bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Effect of Doxorubicin and Zoledronic Acid on Intraosseous versus Extraosseous Breast Tumor GrowthIn vivo
Authors: Ottewell Penelope D. , Deux Blandine , Mönkkönen Hannu , Cross Simon , Coleman Robert E. , Clezardin Philippe , Holen Ingunn 
Published: July 2008

AbstractPurpose: Breast cancer patients with bone metastases are commonly treated with chemotherapeutic agents such as doxorubicin and zoledronic acid to control their bone disease. Sequential administration of doxorubicin followed by zoledronic acid has been shown to increase tumor cell apoptosis in vitro. We have therefore investigated the antitumor effects of clinically relevant doses of these drugs in a mouse model of breast cancer bone metastasis.Experimental Design: MDA-MB-231/BO2 cells were injected via the tail vein into athymic mice. Tumor-induced osteolytic lesions were detected in all animals following X-ray analysis 18 days after tumor cell inoculation (day 18). Mice were administered saline, 100 μg/kg zoledronic acid, 2 mg/kg doxorubicin, doxorubicin and zoledronic acid simultaneously, or doxorubicin followed 24 h later by zoledronic acid. Doxorubicin-treated animals received a second injection on day 25. Tumor growth in the marrow cavity and on the outside surface of the bone was measured as well as tumor cell apoptosis and proliferation. The effects of treatments on bone were evaluated following X-ray and μCT analysis.Results: Sequential treatment with doxorubicin followed by zoledronic acid caused decreased intraosseous tumor burden, which was accompanied by increased levels of tumor cell apoptosis and decreased levels of proliferation, whereas extraosseous parts of the same tumors were unaffected. Administration of zoledronic acid, alone or in combination with doxorubicin, resulted in significantly smaller tumor-induced osteolytic lesions compared with control or doxorubicin-treated animals.Conclusions: This is the first study to show that sequential treatment with clinically relevant doses of doxorubicin, followed 24 h later by zoledronic acid, reduces intraosseous but not extraosseous growth of BO2 breast tumors. Our results suggest that breast cancer patients with metastatic bone disease may benefit from sequential treatment using doxorubicin and zoledronic acid.
Transformation by Oncogenic Mutants and Ligand-Dependent Activation of FLT3 Wild-type Requires the Tyrosine Residues 589 and 591
Authors: Vempati Sridhar , Reindl Carola , Wolf Ulla , Kern Ruth , Petropoulos Konstantin , Naidu Vegi M. , Buske Christian , Hiddemann Wolfgang , Kohl Tobias M. , Spiekermann Karsten 
Published: July 2008

Abstract
Purpose: Mutations in the receptor tyrosine kinase FLT3 are found in up to 30% of acute myelogenous leukemia patients and are associated with an inferior prognosis. In this study, we characterized critical tyrosine residues responsible for the transforming potential of active FLT3-receptor mutants and ligand-dependent activation of FLT3-WT.
Experimental Design: We performed a detailed structure-function analysis of putative autophosphorylation tyrosine residues in the FLT3-D835Y tyrosine kinase domain (TKD) mutant. All tyrosine residues in the juxtamembrane domain (Y566, Y572, Y589, Y591, Y597, and Y599), interkinase domain (Y726 and Y768), and COOH-terminal domain (Y955 and Y969) of the FLT3-D835Y construct were successively mutated to phenylalanine and the transforming activity of these mutants was analyzed in interleukin-3-dependent Ba/F3 cells. Tyrosine residues critical for the transforming potential of FLT3-D835Y were also analyzed in FLT3 internal tandem duplication mutants (FLT3-ITD)and the FLT3 wild-type (FLT3-WT) receptor.
Result: The substitution of the tyrosine residues by phenylalanine in the juxtamembrane, interkinase, and COOH-terminal domains resulted in a complete loss of the transforming potential of FLT3-D835Y-expressing cells which can be attributed to a significant reduction of signal tranducer and activator of transcription 5 (STAT5) phosphorylation at the molecular level. Reintroduction of single tyrosine residues revealed the critical role of Y589 and Y591 in reconstituting interleukin-3-independent growth of FLT3-TKD-expressing cells. Combined mutation of Y589 and Y591 to phenylalanine also abrogated ligand-dependent proliferation of FLT3-WT and the transforming potential of FLT3-ITD-with a subsequent abrogation of STAT5 phosphorylation.
Conclusion: We identified two tyrosine residues, Y589 and Y591, in the juxtamembrane domain that are critical for the ligand-dependent activation of FLT3-WT and the transforming potential of oncogenic FLT3 mutants.
Function of JunB in Transient Amplifying Cell Senescence and Progression of Human Prostate Cancer
Authors: Konishi Noboru , Shimada Keiji , Nakamura Mitsutoshi , Ishida Eiwa , Ota Ichiro , Tanaka Nobumichi , Fujimoto Kiyohide 
Published: July 2008

