bluuebunny/crossref_metadata_2025 huggingface dataset:
CHOICE FUNCTIONS AND UPPER CHOICE FUNCTIONS
Authors: MORDESON JOHN N. , CLARK TERRY D. , LARSON JENNIFER M. , WIERMAN MARK J.
Published: March 2008

Choice functions play an important role in political science. We present structure results of choice functions following an algebraic approach. It is logical that rational political actors are not able to perceive every alternative in a set of alternatives X. They may also choose to exclude some alternatives from consideration. Let S be a subset of X that some set of political actors are not able to perceive. Then the complement X\S is the set comprising those alternatives considered in the decision process. If C is a choice function on X, then C(X\S) are the alternatives chosen and X\C(X\S) are those that are not. We are thus led to the concept of an upper choice function. We define upper choice functions in terms of choice functions and we give relationships between them.
The Fortunate Professor
Authors: Falkow Stanley
Published: March 2008

My professional life can be summarized by a quote from the Talmud.

Much have I learned from my teachers, More from my colleagues, But most from my students.

It is the fortunate professor who learns from the student.
The Sociology of Discrimination: Racial Discrimination in Employment, Housing, Credit, and Consumer Markets
Authors: Pager Devah , Shepherd Hana
Published: March 2008

Persistent racial inequality in employment, housing, and a wide range of other social domains has renewed interest in the possible role of discrimination. And yet, unlike in the pre–civil rights era, when racial prejudice and discrimination were overt and widespread, today discrimination is less readily identifiable, posing problems for social scientific conceptualization and measurement. This article reviews the relevant literature on discrimination, with an emphasis on racial discrimination in employment, housing, credit markets, and consumer interactions. We begin by defining discrimination and discussing relevant methods of measurement. We then provide an overview of major findings from studies of discrimination in each of the four domains; and, finally, we turn to a discussion of the individual, organizational, and structural mechanisms that may underlie contemporary forms of discrimination. This discussion seeks to orient readers to some of the key debates in the study of discrimination and to provide a roadmap for those interested in building upon this long and important line of research.
Subcellular Localization of Activated Leukocyte Cell Adhesion Molecule Is a Molecular Predictor of Survival in Ovarian Carcinoma Patients
Authors: Mezzanzanica Delia , Fabbi Marina , Bagnoli Marina , Staurengo Samantha , Losa Marco , Balladore Emanuela , Alberti Paola , Lusa Lara , Ditto Antonino , Ferrini Silvano , Pierotti Marco A. , Barbareschi Mattia , Pilotti Silvana , Canevari Silvana
Published: March 2008

Purpose: Currently available clinicopathologic prognostic factors are imperfect predictors of clinical course in advanced-stage epithelial ovarian cancer patients. New molecular predictors are needed to identify patients with higher risk of relapse or death from disease. In a retrospective study, we investigated the prognostic impact of activated leukocyte cell adhesion molecule (ALCAM) expression in epithelial ovarian cancer.

Experimental Design: We analyzed the effect of cell-anchorage loss on ALCAM cellular localization in vitro and assessed ALCAM expression by immunohistochemistry in a series of 109 well-characterized epithelial ovarian cancer patient samples. Chi-square test, Kaplan-Meier method, and Cox proportional hazard analyses were used to relate ALCAM cellular localization to clinical-pathologic parameters and to overall survival (OS) rate.

Results: Loss of epithelial ovarian cancer cell anchorage was associated both in vitro and in vivo with decreased ALCAM membrane expression. In vivo, ALCAM was localized to cell membrane in normal surface ovarian epithelium, whereas in 67% of the epithelial ovarian cancer samples, membrane localization was decreased or even lost, and the molecule was mainly expressed in cytoplasm. Median OS in this group of patients was 58 months, whereas a median OS was not yet reached in patients with ALCAM membrane localization (P = 0.036, hazard ratio [HR] = 2.0, 95% confidence interval [CI] 1.1 to 3.5). In a multivariate Cox regression model including all the available clinicopathologic variables, loss of ALCAM membrane expression was an independent factor of unfavorable prognosis (P = 0.042, HR = 2.15, 95% CI: 1.0 to 4.5).

Conclusions: Decreased/lost ALCAM membrane expression is a marker of poorer outcome in epithelial ovarian cancer patients and might help to identify patients who could benefit from more frequent follow-up or alternative therapeutic modalities.
Class I Histone Deacetylase Expression Has Independent Prognostic Impact in Human Colorectal Cancer: Specific Role of Class I Histone Deacetylases In vitro and In vivo
Authors: Weichert Wilko , Röske Annika , Niesporek Silvia , Noske Aurelia , Buckendahl Ann-Christin , Dietel Manfred , Gekeler Volker , Boehm Markus , Beckers Thomas , Denkert Carsten
Published: March 2008

Purpose: Recently, several studies reported a strong functional link between histone deacetylases (HDAC) and the development of tumors of the large intestine. However, despite the importance of these molecules, comparably little is known on expression patterns and functions of specific HDAC isoforms in colorectal cancer.

Experimental Design: We characterized class I HDAC isoform expression patterns in a cohort of 140 colorectal carcinomas by immunohistochemistry. In addition, effects of HDAC inhibition by valproic acid and suberoylanilide hydroxamic acid, and specific HDAC isoform knockdown by short interfering RNA, were investigated in a cell culture model.

