bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potentiation of High-LET Radiation by Gemcitabine: Targeting HER2 with Trastuzumab to Treat Disseminated Peritoneal Disease
Authors: Milenic Diane E. , Garmestani Kayhan , Brady Erik D. , Albert Paul S. , Abdulla Alia , Flynn Joseph , Brechbiel Martin W. 
Published: March 2007

Abstract
Purpose: Recent studies from this laboratory with 212Pb-trastuzumab have shown the feasibility of targeted therapy for the treatment of disseminated peritoneal disease using 212Pb as an in vivo generator of 212Bi. The objective of the studies presented here was improvement of the efficacy of α-particle radioimmunotherapy using a chemotherapeutic agent.
Experimental Design: In a series of experiments, a treatment regimen was systematically developed in which athymic mice bearing i.p. LS-174T xenografts were injected i.p. with gemcitabine at 50 mg/kg followed by 212Pb radioimmunotherapy.
Results: In a pilot study, tumor-bearing mice were treated with gemcitabine and, 24 to 30 h later, with 5 or 10 μCi 212Pb-trastuzumab. Improvement in median survival was observed at 5 μCi 212Pb-trastuzumab in the absence (31 days) or presence (51 days) of gemcitabine: 45 and 70 days with 10 μCi versus 16 days for untreated mice (P &lt; 0.001). Multiple doses of gemcitabine combined with a single 212Pb radioimmunotherapy (10 μCi) administration was then evaluated. Mice received three doses of gemcitabine: one before 212Pb-trastuzumab and two afterwards. Median survival of mice was 63 versus 54 days for those receiving a single gemcitabine dose before radioimmunotherapy (P &lt; 0.001), specifically attributable to 212Pb-trastuzumab (P = 0.01). Extending these findings, one versus two treatment cycles was compared. A cycle consisted of sequential treatment with gemcitabine, 10 μCi 212Pb radioimmunotherapy, then one or two additional gemcitabine doses. In the first cycle, three doses of gemcitabine resulted in a median survival of 90 versus 21 days for the untreated mice. The greatest benefit was noted after cycle 2 in the mice receiving 10 μCi 212Pb-trastuzumab and two doses of gemcitabine with a median survival of 196.5 days (P = 0.005). Pretreatment of tumor-bearing mice with two doses of gemcitabine before 212Pb radioimmunotherapy was also assessed with gemcitabine injected 72 and 24 h before 212Pb-trastuzumab. The median survival was 56 and 76 days with one and two doses of gemcitabine versus 49 days without gemcitabine. The effect may not be wholly specific to trastuzumab because 212Pb-HuIgG with two doses of gemcitabine resulted in a median survival of 66 days (34 days without gemcitabine).
Conclusions: Treatment regimens combining chemotherapeutics with high-LET targeted therapy may have tremendous potential in the management and care of cancer patients.
Molecular Detection of Localized Prostate Cancer Using Quantitative Methylation-Specific PCR on Urinary Cells Obtained Following Prostate Massage
Authors: Rouprêt Morgan , Hupertan Vincent , Yates David R. , Catto James W.F. , Rehman Ishtiaq , Meuth Mark , Ricci Sylvie , Lacave Roger , Cancel-Tassin Géraldine , de la Taille Alexandre , Rozet François , Cathelineau Xavier , Vallancien Guy , Hamdy Freddie C. , Cussenot Olivier 
Published: March 2007