Abstract
Purpose: Replicative senescence in cells acts as a barrier against excessive proliferation and carcinogenesis. Transient amplifying cells (TAC) are a subset of basal cell populations within the prostate from which cancers are thought to originate; therefore, we focused on prostate TAC to investigate the molecular mechanisms by which the TAC may be able to evade senescence.
Experimental Design: TAC clones were isolated from each zone within the whole prostate and analyzed in flow cytometry. Prostate cancer cells were transfected with junB small interfering RNA (siRNA) and examined by chorioallantoic membrane assay for cancer invasion. Immunohistochemical analysis was done in primary and metastatic prostate cancer specimens.
Results: TAC populations showed increased expression of p53, p21, p16, and pRb, resulting in senescence. TAC clones with reduced p16 expression successfully bypassed this phase. We further found close correlation between the levels of junB and p16 expression. Repeated transfection of junB siRNA in prostatic TAC allowed the cells to escape senescence presumably through inactivation of p16/pRb. The chorioallantoic membrane invasion assay showed much lower in invasive cancer cells with high expression of junB; conversely, silencing of junB by transfection with junB siRNA promoted invasion. We also found that metastatic prostate cancers, as well as cancers with high Gleason scores, showed significantly low junB immunopositivity.
Conclusions: JunB is an essential upstream regulator of p16 and contributes to maintain cell senescence that blocks malignant transformation of TAC. JunB thus apparently plays an important role in controlling prostate carcinogenesis and may be a new target for cancer prevention and therapy.
ABCB1 Genetic Variation Influences the Toxicity and Clinical Outcome of Patients with Androgen-Independent Prostate Cancer Treated with Docetaxel
Authors: Sissung Tristan M. , Baum Caitlin E. , Deeken John , Price Douglas K. , Aragon-Ching Jeanny , Steinberg Seth M. , Dahut William , Sparreboom Alex , Figg William D. 
Published: July 2008

Abstract
Purpose: Polymorphisms that are associated with ABCB1 expression and function may be linked to treatment efficacy and the development of neutropenia and neurotoxicity in patients with androgen-independent prostate cancer receiving docetaxel.
Experimental Design: Patients with androgen-independent prostate cancer treated with docetaxel alone (n = 23) or docetaxel and thalidomide (n = 50) were genotyped for the ABCB1 1236C&gt;T, 2677 G&gt;T/A, and 3435 C&gt;T alleles by direct sequencing, and diplotypes were constructed using an EM algorithm. The data were then compared with duration to onset of peripheral neuropathy, neutropenia grade, and survival after docetaxel.
Results: For patients receiving docetaxel alone, individuals carrying a diplotype consisting of the 1236C-2677G-3435C linked alleles had improved overall survival after treatment (P = 0.0017). Additionally, patients treated with docetaxel and thalidomide carrying a diplotype consisting of the 2677T-3435T haplotype had a shorter median survival (P = 0.045). After adjusting for a particular set of polymorphisms and diplotype groupings, a hazard ratio of 10.87 was found for patients carrying the 2677GG genotype versus patients carrying other genotypes (P = 0.0048) in the docetaxel and thalidomide cohort. Among both treatment arms together, individuals carrying the 2677GG genotype also had a significantly longer time to neuropathy (P = 0.035). Finally, there was a strong trend toward patients carrying the 2677TT-3435TT diplotype having higher grades of neutropenia (P = 0.053).
Conclusion: The data suggest that docetaxel-induced neuropathy, neutropenia grade, and overall survival could be linked to ABCB1 allelic variants with ensuing negative implications for docetaxel treatment in patients carrying ABCB1 variant genotypes.
Histone Deacetylase Inhibitor Panobinostat Induces Clinical Responses with Associated Alterations in Gene Expression Profiles in Cutaneous T-Cell Lymphoma
Authors: Ellis Leigh , Pan Yan , Smyth Gordon K. , George Daniel J. , McCormack Chris , Williams-Truax Roxanne , Mita Monica , Beck Joachim , Burris Howard , Ryan Gail , Atadja Peter , Butterfoss Dale , Dugan Margaret , Culver Kenneth , Johnstone Ricky W. , Prince H. Miles 
Published: July 2008