Results: We found class I HDACs highly expressed in a subset of colorectal carcinomas with positivity for HDAC1 in 36.4%, HDAC2 in 57.9%, and HDAC3 in 72.9% of cases. Expression was significantly enhanced in strongly proliferating (P = 0.002), dedifferentiated (P = 0.022) tumors. High HDAC expression levels implicated significantly reduced patient survival (P = 0.001), with HDAC2 expression being an independent survival prognosticator (hazard ratio, 2.6; P = 0.03). Short interfering RNA–based inhibition of HDAC1 and HDAC2 but not HDAC3 suppressed growth of colon cancer cells in vitro, although to a lesser extent than chemical HDAC inhibitors did.

Conclusions: The strong prognostic impact of HDAC isoforms in colorectal cancer, the interactions of HDACs with tumor cell proliferation and differentiation in vivo, and our finding that HDACs are differentially expressed in colorectal tumors suggest that the evaluation of HDAC expression in clinical trials for HDAC inhibitors might help to identify a patient subgroup who will exceptionally profit from such a treatment.
Targeting Hyaluronan Interactions in Malignant Gliomas and Their Drug-Resistant Multipotent Progenitors
Authors: Gilg Anne G. , Tye Sandra L. , Tolliver Lauren B. , Wheeler William G. , Visconti Richard P. , Duncan James D. , Kostova Felina V. , Bolds Letitia N. , Toole Bryan P. , Maria Bernard L.
Published: March 2008

Purpose: To determine if hyaluronan oligomers (o-HA) antagonize the malignant properties of glioma cells and treatment-resistant glioma side population (SP) cells in vitro and in vivo.

Experimental Design: A single intratumoral injection of o-HA was given to rats bearing spinal cord gliomas 7 days after engraftment of C6 glioma cells. At 14 days, spinal cords were evaluated for tumor size, invasive patterns, proliferation, apoptosis, activation of Akt, and BCRP expression. C6SP were isolated by fluorescence-activated cell sorting and tested for the effects of o-HA on BCRP expression, activation of Akt and epidermal growth factor receptor, drug resistance, and glioma growth in vivo.

Results: o-HA treatment decreased tumor cell proliferation, increased apoptosis, and down-regulated activation of Akt and the expression of BCRP. o-HA treatment of C6SP inhibited activation of epidermal growth factor receptor and Akt, decreased BCRP expression, and increased methotrexate cytotoxicity. In vivo, o-HA also suppressed the growth of gliomas that formed after engraftment of C6 or BCRP+ C6SP cells, although most C6SP cells lost their expression of BCRP when grown in vivo. Interestingly, the spinal cord gliomas contained many BCRP+ cells that were not C6 or C6SP cells but that expressed nestin and/or CD45; o-HA treatment significantly decreased the recruitment of these BCRP+ progenitor cells into the engrafted gliomas.

Conclusions: o-HA suppress glioma growth in vivo by enhancing apoptosis, down-regulating key cell survival mechanisms, and possibly by decreasing recruitment of host-derived BCRP+ progenitor cells. Thus, o-HA hold promise as a new biological therapy to inhibit HA-mediated malignant mechanisms in glioma cells and treatment-resistant glioma stem cells.
Correlation of CDA, ERCC1, and XPD Polymorphisms with Response and Survival in Gemcitabine/Cisplatin–Treated Advanced Non–Small Cell Lung Cancer Patients
Authors: Tibaldi Carmelo , Giovannetti Elisa , Vasile Enrico , Mey Valentina , Laan Adrie C. , Nannizzi Sara , Di Marsico Roberta , Antonuzzo Andrea , Orlandini Cinzia , Ricciardi Simona , Del Tacca Mario , Peters Godefridus J. , Falcone Alfredo , Danesi Romano
Published: March 2008

Purpose: Selecting patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in non–small cell lung cancer (NSCLC). Polymorphisms at the xeroderma pigmentosum group D (XPD), excision repair cross-complementing 1 (ERCC1), and cytidine deaminase (CDA) genes have been associated with alterations in enzymatic activity and may change sensitivity to the widely used cisplatin-gemcitabine regimen.

Experimental Design: Analyses of CDA, XPD, and ERCC1 polymorphisms were done on blood samples of 65 chemotherapy-naïve, advanced NSCLC patients treated with cisplatin-gemcitabine. Furthermore, CDA enzymatic activity was evaluated by high-performance liquid chromatography analysis. Association between XPD Asp312Asn and Lys751Gln, ERCC1 C118T, and CDA Lys27Gln polymorphisms and response, clinical benefit, toxicity, time to progression (TTP), and overall survival (OS) was estimated using Pearson's χ2 tests, the Kaplan-Meier method, the log-rank test, and the Cox proportional hazards model.

Results: The CDA Lys27Lys polymorphism significantly correlated with better clinical benefit (P = 0.04) and grade ≥3 neutropenia and thrombocytopenia, as well as with longer TTP and OS (P = 0.006 and P = 0.002, respectively), whereas no significant associations were found among ERCC1 and XPD polymorphisms and both response and clinical outcome. Finally, the enzymatic activity assay showed a significant lower mean in subjects harboring the CDA Lys27Lys polymorphism.