Abstract
Purpose: The diagnosis of localized prostate cancer is difficult due to a lack of cancer-specific biomarkers. Many patients require repeat prostate biopsies to diagnose the disease. We investigated whether aberrant promoter hypermethylation in prostatic fluid could reliably detect prostate cancer.
Experimental Design: Urine samples were collected after prostate massage from 95 patients with localized prostate cancer undergoing radical prostatectomy (63 pT1, 31 pT2, and 1 pT3) and from 38 control patients. Ten genes (GSTP1, RASSF1a, ECDH1, APC, DAPK, MGMT, p14, p16, RARβ2, and TIMP3) were investigated using quantitative real-time methylation-specific PCR. Receiver operator curves were generated.
Results: The frequency of gene methylation ranged from 6.3% (p14) to 83.2% (GSTP1) in prostate cancer patients. At least one gene was hypermethylated in 93% of cancer patients. The specificity of methylation was 0.74. Methylation was significantly more frequent (P &lt; 0.05) in cancer than control patients for all genes except p14 and p16. According to receiver operator curve analysis, the four-gene combination of GSTP1 (0.86), RASSF1a (0.85), RARβ2 (0.80), and APC (0.74) best discriminated malignant from nonmalignant cases. The sensitivity and accuracy of this four-gene set were 86% and 89%, respectively.
Conclusions: The presence of aberrant methylation in urinary cells obtained after prostate massage is significantly associated with prostate cancer. A panel of four genes could stratify patients into low and high risk of having prostate cancer and optimize the need for repeat prostatic biopsies.
Brain Metastases: The HER2 Paradigm
Authors: Lin Nancy U. , Winer Eric P. 
Published: March 2007

Abstract
Between 100,000 and 170,000 patients with cancer develop central nervous system (CNS) metastases each year in the U.S., of which ∼20% carry a primary diagnosis of breast cancer. As a consequence of improvements in systemic therapy, which have allowed patients to live longer with advanced cancer, CNS metastases are emerging as an important sanctuary site, and the incidence may be increasing in patients with particular tumor subtypes. Unless there are improvements in the treatment of CNS disease, a growing proportion of patients may be at risk of experiencing both morbidity and mortality as a result of uncontrolled CNS progression, often at a time when their extra-CNS disease is apparently under control. This article reviews changes in the epidemiology and natural history of women with brain metastases from HER2-positive breast cancer over the last decade and presents the therapeutic challenges and opportunities that have arisen in this setting. First, the apparent increase in CNS disease among women with HER2-positive breast cancer, relative to historical controls, is discussed, followed by consideration of potential causes of this observation. Next, the implications of CNS disease, in terms of prognosis and the potential development of preventive strategies are considered. Finally, new developments in systemic approaches to the treatment of CNS disease, including cytotoxic chemotherapy and targeted therapy, are explored.
Primary Tumor Levels of Human Tissue Kallikreins Affect Surgical Success and Survival in Ovarian Cancer Patients
Authors: Dorn Julia , Schmitt Manfred , Kates Ronald , Schmalfeldt Barbara , Kiechle Marion , Scorilas Andreas , Diamandis Eleftherios P. , Harbeck Nadia 
Published: March 2007

Abstract
Purpose: Proteolytic factors of the human tissue kallikrein (hK) family and the plasminogen activation system play a key role in tumor progression in various malignancies. We determined antigen levels of urokinase-type plasminogen activator (uPA), its inhibitor PAI-1, and hK5-8, hK10, hK11, and hK13 by ELISA in primary tumor tissue extracts of 142 International Federation of Gynecology and Obstetrics (FIGO) I to IV ovarian cancer patients (median follow-up 41 months).
Results: After radical surgery, absence of macroscopically visible residual tumor (RT) was achieved in 72 patients; all patients received postoperative platinum-containing chemotherapy. Significant univariate predictors of poor progression-free survival (PFS) were RT (&gt;0), FIGO stages (III/IV versus I/II/III), ascites volume &gt;500 mL, nodal status, and the difference between PAI-1 and uPA (fractionally ranked). In multivariate analysis, significant independent factors for poor PFS were RT [hazard ratio (HR), 4.53] and low hK11 fractional rank (HR, 0.30). Univariate predictors of poor overall survival were RT, FIGO stages, nodal status, ascites volume, nuclear grade, and low hK10 and hK13. In multivariate analysis, significant independent factors for poor overall survival were RT (HR, 7.49), ascites (HR, 1.97), and low hK10 (HR, 0.196). We constructed a multivariate scoring model estimating RT probability, based on ascites [odds ratio (OR), 13.1], nuclear grade (OR, 2.92), hK6 (OR, 8.54), and hK13 (OR, 0.14), with good in-sample predictive performance (area under receiver operating characteristic, 0.833).
Conclusions: In view of risks and benefits of radical surgery, such a score could support preoperative risk stratification and identify candidates for alternative therapeutic strategies. These results highlight the distinct roles of the hKs for different disease end points in ovarian cancer and their potential to support individualized therapy decisions.
Distinct Mitotic Segregation Errors Mediate Chromosomal Instability in Aggressive Urothelial Cancers
Authors: Jin Yuesheng , Stewénius Ylva , Lindgren David , Frigyesi Attila , Calcagnile Olga , Jonson Tord , Edqvist Anna , Larsson Nina , Lundberg Lena Maria , Chebil Gunilla , Liedberg Fredrik , Gudjonsson Sigurdur , Månsson Wiking , Höglund Mattias , Gisselsson David 
Published: March 2007

