The panel acknowledged that the specific ocular ef fect observed for alachlor would not have been detectable in the rat strain used in the alachlor ESA study. However, this data gap was not considered critical in light of the likely differences in the mode of action between the parent chemicals and these degradates and the fact that uveal degeneration in rats induced by alachlor were not critical effect for the alachlor RfD. A second potential data gap was considered based on data indi cating potential for neurotoxic effects in several acetochlor rat and dog studies. However, there was no indication of a neurotoxic potential for acetochlor degradates. The panel concluded that since no such effects were observed even at limit doses in subchronic studies, these degradates are not likely to be neurotoxic.

Absence of a longer duration systemic toxicity study PDE Inhibitors in a sec ond species was also considered in selecting the appropriate data base uncertainty factor, since only rat studies were available for the degradates. The panel discussed whether a 1 year dog study was needed, since some data for the parent chemicals suggest that the dog is the more sensitive species and effects that occur at 1 year are not found in the 90 day studies. However, the U. S. EPA no longer requires a chronic dog study as part of the required data set for pesticide registration, rather a 13 week study is deemed sufficient. The U. S. EPA Science Advisory Panel recently analyzed the value added by con ducting a 1 year study in the dog and found that the longer dura tion study in dogs does not add significantly to the ability to identify the critical adverse effect level.

The European Food Safety Authority PDE Inhibitors Panel on Plant Protection Products reached a similar conclusion that extension of a dog toxicity study beyond a 13 week duration provides little additional information. The panel compared effect levels from studies of rats versus dogs and for studies of different durations for the parent chemicals to evaluate the importance of missing studies for the degradates. These comparisons were only used as a qualitative guide because of the potential differences in mode of action for the degradates versus the parent chemicals. Similar data were also reviewed for the effect levels for various species and study durations for metola chlor, and its ESA degradate, for which a subchronic dog study was B.

Gadagbui et al. / Regulatory Toxicology and Pharmacology 57 220 234 233 available. This analysis HDAC-42 did not indicate that the subchronic dog study would warrant a greater UF D factor than con sidered by the panel. In no case of the parent chemicals did repro ductive or developmental toxicity drive the assessment, and in all three cases, dog and rat effect levels were roughly quantitatively similar, at the same study exposure length. Given that the four degradates are less reactive, absorbed to a lesser extent, and less metabolized when compared with the parent compounds, greater variability in toxicity among these degradates is not expected than observed with their parent compounds.

A combined value of 10 fold was recom mended by the panel for uncertainties in both the lack of certain studies to determine the critical effect and the lack of a chronic study as a basis of the RfD. This latter factor was considered by the panel to be best Ponatinib judged as 10, although it could be as high as 30, 2 because the available toxicology data for the parent compound suggest only a modest, if any, change between subchronic and chronic NOAELs, and the available information suggests that neither developmental nor reproductive toxicity is the critical effect. More over, the panel concluded that the same UF can be used for develop ing a safe dose for each degradate, because the chemical structures and data bases are similar and all have a similar spectrum of toxicity based on the available array of studies. Furthermore, no data were available that would suggest significant mode of action differences.

Thus, the panel considered that a PARP composite UF of 1000 for each degradate was reasonable. A composite UF of less than 1000 was not considered appropriate. 3. 5. Mode of action data to justify a cumulative risk assessment approach The potential for a cumulative risk assessment for these degra dates was evaluated based on potential commonalities in critical effects and their underlying modes of action. The panel concluded that the data are inadequate to identify the mode of action for any of the observed effects of the degradates, except perhaps for the proposed effect of irritation and the gastric effects observed in the 28 day study for alachlor OXA. In the absence of such data on mode of action, a cumulative risk assessment approach would not be supported for the four degradates.

Gastrointestinal side effects e, ritonavir is associated with nausea and vomiting. This study examines whether fighting Scutellaria baicalensis and its active component flavonoids, baicalein, the gastrointestinal effects HDAC of ritonavir to d. Effects of grass feeding was evaluated in rats with a rat pica model ritonavir, the nausea and vomiting simulated humans. The effects of administration of Kr Utern on gastric emptying in rats were also measured. Ritonavir treatment went Born f Depends kaolin or severe pica, whose intensity was reduced t fa They significantly with S. baicalensis administration. High-performance liquid chromatographic analysis showed the presence of S. baicalensis one ingredient extremely POWERFUL Hige flavonoids baicalein.