Conclusions: Our data suggested the role of CDA Lys27Lys polymorphism as a possible predictive marker of activity, toxicity, TTP, and OS in advanced NSCLC patients treated with cisplatin and gemcitabine. These results may be explained by the lower enzymatic activity associated with the Lys27Lys CDA and offer a potential new tool for treatment optimization.
Identification of Prognostic Biomarkers for Prostate Cancer
Authors: Kosari Farhad , Munz Jan Marie A. , Savci-Heijink C. Dilara , Spiro Craig , Klee Eric W. , Kube Dagmar Marie , Tillmans Lori , Slezak Jeff , Karnes R. Jeffrey , Cheville John C. , Vasmatzis George
Published: March 2008

Purpose: This paper describes a process for the identification of genes that can report on the aggressiveness of prostate tumors and thereby add to the information provided by current pathologic analysis.

Materials and Methods: Expression profiling data from over 100 laser capture microdissection derived samples from nonneoplastic epithelium; Gleason patterns 3, 4, and 5 and node metastasis prostate cancer were used to identify genes at abnormally high levels in only some tumors. These variably overexpressed genes were stratified by their association with aggressive phenotypes and were subsequently filtered to exclude genes with redundant expression patterns. Selected genes were validated in a case-control study in which cases (systemic progression within 5 years) and controls (no systemic progression at 7 years of follow-up) were matched for all clinical and pathologic criteria from time of prostatectomy (n = 175). Both cases and controls, therefore, could have nodal invasion or seminal vesicle involvement at the time of initial treatment.

Results: A number of candidate variably overexpressed genes selected for their association with aggressive prostate cancer phenotype were evaluated in the case control study. The most prominent candidates were SSTR1 and genes related to proliferation, including TOP2A.

Conclusions: The process described here identified genes that add information not available from current clinical measures and can improve the prognosis of prostate cancer.
Prognostic Factors in Renal Cell Carcinoma: Association of Preoperative Sodium Concentration with Survival
Authors: Vasudev Naveen S. , Brown Janet E. , Brown Sarah R. , Rafiq Rumana , Morgan Ruth , Patel Poulam M. , O'Donnell Dearbhaile , Harnden Patricia , Rogers Mark , Cocks Kim , Anderson Kirsty , Paul Alan , Eardley Ian , Selby Peter J. , Banks Rosamonde E.
Published: March 2008

Purpose: Conventional renal cell carcinoma (RCC) has a variable natural history, and determining individual prognosis is important to guide management. We have examined the prognostic significance of a large number of hematologic and biochemical variables, as well as traditional tumor-related factors in patients with RCC.

Experimental Design: Patients undergoing nephrectomy for newly diagnosed RCC between September 1998 and March 2005 were invited to participate. Clinical, pathologic, and laboratory data were recorded in each case, and immunophenotyping was carried out on a subset of patients. A planned subset analysis of patients presenting with N0M0 disease was done.

Results: Two hundred twelve patients with RCC formed the study population. In addition to tumor-related factors, multivariate analyses revealed preoperative serum sodium concentration to be independently and significantly associated with overall survival and disease-free survival when considered as both a continuous variable and when dichotomized to above and below the median value [139 mmol/L; reference range 135-145 mmol/L, hazard ratio 0.44, 95% confidence interval (95% CI) 0.22-0.88, P = 0.014]. Five-year overall survival estimates for patients above and below the median serum sodium were 67.6% (95% CI 54.2-80.9) and 44.3% (95% CI 32.8-55.8), respectively. These findings persisted in the N0M0 subgroup analysis.

Conclusions: We have confirmed the prognostic value of traditional tumor-related factors but, to our knowledge, these are the first data to show that low preoperative sodium concentration may be an important factor associated with reduced survival in patients with RCC, suggesting that serum sodium should be considered with established prognostic variables in modeling survival in RCC.
Inhibition of the Tumor Necrosis Factor-α Pathway Is Radioprotective for the Lung
Authors: Zhang Ming , Qian Jun , Xing Xianying , Kong Feng-Ming , Zhao Lujun , Chen Ming , Lawrence Theodore S.
Published: March 2008

Purpose: Radiation-induced lung toxicity limits the delivery of high-dose radiation to thoracic tumors. Here, we investigated the potential of inhibiting the tumor necrosis factor-α (TNF-α) pathway as a novel radioprotection strategy.

Experimental Design: Mouse lungs were irradiated with various doses and assessed at varying times for TNF-α production. Lung toxicity was measured by apoptosis and pulmonary function testing. TNF receptor 1 (TNFR1) inhibition, achieved by genetic knockout or antisense oligonucleotide (ASO) silencing, was tested for selective lung protection in a mouse lung metastasis model of colon cancer.

Results: Lung radiation induced local production of TNF-α by macrophages in BALB/c mice 3 to 24 hours after radiation (15 Gy). A similar maximal induction was found 1 week after the start of radiation when 15 Gy was divided into five daily fractions. Cell apoptosis in the lung, measured by terminal deoxyribonucleotide transferase–mediated nick-end labeling staining (mostly epithelial cells) and Western blot for caspase-3, was induced by radiation in a dose- and time-dependent manner. Specific ASO inhibited lung TNFR1 expression and reduced radiation-induced apoptosis. Radiation decreased lung function in BALB/c and C57BL mice 4 to 8 weeks after completion of fractionated radiation (40 Gy). Inhibition of TNFR1 by genetic deficiency (C57BL mice) or therapeutic silencing with ASO (BALB/c mice) tended to preserve lung function without compromising lung tumor sensitivity to radiation.

