bluuebunny/crossref_metadata_2025_split huggingface dataset:
Roscovitine Modulates DNA Repair and Senescence: Implications for Combination Chemotherapy
Authors: Crescenzi Elvira , Palumbo Giuseppe , Brady Hugh J.M. 
Published: March 2006

Abstract
Purpose: Treatment of tumor cells by chemotherapy activates a series of responses ranging from apoptosis to premature senescence and repair. Survival responses are characterized by inhibition of cyclin-dependent kinases. Because inhibition of cyclin-dependent kinases represents a distinctive feature of DNA damage–induced prosurvival responses, we investigated the possibility that the cyclin-dependent kinase inhibitor roscovitine modulates drug-induced responses in human adenocarcinoma cells, favoring cell survival.
Experimental Design: Sublethal concentrations of doxorubicin were used to induce premature senescence in human adenocarcinoma cells. The effect of the cyclin-dependent kinase inhibitor roscovitine on the doxorubicin-dependent cell cycle checkpoint activation and DNA repair pathways was evaluated.
Results: Roscovitine reinforces doxorubicin-dependent G1 checkpoint in A549 and HEC1B cells leading to decreased frequency of double-strand breaks and to the preferential induction of senescence and enhanced clonogenic survival. However, in other tumor cell lines, such as HCT116 and H1299, combined treatment with doxorubicin and roscovitine increases the frequency of double-strand breaks and dramatically sensitizes to doxorubicin. This unexpected effect of roscovitine depends on a novel ability to inhibit DNA double-strand break repair processes and requires inactivation of the pRb pathway.
Conclusions: Roscovitine, by hindering DNA repair processes, has the potential to inhibit recovery of mildly damaged tumor cells after doxorubicin treatment and to increase the susceptibility of tumor cells to chemotherapy. However, in some tumor cells, the cell cycle inhibitory function of roscovitine prevails over the DNA repair inhibitory activity, favoring premature senescence and clonogenic growth. These data indicate a novel mechanism underlying combined chemotherapy, which may have wide application in treatment of carcinomas.
Androgen Mediation of Thrombocytosis in Epithelial Ovarian Cancer Biology
Authors: Li Andrew John , Young Karlan Beth 
Published: March 2006

Abstract
Purpose: Preoperative thrombocytosis (platelet count &gt; 400 × 109/L) at initial exploration for epithelial ovarian carcinoma is associated with decreased surgical cytoreducibility and poor survival. Platelets express androgen receptor (AR), which contains a polymorphic CAG trinucleotide repeat sequence of which the length inversely correlates with AR transactivation function. We hypothesized that androgen-mediated thrombocytosis promotes aggressive ovarian cancer biology.
Experimental Design: Sixty-three patients with epithelial ovarian carcinoma underwent genotype analysis of the CAG repeat polymorphism in AR. Medical records were reviewed to assess preoperative thrombocytosis, surgical findings, and survival. Data were examined using the Fisher's exact, logistic regression, and Kaplan-Meier analyses.
Results: AR CAG repeat lengths ranged from 8 to 27, with a median of 23. Fifteen of 63 patients (23.8%) showed preoperative thrombocytosis. Short AR allelotype (≤ 20 CAG repeats) was associated with a higher incidence of thrombocytosis (P = 0.04). The combination of short AR allelotype and thrombocytosis was the only significant factor that predicted inability to achieve optimal surgical cytoreduction (P = 0.02). Women with short AR allelotype and thrombocytosis showed statistically decreased progression-free survival (13 versus 37 months, P = 0.01) and overall survival (37 versus 65 months, P = 0.02) when compared with women with long AR allelotype and normal platelet counts. On multivariate analyses, suboptimal cytoreduction was the only significant factor predictive of disease-specific overall survival (P = 0.0002) but the combination of short AR allelotype and thrombocytosis approached statistical significance (P = 0.08).
Conclusions: Androgen modulation of thrombocytosis may promote aggressive epithelial ovarian cancer biology.
CG0070, a Conditionally Replicating Granulocyte Macrophage Colony-Stimulating Factor–Armed Oncolytic Adenovirus for the Treatment of Bladder Cancer
Authors: Ramesh Nagarajan , Ge Ying , Ennist David L. , Zhu Mingzhu , Mina Mervat , Ganesh Shanthi , Reddy P. Seshidhar , Yu De-Chao 
Published: March 2006