The study aimed to determine whether baicalein contributed in the fight against greenhouse gas pica extract. It was Tivozanib observed that baicalein dose- Ngig reduced pica treated rats with ritonavir. Zus Pica causing tzlich, ritonavir also significantly gastric emptying, the ritonavir-induced gastrointestinal dysfunction can help k Galv Siege. If S. baicalensis extract was administered to rats treated with ritonavir gastric emptying was significantly attenuated Cht. The results suggest that S. baicalensis and component baicalein reduce gastrointestinal dysfunction caused by ritonavir. It is concluded that S. baicalensis may potentially ask a him play in the reduction of drug-induced side effects. Introduction of protease inhibitors are h Frequently used, powerful anti-HIV drugs that act by inhibiting viral replication.
Drugs in this class, especially ritonavir, k Can unpleasant side effects such as gastrointestinal nausea and vomiting. Ritonavir is currently used in the treatment of HIV-rings in addition to other protease inhibitors ritonavir inhibits the enzyme from liver CYP3A used thereby. The plasma concentration and bioavailability of other antiviral drugs Although the dose of ritonavir for the adjuvant effects is less than that required for a direct antiviral effect required, nausea and vomiting continue to be reported in at least 20% of patients. Recent research on the pharmacological effects of other protease inhibitors have their F Ability to stimulate the release of reactive oxygen species in cultured cells demonstrated. Protease inhibitor ritonavir and other stimulate cultured endothelial cells, above the Strength amounts of superoxide radicals produce entered Ing Zellsch And the dysfunction.
Have recently published data suggest that ritonavir, oxidative stress in the human Body to increased hen. Since oxidative Sch Ending of the gastrointestinal mucosa has been been linked to the release of serotonin, and nausea and vomiting due, it was postulated that cause ritonavir k Can gastrointestinal side effects due to a Hnlichen mechanism. nausea and vomiting caused by oxidative caused etiology sensitive. to treatment with antioxidants Thus, the treatment with herbal antioxidants mitigate the effects induced gastrointestinal ritonavir. The present study examined the effect of Scutellaria baicalensis treatment, and its drug baicalein, Ritonavir effects on gastrointestinal side effects with two rat models, the pica model and the model of gastric emptying. Materials and Methods Anima

LY317615 Enzastaurin was limited to patients with CML CP. In the 17 patients treated with 240 mg BID, transaminase elevations were still observed but were less severe. No patients had drug related grade 3 AST elevations and only 1 patient had a drug related grade 3 ALT elevation. Drug related grade 2 ALT elevations occurred at the 240 mg BID dose level in 9 patients, and a grade 2 AST elevation developed in 1 patient. The elevated transaminase levels observed at 240 mg BID resolved when INNO 406 dosing was withheld temporarily and then resumed at a lower dose. Based on these results, an INNO 406 dose of 240 mg BID is proposed for phase 2 studies. In addition to elevated transaminases, the other most common drug related grade 3/4 adverse event noted was thrombocytopenia.
When both drug and non drugrelated thrombocytopenic events were considered, BMY 7378 2 and 3 patients experienced grade 3 and 4 thrombocytopenia, respectively, including 1 patient who initiated INNO 406 treatment with preexisting grade 4 thrombocytopenia. Platelet counts recovered when INNO 406 was withheld and then resumed at a lower dose. This study incorporated a planned central evaluation of electrocardiograms during the first cycle of therapy to assess for QT prolongation. During this period of intense monitoring, the QTcB increased to grade 2 in 4 patients and the QTcF increased to grade 2 in 1 patient. Only 1 patient, who entered the study with a waiver due to a prolonged QTc, developed a QTc 500 msec during this routine monitoring after cycle 1.