Conclusion: Radiation-induced lung TNF-α production correlates with early cell apoptosis and latent lung function damage. Inhibition of lung TNFR1 is selectively radioprotective for the lung without compromising tumor response. These findings support the development of a novel radioprotection strategy using inhibition of the TNF-α pathway.
Aurora Kinases as Anticancer Drug Targets
Authors: Gautschi Oliver , Heighway Jim , Mack Philip C. , Purnell Phillip R. , Lara Primo N. , Gandara David R.
Published: March 2008

The human aurora family of serine-threonine kinases comprises three members, which act in concert with many other proteins to control chromosome assembly and segregation during mitosis. Aurora dysfunction can cause aneuploidy, mitotic arrest, and cell death. Aurora kinases are strongly expressed in a broad range of cancer types. Aurora A expression in tumors is often associated with gene amplification, genetic instability, poor histologic differentiation, and poor prognosis. Aurora B is frequently expressed at high levels in a variety of tumors, often coincidently with aurora A, and expression level has also been associated with increased genetic instability and clinical outcome. Further, aurora kinase gene polymorphisms are associated with increased risk or early onset of cancer. The expression of aurora C in cancer is less well studied. In recent years, several small-molecule aurora kinase inhibitors have been developed that exhibit preclinical activity against a wide range of solid tumors. Preliminary clinical data from phase I trials have largely been consistent with cytostatic effects, with disease stabilization as the best response achieved in solid tumors. Objective responses have been noted in leukemia patients, although this might conceivably be due to inhibition of the Abl kinase. Current challenges include the optimization of drug administration, the identification of potential biomarkers of tumor sensitivity, and combination studies with cytotoxic drugs. Here, we summarize the most recent preclinical and clinical data and discuss new directions in the development of aurora kinase inhibitors as antineoplastic agents.
The Epothilones: Translating from the Laboratory to the Clinic
Authors: Lee James J. , Swain Sandra M.
Published: March 2008

The epothilones are macrolide compounds that have been shown to stabilize microtubules. The epothilones are strong promoters of tubulin polymerization in vitro and have significant antitumor activity against human cancer cells that are taxane resistant, express the multidrug resistance gene MDR-1 (ABCB1), and have acquired tubulin mutations. Several epothilones have been evaluated in clinical trials in a variety of tumor types. Ixabepilone (aza-epothilone B) has significant antitumor activity in breast cancer resistant to an anthracycline and a taxane, and has been approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic or locally advanced breast cancer. There have been sustained efforts to develop pharmacodynamic markers to monitor the pharmacologic effect of the epothilones on tumors and normal tissues. The development of predictive markers for epothilone chemotherapy is highly desired to provide more tailored therapy for patients with cancer.
Proteasome Inhibitors in Cancer Therapy: Lessons from the First Decade
Authors: Orlowski Robert Z. , Kuhn Deborah J.
Published: March 2008

The ubiquitin-proteasome pathway is involved in intracellular protein turnover, and its function is crucial to cellular homeostasis. First synthesized as probes of proteolytic processes, proteasome inhibitors began to be thought of as potential drug candidates when they were found to induce programmed cell death preferentially in transformed cells. They made their first leap into the clinic to be tested as therapeutic agents 10 years ago, and since then, great strides have been made in defining their mechanisms of action, their clinical efficacy and toxicity, and some of their limitations in the form of resistance pathways. Validation of the ubiquitin-proteasome pathway as a target for cancer therapy has come in the form of approvals of the first such inhibitor, bortezomib, for relapsed/refractory multiple myeloma and mantle cell lymphoma, for which this agent has become a standard of care. Lessons learned from this first-in-class agent are now being applied to the development of a new generation of proteasome inhibitors that hold the promise of efficacy in bortezomib-resistant disease and possibly in a broader spectrum of diseases. This saga provides a salient example of the promise of translational medicine and a paradigm by which other agents may be successfully brought from the bench to the bedside.
Newer Cytotoxic Agents: Attacking Cancer Broadly
Authors: Teicher Beverly A.
Published: March 2008

The plasticity and instability of the cancer genome is impressive and is characterized by gene amplifications and deletions, rearrangements, and many silent and active mutations. Although targeted therapeutics have had effect in some diseases, there remains a large role for new cytotoxic agents that have the potential to be broadly active across multiple cancers. Platinum-based regimens are the basis for treatment of several common tumors. Satraplatin and picoplatin are newer platinum complexes that form bulkier lesions in DNA than their forerunners. Microtubules are a key target for anticancer agents. Vinca alkaloid and similar compounds fragment these critical structures, whereas taxanes stabilize them. Vinflunine is a new fluorinated Vinca alkaloid derivative with vascular disrupting effects, as well as antitumor effects. Epothilones are a new class of microtubule stabilizers. Mitosis has been targeted directly and indirectly by many anticancer agents. The aurora kinases are new targets in this class. Inhibitors of aurora kinases are likely to be cytotoxic. Finally, protein regulation is essential for cellular integrity. With the approval of bortezomib (Velcade, PS-341), the proteosome, a master protein regulator, has been validated as an anticancer target. The five articles in this issue of CCR Focus present the current status of these next generation cytotoxic agents.
Expression of the Bric-a-Brac Tramtrack Broad Complex Protein NAC-1 in Cervical Carcinomas Seems to Correlate with Poorer Prognosis
Authors: Yeasmin Shamima , Nakayama Kentaro , Ishibashi Masako , Katagiri Atsuko , Iida Kouji , Purwana Indri Nuryani , Nakayama Naomi , Miyazaki Kohji
Published: March 2008

Purpose: Recent studies have suggested a novel oncogenic role of a bric-a-brac tramtrack broad complex (also known as POZ) domain gene, NAC-1, in ovarian carcinomas. The aim of this study was to clarify the functional role of NAC-1 in human cervical carcinomas.