Abstract
Purpose: Chromosomal instability (CIN) is believed to have an important role in the pathogenesis of urothelial cancer (UC). The aim of this study was to evaluate whether disturbances of mitotic segregation contribute to CIN in UC, if these processes have any effect on the course of disease, and how deregulation of these mechanisms affects tumor cell growth.
Experimental Design: We developed molecular cytogenetic methods to classify mitotic segregation abnormalities in a panel of UC cell lines. Mitotic instabilities were then scored in biopsies from 52 UC patients and compared with the outcome of tumor disease. Finally, UC cells were exposed in vitro to a telomerase inhibitor to assess how this affects mitotic stability and cell proliferation.
Results: Three distinct chromosome segregation abnormalities were identified: (a) telomere dysfunction, which triggers structural rearrangements and loss of chromosomes through anaphase bridging; (b) sister chromatid nondisjunction, which generates discrete chromosomal copy number variations; and (c) supernumerary centrosomes, which cause dramatic shifts in chromosome copy number through multipolar cell division. Chromosome segregation errors were already present in preinvasive tumors and a high rate mitotic instability was an independent predictor of poor survival. However, induction of even higher levels of the same segregation abnormalities in UC cells by telomerase inhibition in vitro led to reduced tumor cell proliferation and clonogenic survival.
Conclusion: Several distinct chromosome segregation errors contribute to CIN in UC, and the rate of such mitotic errors has a significant effect on the clinical course. Efficient tumor cell proliferation may depend on the tight endogenous control of these processes.
High-resolution single-photon emission computed tomography and X-ray computed tomography imaging of Tc-99m–labeled anti-DR5 antibody in breast tumor xenografts
Authors: Kim Hyunki , Chaudhuri Tandra R. , Buchsbaum Donald J. , Wang Deli , Zinn Kurt R. 
Published: March 2007

AbstractA murine, apoptosis-inducing monoclonal antibody (mTRA-8) targeting human DR5 was radiolabeled with Tc-99m. The binding affinity (Kd) and the number of DR5 receptors were measured in MD MBA-231–derived 2LMP cell lines that were “sensitive” or “resistant” to mTRA-8 killing. Single-photon emission computed tomography and X-ray computed tomography (SPECT/CT) evaluated the Tc-99m-mTRA-8 retention and distribution within xenograft tumors; biodistribution analyses confirmed the levels. Scatchard assays showed specific and high binding affinity of Tc-99m-mTRA-8 to DR5; the killing efficacy of mTRA-8 was unchanged by Tc-99m labeling. There was no significant difference between sensitive and resistant 2LMP cells for Kd values (1.5 ± 0.3 nmol/L = acid labile), or DR5 receptors (mean/cell = 11,000). SPECT/CT imaging analyses at 6 h after injection of Tc-99m-mTRA-8 revealed the second 1.5 mm shell from the surface of the mammary fat pad tumors (n = 5; 5,627 mm3) retained 12.7 ± 1.4%ID/g, higher than the other shells, with no difference between the sensitive and resistant 2LMP tumors. Binding of Tc-99m–labeled mTRA-8 in tumor was specific; excess unlabeled mTRA-8 blocked Tc-99m-mTRA-8 retention in tumor by 45%. Retention of Tc-99m–labeled isotype antibody in tumor was consistent with the blocking study, and 30% lower. These studies show that SPECT/CT imaging provided detailed distribution information of Tc-99m–labeled mTRA-8 within breast tumor xenografts. Imaging could provide a mechanism to assess DR5 modulation when DR5 therapy is combined with chemotherapy and radiation, and thereby aid in optimizing the dosing schedule. [Mol Cancer Ther 2007;6(3):866–75]
p53-R273H gains new function in induction of drug resistance through down-regulation of procaspase-3
Authors: Wong Ronald Pak Cheung , Tsang Wing Pui , Chau Pui Yee , Co Ngai Na , Tsang Tsun Yee , Kwok Tim Tak 
Published: March 2007