The patient experienced no further events after discontinuing INNO 406. The NCI categories of adverse events that were experienced by 10% of patients were metabolic/laboratory, gastrointestinal, pain, constitutional symptoms, infection, dermatology/skin, blood/bone marrow, lymphatics, neurology, pulmonary/upper respiratory, cardiac general, hemorrhage/bleeding, and musculoskeletal/soft tissue. Five patients have died since beginning treatment, all deaths were related to leukemia progression. Four deaths were among 16 patients in CML blastic phase or Ph positive ALL, 1 death was among 8 patients in CML accelerated phase, no deaths so far have been recorded among 31 patients in chronic phase. The 5 deaths did not appear to be correlated to dosing regimen: 1 at 30 mg daily, 2 at 120 mg daily, 1 at 480 mg BID, 1 at 360 mg BID.
No cases of pleural or pericardial effusions were noted. Efficacy Table 3 provides a detailed summary of cytogenetic responses. All of the patients who achieved a cytogenetic response had CML CP. No responses were observed in patients with CML AP, CML BP, or Ph positive ALL. Major cytogenetic responses were noted in 6 patients with CML CP. Three patients had a complete cytogenetic response, one at each of the INNO 406 dose schedules of 120 mg QD, 120 mg BID, and 240 mg BID. The remaining3 patients had a partial cytogenetic response: 2 patients at 240 mg BID and 1 patient at 480 mg BID. None of the six major cytogenetic responders had baseline cytogenetic clonal evolution. Thus, 4 of the major cytogenetic responses occurred in patients treated with INNO 406 doses of 240 mg BID or greater. This represents a major cytogenetic responses rate of 11% for all patients enrolled, and a rate of 19%

Sorafenib as a single agent in advanced melanoma have no significant anti-tumor activity T be detected. Only 19% of patients had stable disease with progression-free survival of 16 37 weeks w While 62% had progressive disease with progression-free survival of 11 weeks. No relationship between B RAF mutation status and stable disease was Dapagliflozin observed concerns about the clinical benefit of targeting RAF B treatment of melanoma. The concern over the failure of sorafenib in the hospital led to the first, the development of more effective treatments, and specific inhibitors V600EBRAF targeted. Second Pr clinical trials evaluating whether targeting V600EB RAF alone was sufficient, or whether other members of the MAPK pathway should be targeted in combination for inhibition of melanoma effectively.
Thirdly siRNA targeting by V600EB RAF, MEK1 / 2, ERK1 / 2, cyclin D1, or to determine which member of MAPKpathway to targeted inhibit the development KRN 633 of melanoma, which showed MEK1 / 2 inhibition, the most effective in reducing lung metastases of melanoma development. Fourth, the finding that melanoma with mutated B RAF sensitive to agents targeting MEK in the MAPK pathway are that tumors with wild-type B-RAF or RAS mutation. Fifth, improve sorafenib combination with other drugs for efficacy. Studies sorafenib combined with carboplatin and paclitaxel has shown clinical efficacy only an overall response rate of 26% and myelosuppressive toxicity th Because of the combination with carboplatin and paclitaxel likely.
A Phase II study to evaluate the efficacy of the alkylating agent dacarbazine or temozolomide in combination with sorafenib in advanced stage melanoma patients showed a median progression-free survival with no statistically significant 21.1 weeks for the combination of sorafenib with dacarbazine compared with 11.7 weeks for placebo plus dacarbazine. Unfortunately, no improvement in overall survival was achieved with this combination. A phase III study, the combination of sorafenib with carboplatin and paclitaxel as second-line therapy in patients with unresectable stage III or stage IV melanoma was less promising with a response rate of 12% and 17.9 months, progression-free survival time for placebo plus carboplatin compared with 17.4 months progression-free survival with a combination of sorafenib plus carboplatin.