Experimental Design: NAC-1 expression in cervical cancer was assessed by immunohistochemistry, and data on clinical variables were collected by retrospective chart review. NAC-1 gene knockdown using small interfering RNA and a NAC-1 gene transfection system were used to asses NAC-1 function in cervical cancer in vivo.

Results: Immunohistochemical and gene expression analysis revealed that NAC-1 is significantly overexpressed in cervical adenocarcinomas and adenosquamous carcinomas compared with squamous cell carcinomas. Patients with squamous cell carcinomas positive for NAC-1 expression who received radiotherapy had significantly shorter overall survival than peers whose tumors did not express NAC-1, and multivariate analysis showed that NAC-1 expression was an independent prognostic factor for overall survival after radiotherapy. Overexpressions of the NAC-1 gene stimulated cell proliferation in cervical carcinoma cells of the TCS, CaSki, and HeLa P3 lines, which do not have endogenous NAC-1 expression. NAC-1 gene knockdown inhibited cell growth and induced apoptosis in HeLa, HeLa TG, and ME180 cells, all of which overexpressed NAC-1.

Conclusions: Our findings suggest that NAC-1 may play an important role in cervical carcinomas; moreover, these findings provide a rationale for future development of NAC-1–based therapy for cervical carcinomas that overexpress this candidate oncogene.
Novel Delivery of SN38 Markedly Inhibits Tumor Growth in Xenografts, Including a Camptothecin-11–Refractory Model
Authors: Sapra Puja , Zhao Hong , Mehlig Mary , Malaby Jennifer , Kraft Patricia , Longley Clifford , Greenberger Lee M. , Horak Ivan D.
Published: March 2008

Purpose: Clinical development of SN38, the active metabolite of camptothecin-11 (CPT-11), has been hampered due to its poor solubility. We have developed a novel polymer-drug conjugate, EZN-2208, made by linking SN38 with a multiarm polyethylene glycol via a glycine linker.

Experimental Design: The in vitro cytotoxicity of EZN-2208 was tested using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. The therapeutic efficacy of EZN-2208 was evaluated in various xenografts, including an in vivo–selected CPT-11–refractory model. Tumor and blood concentration of EZN-2208, CPT-11, and SN38 was determined by high-performance liquid chromatography.

Results: In vitro, EZN-2208 was 10- to 245-fold more potent than CPT-11 in a panel of human tumor cell lines. In xenograft models of MX-1 breast, MiaPaCa-2 pancreatic, or HT-29 colon carcinoma, treatment with either a single dose or multiple injections of EZN-2208 was more efficacious (and in some cases produced tumor eradication for >16 weeks) compared with CPT-11 at their respective maximum tolerated doses or corresponding dose levels (P < 0.01). Most interestingly, EZN-2208 showed marked antitumor activity in animals that developed resistance to an 8-day course of CPT-11 treatment, as well as outperformed CPT-11 as second-round therapy in mice initially sensitive to CPT-11. EZN-2208 had prolonged circulation in the blood compared with CPT-11, resulting in high tumor exposure. This resulted in higher and longer-lasting tumor exposure of free SN38 in mice given EZN-2208 compared with those given CPT-11.

Conclusions: Preclinical data suggest that EZN-2208 may be a promising anticancer agent in a wide variety of clinical settings, including tumors refractory to CPT-11 treatment.
Understanding the Biology of Bone Metastases: Key to the Effective Treatment of Prostate Cancer
Authors: Logothetis Christopher J. , Navone Nora M. , Lin Sue-Hwa
Published: March 2008

Advanced prostate cancer is dominated by bone-forming osseous metastases. Understanding the biology behind this striking clinical manifestation is the key to its effective treatment. A clinical trial using a bone-targeting radiopharmaceutical agent, strontium 89, combined with chemotherapy showed increased survival time among patients with progression of prostate cancer in bone, suggesting that therapeutic strategies focused on treating the tumor in bone are effective. We and others thus hypothesize that interactions between prostate cancer cells and the bone microenvironment play a role in the progression of prostate cancer in bone. Clinical trials and basic science investigations aiming to understand such interactions have been carried out in parallel. In the laboratory studies, human bone marrow specimens have been collected for identification of proteins involved in the bidirectional interactions between prostate cancer cells and bone. In addition, specimens from bone biopsies of the cancer lesions have been used to generate xenografts in animals to establish animal models for testing therapeutic strategies. Clinical trials using agents to inhibit the stromal-prostate cancer interactions (e.g., docetaxel/imatinib or thalidomide) have been done. Analyses of the specimens from these trials provided support of our hypothesis and future development of diagnosis and therapy strategies.
Dual inhibition of VEGFR and EGFR signaling reduces the incidence and size of intestinal adenomas in ApcMin/+ mice
Authors: Alferez Denis , Wilkinson Robert W. , Watkins Jim , Poulsom Richard , Mandir Nikki , Wedge Stephen R. , Pyrah Ian T. , Smith Neil R. , Jackson Lynsay , Ryan Anderson J. , Goodlad Robert A.
Published: March 2008