Abstract
Purpose: Histone deacetylase inhibitors can alter gene expression and mediate diverse antitumor activities. Herein, we report the safety and activity of the histone deacetylase inhibitor panobinostat (LBH589) in cutaneous T-cell lymphoma (CTCL) and identify genes commonly regulated by panobinostat.
Experimental Design: Panobinostat was administered orally to patients with CTCL on Monday, Wednesday, and Friday of each week on a 28-day cycle. A dose of 30 mg was considered excessively toxic, and subsequent patients were treated at the expanded maximum tolerated dose of 20 mg. Biopsies from six patients taken 0, 4, 8, and 24 h after administration were subjected to microarray gene expression profiling and real-time quantitative PCR of selected genes.
Results: Patients attained a complete response (n = 2), attained a partial response (n = 4), achieved stable disease with ongoing improvement (n = 1), and progressed on treatment (n = 2). Microarray data showed distinct gene expression response profiles over time following panobinostat treatment, with the majority of genes being repressed. Twenty-three genes were commonly regulated by panobinostat in all patients tested.
Conclusions: Panobinostat is well tolerated and induces clinical responses in CTCL patients. Microarray analyses of tumor samples indicate that panobinostat induces rapid changes in gene expression, and surprisingly more genes are repressed than are activated. A unique set of genes that can mediate biological responses such as apoptosis, immune regulation, and angiogenesis were commonly regulated in response to panobinostat. These genes are potential molecular biomarkers for panobinostat activity and are strong candidates for the future assessment of their functional role(s) in mediating the antitumor responses of panobinostat.
Lenalidomide Enhances Natural Killer Cell and Monocyte-Mediated Antibody-Dependent Cellular Cytotoxicity of Rituximab-Treated CD20+ Tumor Cells
Authors: Wu Lei , Adams Mary , Carter Troy , Chen Roger , Muller George , Stirling David , Schafer Peter , Bartlett J. Blake 
Published: July 2008

AbstractPurpose: Lenalidomide has significant activity in myelodysplastic syndromes, multiple myeloma, and non-Hodgkin's lymphoma (NHL). In previous studies, natural killer (NK) cell expansion by lenalidomide was shown to enhance the cytotoxic effect of rituximab. This study assessed the ability of lenalidomide to enhance antibody-dependent cellular cytotoxicity (ADCC) in rituximab-treated NHL cell lines and primary tumor cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) in vitro.Experimental Design: An in vitro ADCC system was used to assess the ability of lenalidomide to enhance human NK cell and monocyte function in response to rituximab.Results: Lenalidomide directly enhanced IFN-γ production via Fc-γ receptor-mediated signaling in response to IgG. It was also a potent enhancer of NK cell-mediated and monocyte-mediated tumor cell ADCC for a variety of rituximab-treated NHL cell lines in vitro, an effect that was dependent on the presence of antibody and either interleukin-2 or interleukin-12. Lenalidomide also enhanced the ability of NK cells to kill primary tumor cells derived from three patients with B-CLL who have been treated previously with fludarabine plus cyclophosphamide. Enhanced NK cell ADCC was associated with enhanced granzyme B and Fas ligand expression and could be inhibited by a granzyme B inhibitor and partially inhibited by antibody to FasL. Enhanced NK cell Fc-γ receptor signaling is associated with enhanced phosphorylated extracellular signal-related kinase levels leading to enhanced effector function.Conclusions: These findings suggest that lenalidomide has the potential to enhance the rituximab-induced killing of NHL cell lines and primary B-cell chronic lymphocytic leukemia cells via a NK cell-mediated and monocyte-mediated ADCC mechanism in vitro, providing a strong rationale for the combination of lenalidomide with IgG1 antibodies to target tumor-specific antigens in patients with cancer.
KML001 Cytotoxic Activity Is Associated with Its Binding to Telomeric Sequences and Telomere Erosion in Prostate Cancer Cells
Authors: Phatak Pornima , Dai Fangping , Butler Melody , Nandakumar M.P. , Gutierrez Peter L. , Edelman Martin J. , Hendriks Hans , Burger Angelika M. 
Published: July 2008