Sun clinical trials with sorafenib resulted in the conclusion that targeting RAF B can be more effective in combination with other chemotherapeutic agents is pleased t that goal only. Several new compounds have been developed to RAF B, the pharmacological properties improved in comparison with sorafenib, which evaluated in clinical studies target. To go RAF Ren 265 and PLX4032. RAF 265 is a broad spectrum inhibitor of VEGF receptor 2, and the MAP kinase pathway. It inhibits the proliferation of melanoma cells harboring mutations RAF B and to a lesser extent N RAS mutation, wherein substantially no activity t Against cells where these mutations. RAF 265 completely Constantly inhibits the phosphorylation of ERK, and induce regression of melanoma can containing mutant B RAF animal models. PLX4032 is an inhibitor of RAF kinase activity bioavailable with t Times against the RAF V600EB compared to wild-type t

IKK and IKK catalytic subunits and the IKK? regulatory subunit is activated, resulting in I?B phosphorylation and eventual ubiquitinmediated degradation, leading to the nuclear entry of freed NF ?B dimmers. Of the two catalytic subunits, IKK is the one which is most critical for I?B degradation, forming the core of what is known as AT7519 the classical NF ?B activation pathway. By contrast, IKK is required for the inducible processing of the inactive p100 protein to its active derivative p52, thus forming the core of the so called alternative NF ?B pathway. A link between NF ?B and cancer first became evident with the cloning of RelA and the realization of its close kinship with the viral oncoprotein v Rel. The view was further supported by observations of activated NF ?B in many human cancers.
In addition, the Bcl 3 oncogene, activated by chromosomal translocation in B cell chronic lymphocytic leukemia, was identified as a member of the I?B family. More recently, mutations in upstream components of the IKK NF ?B signaling system were identified in multiple myeloma and are thought to lead to cell  autonomous activation of NF ?B, thereby enhancing cell survival and proliferation. However, extensive search failed to identify NF ?B activating mutations in most other cancers and most likely cancer associated constitutive NF ?B activities Bergenin are the result of exposure to pro inflammatory stimuli in the tumor microenvironment. Hepatocyte IKK dependent NF ?B signaling suppresses liver cancer development by promoting hepatocyte survival A key role of NF ?B in liver homeostasis was first revealed by studying RelA/p65 deficient mice, which suffer embryonic lethality with extensive liver apoptosis and degeneration.
This liver apoptosis is induced by TNF and backcrossing of p65 knockout mice with TNFor TNF receptor 1 deficient mice prevents liver damage and the lethal phenotype. Later on, IKK and IKK? knockout mice were found to exhibit very similar phenotypes. These genetic studies clearly demonstrate an anti apoptotic role for IKK dependent NF ?B signaling in hepatocytes, mainly during early liver development. The role of IKK dependent classical NF ?B signaling in adult mouse liver physiology, however, is more complex. Mice with hepatocytes specific ablation of IKK develop normally and their livers are not even sensitive to administration of LPS, a strong TNF inducer.
However, careful analysis suggests that residual hepatocyte IKK activity in Ikk?hep mice may be sufficient for TNF induced NF ?B activation, which is completely blocked by an additional ablation of IKK. These results suggest that IKK and IKK in adult hepatocytes may have somewhat redundant functions in suppressing apoptosis and necrosis. Indeed, unlike Ikk?hep mice, Ikk/Ikk?hep mice or mice deficient of the regulatory component IKK? in hepatocytes suffer from extensive hepatocyte death and liver failure upon TNF inducing challenges. Furthermore, Ikk??hep or Ikk/Ikk?hep mice exhibit spontaneous liver damage, which is not seen in Ikk?hep mice. Like Ikk?hep mice, mice deleted of RelA in hepatocytes are also healthy unless challenged and exposed to TNF. Based on available evidence, it is safe to conclude that the IKK/NF ?B pathway is important for hepatocyte survival and maintenance of liv

Single voxel spectroscopy was performed using the following parameters: PRESS, TR 3000ms/TE 30ms, 90 degree flip angle, NEX 8, FOV 16, with a volume of interest of 2?2?3cm. During each session, bcl-2 two separate SVS sequences were performed, once with the VOI placed in the right anterior insula and once in the right posterior insula. The approximate Montreal Neurological Institute coordinates for the center of the anterior and posterior voxels were: 34,19,0 and 38, 17,8 respectively. These coordinates include regions shown previously to be activated during acute pain. Also functional magnetic resonance imaging trials in FM have shown augmented pain activity in these regions. Given the time constraints for our H MRS session, we examined the right insula since it was contralateral to the pain stimuli previously used in our fMRI trials of FM.