Both the epidermal growth factor (EGF) and the vascular endothelial growth factor (VEGF) pathways are associated with intestinal cancer, and therapeutic approaches targeting either EGF receptor (EGFR) or VEGF receptor (VEGFR) signaling have recently been approved for patients with advanced colorectal cancer. The ApcMin/+ mouse is a well-characterized in vivo model of intestinal tumorigenesis, and animals with this genetic mutation develop macroscopically detectable adenomas from ∼6 weeks of age. Previous work in the ApcMin/+ mouse has shown that therapeutic approaches targeting either VEGFR or EGFR signaling affect predominantly the size or number of adenomas, respectively. In this study, we have assessed the effect of inhibiting both these key pathways simultaneously using ZD6474 (Vandetanib, ZACTIMA), a selective inhibitor of VEGFR and EGFR tyrosine kinases. To assess the effects of ZD6474 on early- and later-stage disease, treatment was initiated in 6- and 10-week-old ApcMin/+ mice for 28 days. ZD6474 markedly reduced both the number and the size of polyps when administered at either an early or a later stage of polyp development. This reduction in both adenoma number and size resulted in a total reduction in tumor burden in the small intestine of nearly 75% in both studies (P < 0.01). The current data build on the concept that EGFR-dependent tumor cell proliferation and VEGF/VEGFR2-dependent angiogenesis and survival are distinct key mechanisms in polyp development. Pharmacologic inhibition of both signaling pathways has significant antitumor effects at both early and late stages of polyp development. Therefore, targeting both VEGFR- and EGFR-dependent signaling may be a beneficial strategy in early intestinal cancer. [Mol Cancer Ther 2008;7(3):590–8]
Recombinant cathepsin S propeptide attenuates cell invasion by inhibition of cathepsin L–like proteases in tumor microenvironment
Authors: Burden Roberta E. , Snoddy Philip , Buick Richard J. , Johnston James A. , Walker Brian , Scott Christopher J.
Published: March 2008

Human cathepsin L along with cathepsin S, K, and V are collectively known as cathepsin L–like proteases due to their high homology. The overexpression and aberrant activity of each of these proteases has been implicated in tumorigenesis. These proteases contain propeptide domains that can potently inhibit both their cognate protease and other proteases within the cathepsin L–like subfamily. In this investigation, we have produced the cathepsin S propeptide recombinantly and have shown that it is a potent inhibitor of the peptidolytic, elastinolytic, and gelatinolytic activities of the cathepsin L–like proteases. In addition, we show that this peptide is capable of significantly attenuating tumor cell invasion in a panel of human cancer cell lines. Furthermore, fusion of an IgG Fc-domain to the COOH terminus of the propeptide resulted in a chimeric protein with significantly enhanced ability to block tumor cell invasion. This Fc fusion protein exhibited enhanced stability in cell-based assays in comparison with the unmodified propeptide species. This approach for the combined inhibition of the cathepsin L–like proteases may prove useful for the further study in cancer and other conditions where their aberrant activity has been implicated. Furthermore, this strategy for simultaneous inhibition of multiple cysteine cathepsins may represent the basis for novel therapeutics to attenuate tumorigenesis. [Mol Cancer Ther 2008;7(3):538–47]
Synergistic antitumor effect of S-1 and the epidermal growth factor receptor inhibitor gefitinib in non-small cell lung cancer cell lines: role of gefitinib-induced down-regulation of thymidylate synthase
Authors: Okabe Takafumi , Okamoto Isamu , Tsukioka Sayaka , Uchida Junji , Iwasa Tsutomu , Yoshida Takeshi , Hatashita Erina , Yamada Yuki , Satoh Taroh , Tamura Kenji , Fukuoka Masahiro , Nakagawa Kazuhiko
Published: March 2008

Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the therapeutic response to EGFR tyrosine kinase inhibitors (TKI) in patients with advanced non-small cell lung cancer (NSCLC). The response rate to these drugs remains low, however, in NSCLC patients with wild-type EGFR alleles. Combination therapies with EGFR-TKIs and cytotoxic agents are considered a therapeutic option for patients with NSCLC expressing wild-type EGFR. We investigated the antiproliferative effect of the combination of the oral fluorouracil S-1 and the EGFR-TKI gefitinib in NSCLC cells of differing EGFR status. The combination of 5-fluorouracil and gefitinib showed a synergistic antiproliferative effect in vitro in all NSCLC cell lines tested. Combination chemotherapy with S-1 and gefitinib in vivo also had a synergistic antitumor effect on NSCLC xenografts regardless of the absence or presence of EGFR mutations. Gefitinib inhibited the expression of the transcription factor E2F-1, resulting in the down-regulation of thymidylate synthase at the mRNA and protein levels. These observations suggest that gefitinib-induced down-regulation of thymidylate synthase is responsible, at least in part, for the synergistic antitumor effect of combined treatment with S-1 and gefitinib and provide a basis for clinical evaluation of combination chemotherapy with S-1 and EGFR-TKIs in patients with solid tumors. [Mol Cancer Ther 2008;7(3):599–606]
Preclinical modeling of cytosine arabinoside response inMll-Enltranslocator mouse leukemias
Authors: Cano Florencia , Pannel Richard , Follows George A. , Rabbitts Terence H.
Published: March 2008