Abstract
Purpose: KML001 (sodium metaarsenite) is an orally bioavailable arsenic compound that has entered phase I/II clinical trials in prostate cancer. In this study, we elucidated the mode of action of KML001 and investigated its effects on telomerase and telomeres.
Experimental Design: We compared telomere length to KML001 cytotoxic activity in a panel of human solid tumor cell lines. Duration of exposure and concentrations of KML001 that affect telomerase and telomeres were evaluated in relation to established mechanisms of arsenite action such as reactive oxygen species–related DNA damage induction. Binding of KML001 to telomeres was assessed by matrix-assisted laser desorption/ionization mass spectrometry.
Results: We established a significant inverse correlation (r2 = 0.9) between telomere length and cytotoxicity. KML001 exhibited activity in tumor cells with short telomeres at concentrations that can be achieved in serum of patients. We found that telomerase is not directly inhibited by KML001. Instead, KML001 specifically binds to telomeric sequences at a ratio of one molecule per three TTAGGG repeats leading to translocation of the telomerase catalytic subunit into the cytoplasm. In prostate cancer cells with short telomeres, KML001 caused telomere-associated DNA damage signaling as shown by γ-H2AX induction and chromatin immunoprecipitation assays as well as a rapid telomere erosion shown by metaphase fluorescence in situ hybridization. These effects were not seen in a lung cancer cell line with long telomeres. Importantly, arsenification of telomeres preceded DNA lesions caused by reactive oxygen species production.
Conclusions: Sodium metaarsenite is a telomere targeting agent and should be explored for the treatment of tumors with short telomeres.
Local Administration of PF-3512676 CpG-B Instigates Tumor-Specific CD8+ T-Cell Reactivity in Melanoma Patients
Authors: Molenkamp Barbara G. , Sluijter Berbel J.R. , van Leeuwen Paul A.M. , Santegoets Saskia J.A.M. , Meijer Sybren , Wijnands Pepijn G.J.T.B. , Haanen John B.A.G. , van den Eertwegh Alfons J.M. , Scheper Rik J. , de Gruijl Tanja D. 
Published: July 2008

Abstract
Purpose: Impaired immune effector functions in the melanoma sentinel lymph node (SLN) may allow for early metastatic events. Local administration of PF-3512676 (formerly known as CpG 7909) has shown immunostimulatory effects of both dendritic cell and T-cell subsets in the melanoma SLN. Here, we set out to ascertain whether these PF-3512676-induced immunostimulatory effects translate into higher frequencies of melanoma-specific CD8+ T cells.
Experimental Design: Twenty-four stage I to III melanoma patients were randomized to preoperative local administration of either PF-3512676 or saline. CD8+ T cells from SLN and peripheral blood were tested for reactivity by IFN-γ ELISPOT assay against several HLA-A1/A2/A3-restricted epitopes derived from various melanoma-associated antigens (MAA) in 21 of 24 enrolled patients. Frequencies of natural killer (NK) cells and frequencies and maturation state of dendritic cell subsets in the SLN were determined by flow cytometry.
Results: Melanoma-specific CD8+ T-cell response rates against &gt;1 MAA epitope in the SLN were 0 of 11 for the saline group versus 5 of 10 for the PF-3512676-administered group (P = 0.012). Of these 5 responding patients, 4 also had a measurable response to &gt;1 MAA epitope in the blood. Increased frequencies in the SLN of both MAA-specific CD8+ T cells and NK cells correlated to CpG-induced plasmacytoid dendritic cell maturation.
Conclusions: These data show an increase in melanoma-specific CD8+ T-cell frequencies as well as an increased effector NK cell rate after a single dose of PF-3512676 and thus support the utility of local PF-3512676 administration as adjuvant treatment in early-stage melanoma to try and halt metastatic spread.
Comparison of Nomograms With Other Methods for Predicting Outcomes in Prostate Cancer: A Critical Analysis of the Literature
Authors: Shariat Shahrokh F. , Karakiewicz Pierre I. , Suardi Nazareno , Kattan Michael W. 
Published: July 2008