Abstract
Purpose: The purpose of this study was to examine the tumor specificity, cytotoxicity, and granulocyte macrophage colony-stimulating factor expression of CG0070, a conditionally replicating oncolytic adenovirus, in human bladder transitional cell carcinoma (TCC) cell lines and determine its antitumor efficacy in bladder TCC tumor models.
Experimental Design: Virus yield and cytotoxicity assays were used to determine tumor specificity and virus replication-mediated cytotoxicity of CG0070 in a panel of human bladder TCC cell lines and primary cells in vitro. Two s.c. and one orthotopic bladder TCC xenograft tumor models were used to assess antitumor activity of CG0070.
Results: In a matched isogenic pair of cell lines with differing retinoblastoma (Rb) pathway status, CG0070 showed selective E1a and granulocyte macrophage colony-stimulating factor (GM-CSF) expression in Rb pathway–defective cells. CG0070 replicated in Rb-defective bladder TCC cell lines as efficiently as wild-type adenovirus but produced 100-fold less virus in normal human cells. CG0070 was up to 1,000-fold more cytotoxic in Rb pathway–defective bladder TCC cells in comparison with normal human cells. Antitumor activity of CG0070 was shown in two bladder TCC s.c. xenograft tumor models following intratumoral injections and intravesical treatment in an orthotopic xenograft tumor model when compared with PBS treatment.
Conclusions: In vitro and in vivo studies showed the selective replication, cytotoxicity, GM-CSF production, and antitumor efficacy of CG0070 in several bladder TCC models, suggesting a potential utility of this oncolytic agent for the treatment of bladder cancer. Further studies are warranted to show the role of human GM-CSF in the antitumor efficacy of CG0070.
Synergistic Interaction between Histone Deacetylase and Topoisomerase II Inhibitors Is Mediated through Topoisomerase IIβ
Authors: Marchion Douglas C. , Bicaku Elona , Turner Joel G. , Daud Adil I. , Sullivan Daniel M. , Munster Pamela N. 
Published: March 2006

Abstract
Background: DNA topoisomerase II inhibitors and poisons are among the most efficacious drugs for the treatment of cancer. Sensitivity of cancer cells to the cytotoxic effects of topoisomerase II targeting agents is thought to depend on the expression of the topoisomerase IIα isoform, and drug resistance is often associated with loss or mutation of topoisomerase IIα. Histone deacetylase inhibitors (HDACi) are a novel class of compounds that potentiate the antitumor effects of topoisomerase II–targeting agents.
Methods: The interaction between HDACi and topoisomerase II–targeting agents in cancer cells was evaluated as a function of topoisomerase IIα and topoisomerase IIβ expression. Topoisomerase II isoforms were selectively depleted using small interfering RNA and antisense. Drug-induced formation of cleavable complexes involving topoisomerase IIα and topoisomerase IIβ was evaluated by trapped-in-agarose DNA immunostaining and band depletion assays in the presence and absence of HDACi.
Results: Preexposure to HDACi increased the cytotoxicity of topoisomerase II poisons. This was associated with a down-regulation of topoisomerase IIα expression but had no effects on topoisomerase IIβ. In the setting of HDACi-induced chromatin decondensation and topoisomerase IIα depletion, topoisomerase II poison cytotoxicity was mediated through topoisomerase IIβ cleavable complex formation. The HDACi-induced sensitization was also observed in cells with target-specific resistance to topoisomerase II poisons.
Conclusions: The recruitment of topoisomerase IIβ as a target may overcome primary or emergent drug resistance to topoisomerase II–targeting agents and hence may broaden the applicability of this important class of anticancer agents.
Lymphangiogenesis Correlates with Lymph Node Metastasis, Prognosis, and Angiogenic Phenotype in Human Non–Small Cell Lung Cancer
Authors: Renyi-Vamos Ferenc , Tovari Jozsef , Fillinger Janos , Timar Jozsef , Paku Sandor , Kenessey Istvan , Ostoros Gyula , Agocs Laszlo , Soltesz Ibolya , Dome Balazs 
Published: March 2006