Mouse models of human cancer are a potential preclinical setting for drug testing and for development of methods for delivery of macromolecular drugs to tumors. We have assessed a mouse model of leukemia caused by Mll-Enl protein fusion as a preclinical situation in which myeloid-lineage leukemia results from de novo occurrence of chromosomal translocations between Mll and Enl genes. Here, we show that the mouse leukemias respond to cytosine arabinoside, a frontline treatment for human leukemia. The observations show that the myeloid cells are susceptible to the drug and the mice undergo a remission that comprises a reduction of the myeloid population of cells and recovery of the lymphoid population. This translocator model should therefore prove useful for future drug assessments against the recurrent mixed-lineage leukemia–associated translocations. [Mol Cancer Ther 2008;7(3):730–5]
Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo
Authors: Maksimovic-Ivanic Danijela , Mijatovic Sanja , Harhaji Ljubica , Miljkovic Djordje , Dabideen Darrin , Fan Cheng Kai , Mangano Katia , Malaponte Graziella , Al-Abed Yousef , Libra Massimo , Garotta Gianni , Nicoletti Ferdinando , Stosic-Grujicic Stanislava
Published: March 2008

Preclinical studies have shown that nitric oxide (NO)–donating nonsteroidal anti-inflammatory drugs possess anticancer activities. Here, we report in vitro and in vivo studies showing the antitumor effect of the NO-donating isoxazole derivative (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid (GIT-27NO). GIT-27NO, but not the NO-deprived parental compound VGX-1027, significantly affected viability of both rodent (L929, B16, and C6) and human (U251, BT20, HeLa, and LS174) tumor cell lines. GIT-27NO triggered either apoptotic cell death (e.g., L929 cells) or autophagic cell death (C6 and B16 cells). Moreover, GIT-27NO hampered the viability of cisplatin-resistant B16 cells. NO scavenger hemoglobin completely prevented GIT-27NO-induced death, indicating that NO release mediated the tumoricidal effect of the compound. Increase in intracellular NO upon on the treatment was associated with intensified production of reactive oxygen species, whereas their neutralization by antioxidant N-acetylcysteine resulted in partial recovery of cell viability. The antitumor activity of the drug was mediated by the selective activation of mitogen-activated protein kinases in a cell-specific manner and was neutralized by their specific inhibitors. In vivo treatment with GIT-27NO significantly reduced the B16 melanoma growth in syngeneic C57BL/6 mice. The therapeutic effect occurred at dose (0.5 mg/mouse) up to 160 times lower than those needed to induce acute lethality (80 mg/mouse). In addition, a dose of GIT-27NO five times higher than that found effective in the melanoma model was well tolerated by the mice when administered for 4 consecutive weeks. These data warrant additional studies to evaluate the possible translation of these findings to the clinical setting. [Mol Cancer Ther 2008;7(3):510–20]
Mitochondrial regulation by c-Myc and hypoxia-inducible factor-1α controls sensitivity to econazole
Authors: Yu Yongmao , Niapour Maryam , Zhang Yicheng , Berger Stuart A.
Published: March 2008

Econazole is an azole antifungal with anticancer activity that blocks Ca2+ influx and stimulates endoplasmic reticulum (ER) Ca2+ release through the generation of mitochondrial reactive oxygen species (ROS), resulting in sustained depletion of ER Ca2+ stores, protein synthesis inhibition, and cell death. c-Myc, a commonly activated oncogene, also promotes apoptosis in response to growth factor withdrawal and a variety of chemotherapeutic agents. We have investigated the role of c-myc in regulating sensitivity to econazole. Here, we show that c-myc-negative cells are profoundly resistant to econazole. c-Myc-negative rat fibroblasts failed to generate mitochondrial ROS in response to econazole and consequently failed to deplete the ER of Ca2+. HL60 cells knocked down for c-myc expression also displayed decreased ROS generation and decreased econazole sensitivity. Addition of H2O2 restored sensitivity to econazole in both c-myc-negative rat fibroblasts and c-myc knocked-down HL60 cells, supporting a role for ROS in cell death induction. c-Myc-negative cells and HL60 cells knocked down for c-myc have reduced mitochondrial content compared with c-myc-positive cells. The hypoxia sensor, hypoxia-inducible factor-1α (HIF-1α), interacts antagonistically with c-myc and also regulates mitochondrial biogenesis. Knockdown of HIF-1α in c-myc-negative cells increased mitochondrial content restored ROS generation in response to econazole and increased sensitivity to the drug. Taken together, these results show that c-myc and HIF-1α regulate sensitivity to econazole by modulating the ability of the drug to generate mitochondrial ROS. [Mol Cancer Ther 2008;7(3):483–91]
A small-molecule inhibitor of Tcf/β-catenin signaling down-regulates PPARγ and PPARδ activities
Authors: Handeli Shlomo , Simon Julian A.
Published: March 2008

Activation of the Wnt/β-catenin signaling pathway occurs in several types of cancers and thus it is an attractive target for anticancer drug development. To identify compounds that inhibit this pathway, we screened a chemical library using a cell-based β-catenin/Tcf–responsive reporter. We identified FH535, a compound that suppresses both Wnt/β-catenin and peroxisome proliferator–activated receptor (PPAR) signaling. FH535 antagonizes both PPARγ and PPARδ ligand–dependent activation and shows structural similarity to GW9662, a known PPARγ antagonist. The effect of FH535 on β-catenin/Tcf activity is reduced in cells carrying a deletion of the PPARδ gene, as well as by the PPARγ agonist lysophosphatidic acid. Mechanistically, FH535 inhibits recruitment of the coactivators β-catenin and GRIP1 but not the corepressors NCoR and SMRT. Its repression of β-catenin recruitment, in comparison with GW9662, is linked to FH535′s unique capability to inhibit the Wnt/β-catenin signaling pathway. The antiproliferation effect of the compound observed on some transformed colon lung and liver cell lines is suggestive of its potential therapeutic value in the treatment of cancer. [Mol Cancer Ther 2008;7(3):521–9]
Effects of sustained and intermittent paclitaxel therapy on tumor repopulation in ovarian cancer
Authors: Vassileva Vessela , Allen Christine J. , Piquette-Miller Micheline
Published: March 2008