Participants were at rest during the H MRS session. The raw data from each single voxel MR spectroscopy sequence underwent manual post processing using H MRS software. LCModel uses a linear combination of individual spectra obtained from pure molecular species to fit the experimental spectra. Values for Glu, glutamine, combined GluGln, and other metabolites including: N acetyl aspartate, INCB018424 choline compounds, creatine, and myoinositol were calculated as absolute concentrations using the water signal for normalization. Resulting metabolite absolute concentrations were reported in arbitrary institutional units. Since our voxels incorporated cerebrospinal fluid and the volume of CSF dilutes H MRS derived metabolite values, we corrected our metabolite levels for CSF volume for each participant.
For this we used Voxel Based Morphometry, a toolbox which operates within the image analysis program Statistical Parametric Mapping. High resolution T1 images were segmented into gray matter, white matter, and CSF and then regions of interest within the anterior and posterior insula were used to extract gray matter, white matter, and CSF volumes from these images using the SPM2 toolbox Marsbar. Metabolite values were corrected by dividing the observed concentration in AIU by the percentage of volume of the entire voxel that was not occupied by CSF. Corrected metabolite concentrations were entered into SPSS v. 16 for calculation of differences between FM and HC groups and correlational analyses with pain outcomes. Harris et al.
Page 3 Arthritis Rheum. Author manuscript, available in PMC 2010 October 1. Experimental Pain Pressure pain tenderness was assessed prior to the H MRS session as described previously. Briefly, discrete pressure stimuli were applied to the subject,s thumbnail using a stimulation device which eliminates any direct examiner/subject interaction. Pain intensity ratings were recorded on the Gracely Box Scale questionnaire using a random presentation paradigm. During the testing, stimulus pressures were determined interactively: a computer program continuously adjusted stimulus pressure levels to produce the same response distribution in each subject. Pressure pain thresholds were then correlated with H MRS derived metabolite levels using SPSS v. 16. Statistical Analyses Metabolite levels and pain ratings were entered into SPSS v. 16. We performed two way ANOVAs to determine differences in metabolite levels wit

. The hearts were with PBS containing 3% formalin in OCT compound and 6 m thick serial sections were embedded perfused using a cryostat. Four sections, each separated by 60 m, PHA-680632 Aurora Kinase inhibitor were used in order to evaluate L versions: two at the end of the aortic sinus and two at the junction of the aortic sinus and the ascending aorta. Sections were matoxylin with resistance L-red O and H. Images of the sections were mounted with a digital camera on an optical microscope and analyzed caught with Photoshop 6.0. Other methods of analysis. Protein concentrations were determined by the Bradford method using the Bio-Rad protein assay kit. Statistics. All experimental data are expressed as mean SD. The significance of the mean difference was r with the Student test. A p-value of 0.05 was considered significant.
Regression analyzes were performed using StatView. Inhibition results in the accumulation of droplets Lipidtr Beauveriolides in macrophages. In this assay, macrophages, large amounts of e Lipidtr Droplets INCB018424 accumulated in the cytosol when macrophages were incubated with the liposome. Under these conditions, a dose–Dependent inhibition of the accumulation of Lipidtr Droplets by beauveriolides I and III caused no morphological changes and changes Or cytotoxic effects were observed in macrophages at concentrations up to 20 M. However, in structurally related Cyclodepsipetides as Enniatins showed no or only minor inhibition of the accumulation of droplets Lipidtr even at 20 M, and although beauvericin showed inhibition of the accumulation of droplets Lipidtr he was severe morphological Ver accompanies changes and cytotoxicity t of macrophages.
Thus, among the tested Cyclodepsipetides beauveriolides I and III are very specific inhibitors of lipid accumulation in the cytosolic tears droplets mouse peritoneal macrophages. Selective inhibition of CE synthesis in macrophages by Beauveriolides. In view of the enrichment of Fetttr Droplets in murine macrophages, 40% Ls Ure was exogenous neutral lipids, cholesterol and triglycerides, oleate, which are the main constituents of the droplets Lipidtr Are incorporated cytosols. As shown in FIG. 2 beauveriolides I and III strongly inhibited the synthesis of EC dosedependent manner with IC50 values of 0.78 and 0.41 m, respectively, but showed almost no inhibition of TG synthesis and in the h Next dose h from What indicating that the synthesis inhibit beauveriolides EC in macrophages.