Abstract
Purpose: Recent experimental studies have revealed that lymphangiogenesis plays an important role in cancer progression, but its clinical significance in the case of non-small cell lung cancer (NSCLC) remains unclear. Our aim was to assess the lymphangiogenesis of human NSCLC, and to correlate this with angiogenic phenotype (angiogenic versus nonangiogenic growth pattern) and clinical behavior.
Experimental Design: One hundred and three patients with NSCLC and complete follow-up information were included. Tumor samples were immunostained for vascular endothelial growth factor-C (VEGF-C), the lymphatic endothelial markers, LYVE-1 and D2-40/Podoplanin, and the panvascular marker, CD31. Lymphatic vessel density (LVD) and perimeters were evaluated within the tumor and peritumorally.
Results: LVDs at the tumor periphery were significantly higher in lymph node metastatic tumors (P &lt; 0.005) and high LVDs correlated with poor overall survival (P &lt; 0.001). However, this tendency proved to be significant only in the angiogenic tumor group (P &lt; 0.001). Although 68% of the patients with nonangiogenic tumors had lymph node metastasis (P = 0.0048 versus angiogenic tumors), in the patient group with nonangiogenic NSCLCs, there was no information from the LVDs in any investigated tumor area (P &gt; 0.05). In contrast to angiogenic tumors, which had actively sprouting lymphatics in all of the investigated tumor areas, nonangiogenic tumors showed no Ki67 staining intratumorally.
Conclusions: Our results reveal tumor lymphangiogenesis as a novel prognostic indicator for the risk of lymph node metastasis in NSCLC. Moreover, it also provides the first evidence that nonangiogenic NSCLCs mainly co-opt host tissue lymphatics during their growth, in contrast to most of the angiogenic tumors, which expand with concomitant lymphangiogenesis.
Phosphatidylinositol 3-Kinase Inhibition by LY294002 Radiosensitizes Human Cervical Cancer Cell Lines
Authors: Lee Christopher M. , Fuhrman Christa B. , Planelles Vicente , Peltier Morgan R. , Gaffney David K. , Soisson Andrew P. , Dodson Mark K. , Tolley H. Dennis , Green Christopher L. , Zempolich Karen A. 
Published: March 2006

Abstract
Purpose: The phosphatidylinositol 3-kinase (PI3K) catalytic subunit is amplified in cervical cancers, implicating PI3K in cervical carcinogenesis. We evaluated the radiosensitizing effect of PI3K inhibition by LY294002 on clonogenic survival, growth characteristics, and gene expression in cervical cancer cell lines (HeLa and CaSki).
Experimental Design: Cervical cancer cells were treated separately and concurrently with the PI3K inhibitor LY294002 (10 μmol/L) and radiation (2 Gy) with serial analysis of cell count, apoptosis, and flow cytometry. PI3K inhibition was assessed by protein analysis of phosphorylated Akt. Clonogenic assays were done with varying doses of radiation and LY294002 and varied time points of administration of LY294002 proximate to the radiation dose. Surviving fractions and dose modification factors (DMF) were calculated. Each experiment was done in triplicate and analyzed using ANOVA regression analysis and Dunnett's t Test. Microarray gene expression analysis was done on the HeLa cell line.
Results: PI3K inhibition with LY294002 alone did not decrease cell survival. However, treatment with LY294002 significantly radiosensitized HeLa and CaSki cell lines with DMFs (1 log cell kill) of 1.95 and 1.37, respectively. Compared with post-irradiation, pretreatment produced more radiosensitization (P &lt; 0.0001). DMFs were 2.2, 2.0, 2.0, and 1.2 for LY294002 added at 6, 2, and 0.5 hours before irradiation and 6 hours after irradiation, respectively. LY294002 pretreatment in irradiated HeLa cells led to altered gene expression.
Conclusions: Although LY294002 alone did not produce cytotoxic effects, PI3K inhibition with LY294002 produced significant radiosensitization, showed significant time-dependent effects, increased apoptosis, and altered gene expression. These findings support future investigation of PI3K inhibitors in combination with radiation therapy for carcinoma of the cervix.
Novel Oncolytic Adenovirus Selectively Targets Tumor-Associated Polo-Like Kinase 1 and Tumor Cell Viability
Authors: Zhou Jianfeng , Gao Qinglei , Chen Gang , Huang Xiaoyuan , Lu Yunping , Li Kanyan , Xie Daxing , Zhuang Liang , Deng Jingniu , Ma Ding 
Published: March 2006