Abstract
Development of drug resistance is one of the major obstacles in cancer chemotherapy. The molecular mechanism leading to drug resistance is still not fully understood. A10A cells, a doxorubicin-resistant subline of human squamous cell carcinoma A431 cells, showed cross-resistance to methotrexate and also resistance to the drug-induced apoptosis. The cells also showed overexpression of a mutated form of p53, p53-R273H (Arg to His at codon 273), and down-regulation of procaspase-3. Knockdown of p53-R273H by p53 small interfering RNA in A431 cells increased procaspase-3 level and sensitized the cells to drug-induced apoptosis. On the other hand, transfection of p53-R273H into p53 null human osteosarcoma Saos-2 cells down-regulated procaspase-3 level and induced resistance to the drug toxicity and drug-induced apoptosis. The results support the idea that p53-R273H may gain new functions in induction of drug resistance and impairment in drug-induced apoptosis through down-regulation of procaspase-3 level. The study sheds new light on the understanding of the gain of function and drug resistance mechanisms associated with mutant p53. [Mol Cancer Ther 2007;6(3):1054–8]
A duplexed phenotypic screen for the simultaneous detection of inhibitors of the molecular chaperone heat shock protein 90 and modulators of cellular acetylation
Authors: Hardcastle Anthea , Tomlin Peter , Norris Clair , Richards Juliet , Cordwell Matthew , Boxall Katherine , Rowlands Martin , Jones Keith , Collins Ian , McDonald Edward , Workman Paul , Aherne Wynne 
Published: March 2007

Abstract
Histone deacetylases (HDACs), histone acetyltransferases (HATs), and the molecular chaperone heat shock protein 90 (HSP90) are attractive anticancer drug targets. High-throughput screening plays a pivotal role in modern molecular mechanism-based drug discovery. Cell-based screens are particularly useful in that they identify compounds that are permeable and active against the selected target or pathway in a cellular context. We have previously developed time-resolved fluorescence cell immunosorbent assays (TRF-Cellisas) for compound screening and pharmacodynamic studies. These assays use a primary antibody to the single protein of interest and a matched secondary immunoglobulin labeled with an europium chelate (Eu). The availability of species-specific secondary antibodies labeled with different lanthanide chelates provides the potential for multiplexing this type of assay. The approach has been applied to the development of a 384-well duplexed cell-based screen to simultaneously detect compounds that induce the co-chaperone HSP70 as a molecular marker of potential inhibitors of HSP90 together with those that modulate cellular acetylation (i.e., potential inhibitors of histone deacetylase or histone acetyltransferase activity). The duplexed assay proved reliable in high-throughput format and ∼64,000 compounds were screened. Following evaluation in secondary assays, 3 of 13 hits from the HSP70 arm were confirmed. Two of these directly inhibited the intrinsic ATPase activity of HSP90 whereas the third seems to have a different mechanism of action. In the acetylation arm, two compounds increased cellular acetylation, one of which inhibited histone deacetylase activity. A third compound decreased cellular histone acetylation, potentially through a novel mechanism of action. [Mol Cancer Ther 2007;6(3):1112–22]
Tetrathiomolybdate promotes tumor necrosis and prevents distant metastases by suppressing angiogenesis in head and neck cancer
Authors: Hassouneh Basil , Islam Mozaffarul , Nagel Thomas , Pan Quintin , Merajver Sofia D. , Teknos Theodoros N. 
Published: March 2007