Beauvericin, Enniatins bassianolides and showed no selective inhibition not only CE and TG synthesis, but the synthesis 14Cphospholipid were blocked with Hnlichen IC50 values, indicating that it was due to their cytotoxic effect on macrophages. Thus, among the beauveriolides Cyclodepsipetides I and III are the only compounds that selectively inhibit the synthesis of CE. Best this data Correct the results of the accumulation of Lipidtr Droplets in macrophages, as described above. Inhibition of cholesterol metabolism in macrophages by Postlysosomal Beauveriolides. To beauveriolides an insight into the target molecule in the inhibition of Anh Ufung of Lipidtr Droplets get into macrophages, the effect of the method beauveriolides postlysosomal cholesterol metabolism was examined. When macrophages were incubated spirit

Al development before diseases other than cancer PHA-680632 overexpressing HER2 aligned. It’s anti-tumor activity t in HER2 overexpressing cancer t is not known, but it has little activity t in T sloping breast cancer overexpressing HER2 Hlt and ovarian cancer. Activity 2C4 or pertuzumab e were on the signaling pathways investigators Hlt weight was reported there. These funds are not in the community gr Eren available science compared with mAb 4D5 or trastuzumab, a monoclonal antibody Body 2C4 body antiproliferative activity T tr in vitro Gt much less studied, but in vivo Antitumoraktivit Tt in a number of tumor types, including normal normal without tumors overexpress HER2. 2C4 is reported to inhibit HER2-mediated heregulin complex formation, phosphorylation and activation of Akt and MAPK in breast cancer cells without HER2 overexpression.
Determine the effect of pertuzumab in HER2 overexpression expected much more studies and clinical pr. Targeting HER2 kinase inhibitors with the technique was selective inhibitors WZ3146 of the tyrosine kinase human therapeutics for old K Body. Able to develop almost a decade This means, at least in theory, have some advantages over the old K Body therapies for the treatment of HER2-amplified tumors. Antique cell therapies K Body know undurchl SVGW agents who extracellular Re Dom Ren does the HER2 protein, and to this day we have not known whether and how this binding activity tt Suppress the function of the HER2 oncogene induce even if they clinically significant immunological k bind k can specifically target cancer cells overexpressing HER2.
TKI-dependent agents are cell-permeable and kmh Lt can Kinaseaktivit inhibit T-dependent-Dependent ligand-dependent And independent-Dependent intracellular Ren Ren HER2 load makes Cathedral. This strategy is based on a solid foundation, like a T-kinase activity of t Again for efficient oncogenic function or HER2 is based. At least in theory, this means the possibility M M, the function of the HER2 kinase in cancer patients, HER2 overexpression and for the first time directly test the hypothesis that patients clear HER2 oncogene. TKI, but don t have. Target property of the unique old Ren Rpern and their effects called potentially limiting their wide therapeutic index compared to the old rpern The development of selective inhibitors ITS TKI synthetic and natural structures different kinases have been studied in the 1990s, but their limited power and specificity t E Prevents use as an antitumor agent.
The field has been revolutionized by the discovery of quinazoline ge Changed highly specific and potent inhibitors of the epidermal growth factor receptor. Extensive structure-activity Ts relationships were determined Ts and improved many quinazoline were then with th selectivity Stop for various functions makes your family have been developed. Quinazolines year other structures have been found fa POWERFUL Hige and selectively inhibit HER-kinases. In Table 2, a number of TKI was disclosure Public and pr available clinical data were available. In addition, many other agents are in development that have not yet announced in this post. Almost all of these agents are analogs of ATP and

Woon Kim, and Bo Lu1 Department of Radiation Oncology, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee Abstract Aurora kinase B is critical SRT1720 SRT-1720 to the process of mitosis, aiding in chromosome condensation by phosphorylating histone H3. We investigated the effects of AZD1152, an AURKB inhibitor, on radiosensitivity of androgen insensitive prostate cancer cells. The goal of this study was to test whether AZD1152 increases the susceptibility of hormone refractory prostate cancer cells to radiation induced DNA damage and to determine the conditions of AZD1152 treatment that maximize radiosensitization. PC3 and DU145 cells were treated with various AZD1152 doses for various durations to elucidate the conditions that yielded maximal increases in G2/M phase and polyploid cells.