Abstract
Purpose: Polo-like kinase 1 (plk1) is a serine/threonine protein kinase essential for multiple mitotic processes. Previous observations have validated plk1 as a promising therapeutic target. Despite being conceptually attractive, the potency and specificity of current plk1-based therapies remain limited. We sought to develop a novel plk1-targeting strategy by constructing an oncolytic adenovirus to selectively silence plk1 in tumor cells.
Experimental Design: Two artificial features were engineered into one wild-type adenovirus type 5 (wt-Adv5) genome to generate a new oncolytic adenovirus (M1). First, M1 contains a 27-bp deletion in E1A region, which confers potent, oncolytic efficacy. Second, M1 is armed with a fragment of antisense plk1 cDNA that substitutes the E3 region encoding 6.7K and gp19K. In this design, tumor-selective replication of M1 would activate the native adenovirus E3 promoters to express the antisense plk1 cDNA preferentially in tumor cells and silence tumor-associated plk1 protein.
Results: By virtue of combining oncolysis with plk1 targeting, M1 exhibited potent antitumoral efficacy in vitro and in vivo. Systemic administration of M1 plus cisplatin induced complete tumor regression in 80% of orthotopic hepatic carcinoma model mice that were otherwise resistant to cisplatin and disseminated metastases.
Conclusions: Coupling plk1 targeting with oncolysis had shown superior antitumor efficacy. Present findings would benefit the development of novel oncolytic adenoviruses generally applicable to a wide range of molecule-based therapeutics.
Prevention of Hepatocellular Carcinoma by Universal Vaccination against Hepatitis B Virus: The Effect and Problems
Authors: Chang Mei-Hwei , Chen Tony Hsiu-Hsi , Hsu Hsu-Mei , Wu Tzee-Chung , Kong Man-Shan , Liang Der-Cherng , Ni Yen-Hsuan , Chen Chien-Jen , Chen Ding-Shinn ,   for the Taiwan Childhood HCC Study Group
Published: March 2006

Abstract
Purpose: In spite of the success of hepatitis B immunization, still a significant proportion of childhood hepatocellular carcinoma (HCC) failed to be prevented by the hepatitis B immunization program. This study is aimed to investigate the problems in the HCC prevention in children.
Experimental Design: All HCC children ages 6 to 14 diagnosed between 1981 and 2000 in Taiwan were collected from two national childhood HCC registry systems. We analyzed the causes of HCC prevention failure and the risk ratio of HCC among hepatitis B carriers born before versus after the vaccination program.
Results: The incidence of HCC per 100,000 children declined from 0.54 to 0.20 in those born before versus after the vaccination program (risk ratio, 0.36). Vaccine failure (33.3-51.4%) and failure to receive hepatitis B immunoglobulin at birth (42.4-57.5%) were the main causes of HCC prevention failure. Mother-to-child transmission of hepatitis B virus infection is an important risk factor of HCC development. This is evidenced by the very high hepatitis B surface antigen seropositive rate in our HCC children (97%) and their mothers (96%). Hepatitis B carrier children born after the vaccination program had a higher risk of developing HCC than those born before the program (risk ratio, 2.3-4.5).
Conclusions: Vaccine failure and failure to receive hepatitis B immunoglobulin are the main problems preventing eradication of HCC. Hepatitis B carrier children born after the immunization program have a higher risk of developing HCC than those born before.
Hypermethylation of 18S and 28S Ribosomal DNAs Predicts Progression-Free Survival in Patients with Ovarian Cancer
Authors: Chan Michael W.Y. , Wei Susan H. , Wen Ping , Wang Zailong , Matei Daniela E. , Liu Joseph C. , Liyanarachchi Sandya , Brown Robert , Nephew Kenneth P. , Yan Pearlly S. , Huang Tim H-M. 
Published: March 2006

Abstract
Purpose: Repetitive ribosomal DNA (rDNA) genes are GC-rich clusters in the human genome. The aim of the study was to determine the methylation status of two rDNA subunits, the 18S and 28S genes, in ovarian tumors and to correlate methylation levels with clinicopathologic features in a cohort of ovarian cancer patients.
Experimental Design: 18S and 28S rDNA methylation was examined by quantitative methylation-specific PCR in 74 late-stage ovarian cancers, 9 histologically uninvolved, and 11 normal ovarian surface epithelial samples. In addition, methylation and gene expression levels of 18S and 28S rDNAs in two ovarian cancer cell lines were examined by reverse transcription-PCR before and after treatment with the demethylating drug 5′-aza-2′-deoxycytidine.
Results: The methylation level (amount of methylated rDNA/β-actin) of 18S and 28S rDNAs was significantly higher (P &lt; 0.05) in tumors than in normal ovarian surface epithelial samples. Methylation of 18S and 28S rDNA was highly correlated (R2 = 0.842). Multivariate analysis by Cox regression found that rDNA hypermethylation [hazard ratio (HR), 0.25; P &lt; 0.01], but not age (HR, 1.29; P = 0.291) and stage (HR, 1.09; P = 0.709), was independently associated with longer progression-free survival. In ovarian cancer cell lines, methylation levels of rDNA correlated with gene down-regulation and 5′-aza-2′-deoxycytidine treatment resulted in a moderate increase in 18S and 28S rDNA gene expressions.
Conclusion: This is the first report of rDNA hypermethylation in ovarian tumors. Furthermore, rDNA methylation levels were higher in patients with long progression-free survival versus patients with short survival. Thus, rDNA methylation as a prognostic marker in ovarian cancer warrants further investigation.
Allogeneic tumor cells expressing fusogenic membrane glycoproteins as a platform for clinical cancer immunotherapy.
Authors: Errington Fiona , Bateman Andrew , Kottke Tim , Thompson Jill , Harrington Kevin , Merrick Alison , Hatfield Paul , Selby Peter , Vile Richard , Melcher Alan 
Published: March 2006