Abstract
Purpose: Accurate estimates of risk are essential for physicians if they are to recommend a specific management to patients with prostate cancer. Accurate risk estimates are also required for clinical trial design, to ensure homogeneous patient groups. Because there is more than one model available for prediction of most outcomes, model comparisons are necessary for selection of the best model. We describe the criteria based on which to judge predictive tools, describe the limitations of current predictive tools, and compare the different predictive methodologies that have been used in the prostate cancer literature.
Experimental Design: Using MEDLINE, a literature search was done on prostate cancer decision aids from January 1966 to July 2007.
Results: The decision aids consist of nomograms, risk groupings, artificial neural networks, probability tables, and classification and regression tree analyses. The following considerations need to be applied when the qualities of predictive models are assessed: predictive accuracy (internal or ideally external validation), calibration (i.e., performance according to risk level or in specific patient subgroups), generalizability (reproducibility and transportability), and level of complexity relative to established models, to assess whether the new model offers advantages relative to available alternatives. Studies comparing decision aids have shown that nomograms outperform the other methodologies.
Conclusions: Nomograms provide superior individualized disease-related risk estimations that facilitate management-related decisions. Of currently available prediction tools, the nomograms have the highest accuracy and the best discriminating characteristics for predicting outcomes in prostate cancer patients.
Paclitaxel Encapsulated in Cationic Liposomes Increases Tumor Microvessel Leakiness and Improves Therapeutic Efficacy in Combination with Cisplatin
Authors: Strieth Sebastian , Eichhorn Martin E. , Werner Alexander , Sauer Birgitta , Teifel Michael , Michaelis Uwe , Berghaus Alexander , Dellian Marc 
Published: July 2008

Abstract
Purpose: Paclitaxel encapsulated in cationic liposomes (EndoTAG-1) is a vascular targeting formulation for the treatment of solid tumors. It triggers intratumoral microthrombosis, causing significant inhibition of tumor perfusion and tumor growth associated with endothelial cell apoptosis. Here, we quantified the effects of repeated EndoTAG-1 therapy on tumor microvascular leakiness with respect to leukocyte-endothelial cell interactions, the targeting property of cationic liposomes, and the therapeutic combination with conventional cisplatin chemotherapy.
Experimental Design: Using dorsal skinfold chamber preparations in Syrian Golden hamsters, in vivo fluorescence microscopy experiments were done after repeated EndoTAG-1 treatment of A-Mel-3 tumors. Controls received glucose, paclitaxel alone, or cationic liposomes devoid of paclitaxel. Extravasation of rhodamine-labeled albumin was measured to calculate microvessel permeability, and intratumoral leukocyte-endothelial cell interactions were quantified. Subcutaneous tumor growth was evaluated after combination therapy followed by histologic analysis.
Results: Microvascular permeability was significantly increased only after treatment with EndoTAG-1, whereas intratumoral leukocyte-endothelial cell interactions were not affected by any treatment. In separate skinfold chamber experiments, fluorescently labeled cationic liposomes kept their targeting property for tumor endothelial cells after repeated EndoTAG-1 treatment and no signs of extravasation were observed. Subcutaneous A-Mel-3 tumor growth was significantly inhibited by the combination of cisplatin and EndoTAG-1.
Conclusions: These data show that vascular targeting with EndoTAG-1 increases tumor microvessel leakiness probably due to vascular damage. This mechanism is not mediated by inflammatory leukocyte-endothelial cell interactions. Manipulating the blood-tumor barrier by repeated tumor microvessel targeting using EndoTAG-1 can effectively be combined with tumor cell–directed conventional cisplatin chemotherapy.
Targeted Therapies to Improve Tumor Immunotherapy
Authors: Begley Jonathan , Ribas Antoni 
Published: July 2008

Abstract
Durable tumor regression and potential cures of metastatic solid cancers can be achieved by a variety of cellular immunotherapy strategies, including cytokine therapy, dendritic cell–based vaccines, and immune-activating antibodies, when used in so-called immune-sensitive cancers such as melanoma and renal cell carcinoma. However, these immunotherapy strategies have very low tumor response rates, usually in the order of 5% to 10% of treated patients. We propose that the antitumor activity of adequately stimulated tumor antigen–specific T cells is limited by local factors within the tumor milieu and that pharmacologic modulation of this milieu may overcome tumor resistance to immunotherapy. By understanding the mechanisms of cancer cell immune escape, it may be possible to design rational combinatorial approaches of novel therapies able to target immunosuppressive or antiapoptotic molecules in an attempt to reverse resistance to immune system control. We term this mode of treatment “immunosensitization.” Ideal candidates for immunosensitizing drugs would be targeted drugs that block key oncogenic mechanisms in cancer cells resulting in a proapoptotic cancer cell milieu and at the same time do not negatively interfere with critical lymphocyte functions.