To assess DNA damage, γ H2AX phosphorylation was quantified for cells grown under radiosensitizing conditions and subjected to either no radiation or 5 Gy radiation. Radiosensitivity was determined Triciribine by clonogenic assays. Cell cycle effects in both cell lines were maximized by treatment with 60 nM AZD1152 for 48 h. AZD1152 treated cells exhibited significantly increased DNA damage 30 min postirradiation , with additional DNA damage 6 h postirradiation . Radiosensitivity was increased in both cell lines, with dose enhancement ratios of 1.53 for PC3 cells and 1.71 for DU145 cells . This study identifies the optimal AZD1152 treatment conditions to maximize the radiosensitization of PC3 and DU145 cells. These results suggest a major role for DNA damage and impairment of DNA repair mechanisms in AZD1152 induced radiosensitization of prostate cancer cells.
INTRODUCTION Prostate cancer is the most commonly diagnosed non cutaneous malignancy in men in the U.S., with an estimated 186,320 new cases in 2008 . Surgical resection, radiation therapy and hormone therapy are the main treatment modalities for prostate cancer. Although there are several promising treatment strategies, prostate cancer continues to be a major cause of cancer death in males in the U.S. The most challenging cases of prostate cancer include those that are insensitive to androgen blockade and those that have become hormone refractory after initial hormone and radiotherapy treatment. Aurora Kinase B has recently emerged as a promising therapeutic target for several malignancies.
Aurora kinases are a class of serine/threonine kinases necessary for cell cycle progression. AURKB is a component of the chromosomal passenger complex, functioning in chromosome orientation and in regulation of spindle attachment . © 2011 by Radiation Research Society. 1Address for correspondence: Department of Radiation Oncology, Vanderbilt University, 1301 22nd Avenue South, B 902 TVC, Nashville, TN, bo.luvanderbilt. NIH Public Access Author Manuscript Radiat Res. Author manuscript, available in PMC 2012 April 1. Published in final edited form as: Radiat Res. 2011 April , 175: 444 451. doi:10.1667/RR2317.1. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript AURKB phosphorylates histone H3 at the serine 10 position, allowing for chromosome condensation, thus facilitating cytokinesis .
In normal cell lines, expression of AURKB naturally peaks at the G2/M cell cycle phase transition, thus facilitating cell cycle progression at this juncture . AURKB overexpression is associated with increased genomic instability, and upregulation of the protein has been detected in a number of solid tumors, including prostate cancer . Additionally, its expression has been associated with poorer prognoses in ovarian, brain and hepatocellular carcinomas . Inhibition of AURKB activity has been shown to result in shrinkage of tumor xenografts via induction of apoptosis and radiosensitization . Because of the association of AURKB upregulation with tumorigenesis, inhibition of this kinase may prove to be a promising treatment strategy for a variety of cancers. AZD1152, along with other inhibitors o

ced hematological malignancies. BMS-754807 BMS754807 Blood . 2008, 112 abstr 2963. 150. Mahadevan D, Qi W, Cooke L, et al. Targeting aurora kinase in aggressive B cell non Hodgkin,s lymphomas. Blood . 2009, 114 abstr 284. 151. den Hollander J, Rimpi S, Doherty JR, et al. Aurora kinases A and B are up regulated by Myc and are essential for maintenance of the malignant state. Blood. 2010, 116:1498 505. 152. Yang D, Liu H, Goga A, et al. Therapeutic potential of a synthetic lethal interaction between the MYC proto oncogene and inhibition of aurora B kinase. Proc Natl Acad Sci U S A. 2010, 107:13836 41. Green et al. Page 22 Expert Opin Drug Discov. Author manuscript, available in PMC 2012 March 1. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript Figure 1.