Abstract
PURPOSE: Fusogenic membrane glycoproteins (FMG), such as the vesicular stomatitis virus G glycoprotein (VSV-G), represent a new class of gene therapy for cancer that cause cytotoxic fusion on expression in tumor cells. In addition, FMG-mediated tumor cell death stimulates antitumor immunity, suggesting potential applications for FMG-expressing cellular vaccines. This study addresses the promise of FMG-expressing allogeneic tumor cells, which are most practical for clinical use, as a novel platform for ex vivo and in situ vaccination. EXPERIMENTAL DESIGN: Murine B16 melanoma-derived cell lines expressing autologous or allogeneic MHC class I, expressing fusogenic or nonfusogenic VSV-G, were used to vaccinate mice in vivo against a live tumor challenge. Exosome-like vesicles released by fusing allogeneic cells (syncitiosomes) and intratumoral injection of fusing vaccines were also tested as novel therapeutic strategies for their antitumor effects. RESULTS: Expression of fusogenic VSV-G enhanced the immunogenicity of an allogeneic cellular vaccine, which was more effective than a fusing autologous vaccine. Allogeneic syncitiosomes were only as effective as cellular vaccines when administered with adjuvant, demonstrating that syncitiosomes cannot account entirely for the mechanism of immune priming. Intratumoral injection of FMG-expressing allogeneic cells led to significant tumor regression using both fusogenic or nonfusogenic VSV-G. However, specific priming against tumor-associated antigenic epitopes and protection against secondary rechallenge only occurred if the initial vaccine was competent for cell fusion. CONCLUSIONS: FMG-expressing allogeneic tumor cells are a potent source of antitumor vaccines. Syncitiosomes given with adjuvant and intratumoral injection of fusing cells represent novel strategies well-suited to clinical translation.
Targeting Tumor Angiogenesis with Histone Deacetylase Inhibitors: the Hydroxamic Acid Derivative LBH589
Authors: Qian David Z. , Kato Yukihiko , Shabbeer Shabana , Wei Yongfeng , Verheul Hendrik M.W. , Salumbides Brenda , Sanni Tolib , Atadja Peter , Pili Roberto 
Published: March 2006

Abstract
Purpose: Angiogenesis is required for tumor progression and represents a rational target for therapeutic intervention. Histone deacetylase (HDAC) inhibitors have been shown to have activity against various tumor cell types by inhibiting proliferation and inducing apoptosis both in vitro and in vivo. HDAC inhibitors have also been reported to inhibit angiogenesis. The goal of this study was to characterize the antiangiogenic and antitumor activity of a recently developed HDAC inhibitor, the hydroxamic derivative LBH589.
Materials and Methods: To evaluate the antiangiogenesis activity of LBH589, we did cell cycle analysis, cell proliferation, tube formation, invasion assays in vitro, and Matrigel plug assay in vivo. To determine the antitumor activity of LBH589, we established human prostate carcinoma cell PC-3 xenografts in vivo. To evaluate the effect of LBH589 on endothelial signaling pathways, gene expression, and protein acetylation, we did Western blots and reverse transcription-PCR in human umbilical vein endothelial cells (HUVEC). Immunohistochemical analysis was done to evaluate new blood vessel formation in vivo.
Results: LBH589 induced acetylation of histone H3 and α-tubulin protein in HUVECs. Histone and nonhistone protein acetylation correlated with induction of G2-M cell cycle arrest, inhibition of HUVEC proliferation, and viability. Noncytotoxic concentrations of LBH589 inhibited endothelial tube formation, Matrigel invasion, AKT, extracellular signal-regulated kinase 1/2 phosphorylation, and chemokine receptor CXCR4 expression. In vivo dosing of mice with LBH589 (10 mg/kg/d) reduced angiogenesis and PC-3 tumor growth.
Conclusion: This study provides evidence that LBH589 induces a wide range of effects on endothelial cells that lead to inhibition of tumor angiogenesis. These results support the role of HDAC inhibitors as a therapeutic strategy to target both the tumor and endothelial compartment and warrant the clinical development of these agents in combination with angiogenesis inhibitors.