Tumor repopulation between cycles of chemotherapy likely has a negative effect on clinical outcome in ovarian cancer patients. Thus, avoiding treatment-free periods when tumor cells proliferate by providing sustained chemotherapy regimens may improve clinical response. We investigated the effect of sustained versus intermittent paclitaxel administration on tumor repopulation in ovarian cancer. Growth, clonogenic survival, and apoptosis were followed in SKOV3 and A2780 cells after equivalent exposure to intermittent and sustained levels of paclitaxel. In vivo tumor repopulation in response to sustained and intermittent paclitaxel therapy was investigated in an i.p. xenograft model of human ovarian cancer. Tumor growth, proliferation, and apoptosis were evaluated at different intervals during and after the course of treatment using 5-bromo-2-deoxyuridine uptake, caspase-3, and terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling immunoassays. Sustained treatment significantly reduced survival in vitro in both cell lines, whereas an increase in clonogenic survival was observed in the intermittent group with each treatment gap, indicating a gradual acceleration in repopulation rates. Similarly, in vivo, sustained therapy resulted in a significant reduction of tumor growth and proliferation. Intermittent therapy resulted in increased tumor proliferation and no efficacy. The percentage of apoptotic tumor cells significantly increased in the sustained group, whereas no significant changes were seen in the control and intermittent groups. Intermittent administration of paclitaxel significantly augmented both in vitro and in vivo tumor repopulation rates, whereas sustained delivery inhibited tumor growth and repopulation. Sustained administration of paclitaxel may increase chemoresponsiveness and clinical response in ovarian cancer by attenuating tumor repopulation. [Mol Cancer Ther 2008;7(3):630–7]
Preclinical evaluation of M30 and M65 ELISAs as biomarkers of drug induced tumor cell death and antitumor activity
Authors: Cummings Jeffrey , Hodgkinson Cassandra , Odedra Rajesh , Sini Patrizia , Heaton Simon P. , Mundt Kirsten E. , Ward Tim H. , Wilkinson Robert W. , Growcott Jim , Hughes Andrew , Dive Caroline
Published: March 2008

M30 and M65 are ELISAs that detect different circulating forms of cytokeratin 18. Using the aurora kinase inhibitor AZD1152 and the SW620 human colon cancer xenograft, experiments were conducted to qualify preclinically both assays as serologic biomarkers of cell death. Using two different apoptotic markers, the kinetics of cell death induced by AZD1152 was first characterized in vitro in three different cell lines and shown to peak 5 to 7 days after drug addition. Treatment of non-tumor-bearing rats with AZD1152 (25 mg/kg) produced no alterations in circulating baseline values of M30 and M65 antigens. In treated, tumor-bearing animals, M30 detected a 2- to 3-fold (P < 0.05) increase in plasma antigen levels by day 5 compared with controls. This correlated to a 3-fold increase in the number of apoptotic cells detected on day 5 in SW620 xenografts using immunohistochemistry. By contrast, M65 did not detect a drug-induced increase in circulating antigen levels at day 5. However, M65 plasma levels correlated to changes in tumor growth in control animals (r2 = 0.93; P < 0.01) and also followed the magnitude of the temporal effect of AZD1152 on tumor growth. An intermediate but active dose of AZD1152 (12.5 mg/kg) produced a less significant increase in M30 plasma levels at day 5. It was also confirmed that the plasma profiles of M30 and M65 mirrored closely those measured in whole tumor lysates. We conclude that M30 is a pharmacodynamic biomarker of AZD1152-induced apoptosis in the SW620 xenograft model, whereas M65 is a biomarker of therapeutic response. [Mol Cancer Ther 2008;7(3):455–63]
p37 from Mycoplasma hyorhinis promotes cancer cell invasiveness and metastasis through activation of MMP-2 and followed by phosphorylation of EGFR
Authors: Gong Manman , Meng Lin , Jiang Beihai , Zhang Jianzhi , Yang Hua , Wu Jian , Shou Chengchao
Published: March 2008

High Mycoplasma infection in gastric cancer tissues suggests a possible association between Mycoplasma infection and tumorigenesis. By using human gastric cancer cells AGS and mouse melanoma cells B16F10 stably expressing p37, the major immunogen of Mycoplasma hyorhinis, we found that p37 enhanced cell motility, migration, and invasion in vitro. With experimental metastasis model in C57BL/6 mice, p37 adenovirus-infected B16F10 cells formed more metastasis lesions in the lung. Furthermore, p37 promoted the phosphorylation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase and the activity of matrix metalloproteinase-2 (MMP-2). Inhibitor of MMPs significantly blocked p37-induced EGFR but has little effect on extracellular signal-regulated kinase phosphorylation, whereas the p37-induced MMP-2 activation was only partially suppressed by inhibitor of MEK1/2 or by inhibitor of EGFR. However, all these inhibitors significantly reduced the p37-induced invasiveness of AGS cells. These results suggest that p37 may stimulate invasion by increasing the activity of MMP-2, thereby inducing EGFR phosphorylation and contributing to tumor metastasis on M. hyorhinis infection. p37 and its regulated molecules could be the potential targets for cancer therapy. [Mol Cancer Ther 2008;7(3):530–7]