Sensitizing Cancer Cells to SAC inhibition plus microtubule targeting agents to optimize enhanced Apoptosis Green et al. Page 23 Expert Opin Drug Discov. Author manuscript, available in PMC 2012 March 1. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript Green et al. Page 24 Table 1 IC50 for JNJ-38877605 selected Aurora kinase inhibitors IC50 values in nM Aurora A kinase Aurora B kinase Aurora C kinase Reference ENMD 981693 25 700 NA 23 ENMD 2076 14 350 NA 24 MK 5108/VX 689 0.064 14 12 29 MLN 8054 4 172 NA 32 MLN 8237 1 >200 NA 44 XL 228 3 NA NA 52 KW 2449 48 NA NA 55 Hesperadin NA 50 NA 10 BI 811283 NA 9 NA 57 AZD 1152 1369 0.36 17 20 GSK 1070916 490 0.38 1.5 81 ZM 447439 100 100 NA 77 JNJ 7706621 11 15 NA 89 AT 9283 3 3 NA 90 PF 03814735 5 0.
8 NA 101 VX 680/MK 0457 0.7 18 4.6 10 PHA 680632 27 135 120 64 PHA 739358 13 79 61 125 CYC 116 44 19 65 131 SNS 314 9 31 3.4 136 AMG 900 5 4 1 139 VE 465 1 26 8.7 142 AS 703569 4 4.8 6.8 145 NA = Not available Expert Opin Drug Discov. Author manuscript, available in PMC 2012 March 1. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript Green et al.
Page 25 Table 2 Evidence of clinical activity of Aurora kinase inhibitors by malignancy and study design* Breast Bladder Head and Neck Lung Prostate Renal Cell Colorectal Pancreatic Hepatocellular Melanoma Glioma Ovarian Endometroid Carcinoma Cervix Acute Myelogenous Leukemia Chronic Myelogenous Leukemia Acute Lymphoblastic Leukemia Multiple Myeloma Lymphomas Mantle Cell Lymphoma Myeloproliferative Disorders ENMD 981693 1 1 1 1 1 ENMD 2076 1,2 1,4 1 4 1 1,2 MK 5108/VX 689 1 1 1 1 1,2 1 1 MLN 8054 1,6 6 6 1,6 1 1,6 6 6 6 1,6 1 MLN 8237 1,2 4 1,4 2 1,4 4 1,2 1,2 1 1 1,2 1,2 XL 228 4 1,4 1,4 KW 2449 1,4 1,4 1 BI 811283 1 1 AZD 1152 1 1 1,2 1 1 1 1 1,2 1 1,2 1 1,2 GSK 1070916 1,3 1 1 1 1 ZM 447439 1 1 1 1 1 JNJ 7706621 1 1 1 1 1 1 AT 9283 1 1,4,6 1,6 1 1 1,4 1,4 1 1 PF 03814735 1,6 6 6 1,6 6 1,6 6 1 1 VX 680/MK 0457 1,2 6 2,6 1,2,6 1,6 1,6 1,6 1,2,6 1,2,4 1,2,4,5 1,2,4,5 1 1,2 1,4 PHA 680632 1 1 1 1 1 1 PHA 739358 1,5,6,7 1,4 1,6 1,6 1,5,6 6,7 1 1,5,6,7 1 1 1,2,4 1,4 CYC 116 1 1 1 1 SNS 314 1 1 1 1,2 AMG 900 1 1 1 1 1 1 1 1 1 1 1 1 1 VE 465 1,2 1 1 1,2 1,2 1,2 1,2 AS 703569/R 763 1 1 1 1 1 1 1 1,4 1,4 1 1 1 Single drug efficacy, Preclinical�? 2 Combination efficacy, Preclinical�? Expert Opin Drug Discov.
Author manuscript, available in PMC 2012 March 1. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript Green et al. Page 26 3 No/minimal efficacy, Preclinical�? 4 Single drug efficacy, Phase I�? 5 Combination efficacy, Phase I�? 6 No/minimal efficacy, Phase I�? 7 Single drug efficacy, Phase II�?* Where data available/reported, �?Defined as objective response or partial/complete response, �?Defined as stable disease or no objective response Expert Opin Drug Discov. Author manuscript, available in PMC 2012 March 1. Enhanced Radiosensitivity of Androgen Resistant Prostate Cancer: AZD1152 Mediated Aurora Kinase B Inhibition Kenneth J. Niermann, Luigi Moretti, Nicholas J. Giacalone, Yunguang Sun, Stephen M. Schleicher, Prapaporn Kopsombut, Lauren R. Mitchell, Kwang