients with advanced non-small-cell lung cancer: a multicenter phase II study.

First-line chemotherapy with planned sequential administration of cisplatin/gemcitabine followed by docetaxel in elderly 'unfrail' patients with advanced non-small-cell lung cancer: a multicenter phase II study.

J Cancer Res Clin Oncol. 2012 Jul 6;

Authors: Tibaldi C, Camerini A, D'Incecco A, Vasile E, Fabbri A, Amoroso D, Cappuzzo F

Abstract
PURPOSE: The role of cisplatin in the first-line treatment for elderly advanced non-small-cell lung cancer is not completely defined. We previously reported in this subset of patients an interesting efficacy and tolerability of a sequential schedule of gemcitabine followed by docetaxel. METHODS: Patients agedÂ â‰¥70Â years and with Eastern Cooperative Oncology Group performance status 0 or 1 received cisplatin 60Â mg/m(2) on Day 1 and gemcitabine 1,000Â mg/m(2) on Day 1 and 8 every 3Â weeks for 3 courses followed by 3 courses of docetaxel 37.5Â mg/m(2) on Day 1 and 8 every 3Â weeks, provided there was no evidence of disease progression. Patients were excluded if considered 'frail' according to the Multidimensional Geriatric Assessment. The main objective of the study was the 4-month progression-free survival rate. Simon's two-stage minimax design was applied to calculate the sample size. RESULTS: After 30 patients were enroled into the study, the 4-month progression-free survival rate was 53.3Â % and the study was closed at the first stage for futility; the overall response rate was 16.7Â %; the median time to progression and median duration of survival were 5.1 and 8.6Â months, respectively; the 1-year survival rate was 30Â %. CONCLUSION: The incorporation of cisplatin in a sequential schedule of gemcitabine followed by docetaxel is feasible but did not yield a substantial advantage to deserve further investigations.

PMID: 22767317 [PubMed - as supplied by publisher]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22767317?dopt=Abstract

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Pharmacologic modulation strategies to reduce dose requirements of anticancer therapy while preserving clinical efficacy.

Pharmacologic modulation strategies to reduce dose requirements of anticancer therapy while preserving clinical efficacy.

Future Oncol. 2012 Jun;8(6):731-49

Authors: Zee YK, Goh BC, Lee SC

Abstract
Drug interactions may be exploited to overcome pharmacokinetic issues in order to improve the therapeutic index of a drug, with clinical goals of reducing the dose of the active drug while preserving efficacy or reducing toxicity. This strategy has been used in infectious disease and transplant medicine, and, more recently, in oncology. Pharmacologic modulation strategies range from coadministration of either a drug that inhibits a metabolizing enzyme that would inactivate the drug of interest, a drug that induces an enzyme that activates the drug of interest or a drug that inhibits transporters that affect the uptake or elimination of the drug of interest. This review will discuss pharmacologic modulation strategies that have been tested clinically in order to increase systemic drug exposure. Important examples include ketoconazole inhibition of hepatic CYP3A4 in order to increase systemic exposure to docetaxel, irinotecan and etoposide, and cyclosporine inhibition of intestinal ATP-binding cassette transporters in order to decrease the toxicity of irinotecan and increase the bioavailability of oral docetaxel, paclitaxel and topotecan.

PMID: 22764771 [PubMed - in process]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22764771?dopt=Abstract

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mTOR Is Essential for the Proteotoxic Stress Response, HSF1 Activation and Heat Shock Protein Synthesis.

mTOR Is Essential for the Proteotoxic Stress Response, HSF1 Activation and Heat Shock Protein Synthesis.

PLoS One. 2012;7(6):e39679

Authors: Chou SD, Prince T, Gong J, Calderwood SK

PMID: 22768106 [PubMed - in process]

Source: http://www.ncbi.nlm.nih.gov/PubMed/22768106?dopt=Abstract

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