Abstract
Angiogenesis is well recognized as an essential process that influences not only the growth of head and neck squamous cell carcinoma (HNSCC) but also promotes its invasive and metastatic behavior. The critical role of copper in multiple facets of angiogenesis makes it an important therapeutic target. Tetrathiomolybdate is a potent copper chelator, which has shown remarkable ability to suppress angiogenesis. Although this may involve multiple mechanisms, the effects on vascular endothelial growth factor (VEGF) are pivotal. In previous work, tetrathiomolybdate suppressed production of several proangiogenic cytokines by HNSCC cell lines. Given these results, we hypothesized that tetrathiomolybdate would impair tumor growth and metastasis by HNSCC. To test this concept, we evaluated the effects of long-term tetrathiomolybdate treatment on the growth and metastatic progression of HNSCC using a xenograft animal model. The results showed that tetrathiomolybdate treatment is able to maintain effective inhibition of angiogenesis. There was a significant reduction in the tumor size and vascularity with evident gross necrosis in the tetrathiomolybdate-treated animals. These effects were highly correlated with suppression of human VEGF expressed in the developing tumors as well as the mouse VEGF levels detected in the plasma. Moreover, tetrathiomolybdate treatment drastically suppressed the development of lung metastases. Taken together, these results show that tetrathiomolybdate can act long-term as a suppressor of vascularity and inhibit the growth of metastasis in this model of HNSCC. [Mol Cancer Ther 2007;6(3):1039–45]
Curcumin potentiates the apoptotic effects of chemotherapeutic agents and cytokines through down-regulation of nuclear factor-κB and nuclear factor-κB–regulated gene products in IFN-α–sensitive and IFN-α–resistant human bladder cancer cells
Authors: Kamat Ashish M. , Sethi Gautam , Aggarwal Bharat B. 
Published: March 2007

Abstract
Bladder cancer mortality varies between the countries; whereas being highest in Western countries, it is lowest in Eastern countries, such as India. Cigarette smoking is one of the major risk factors for bladder cancer in affluent nations, such as United States. Localized early-stage bladder cancer is treated with resection and intravesical cytokine therapy, whereas metastatic cancer is typically treated with various combinations of systemic chemotherapy. Whether curcumin, a yellow curry pigment commonly consumed in countries, such as India, has any role in prevention or treatment of bladder cancer was investigated. We found that curcumin inhibited the proliferation, induced cell cycle arrest, and DNA fragmentation in both IFN-α–sensitive (RT4V6) and IFN-α–resistant (KU-7) bladder cancer cells. Curcumin also potentiated the apoptotic effects of the chemotherapeutic agents (gemcitabine and paclitaxel) and of cytokines [tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand]. This effect of curcumin was independent of sensitivity and resistance to IFN-α, commonly used for treatment of bladder cancer. Whether the effects of curcumin are mediated through modulation of the nuclear factor-κB (NF-κB) pathway known to mediate antiapoptosis was investigated. Both gemcitabine and TNF activated NF-κB in bladder cancer cells and curcumin suppressed this activation. Similarly, cigarette smoke, a major risk factor for bladder cancer, also activated NF-κB and curcumin suppressed it. Cigarette smoke–induced expression of the NF-κB–regulated gene products cyclooxygenase-2 and vascular endothelial growth factor, linked with proliferation and angiogenesis, respectively, was also down-regulated by curcumin. [Mol Cancer Ther 2007;6(3):1022–30]
Colon carcinoma cells harboring PIK3CA mutations display resistance to growth factor deprivation induced apoptosis
Authors: Wang Jing , Kuropatwinski Karen , Hauser Jennie , Rossi Michael R. , Zhou Yunfei , Conway Alexis , Kan Julie L.C. , Gibson Neil W. , Willson James K.V. , Cowell John K. , Brattain Michael G. 
Published: March 2007

Abstract
PIK3CA, encoding the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is mutated in a variety of human cancers. We screened the colon cancer cell lines previously established in our laboratory for PIK3CA mutations and found that four of them harbored gain of function mutations. We have now compared a panel of mutant and wild-type cell lines for cell proliferation and survival in response to stress. There was little difference in PI3K activity between mutant PIK3CA-bearing cells (mutant cells) and wild-type PIK3CA-bearing cells (wild-type cells) under optimal growth conditions. However, the mutant cells showed constitutive PI3K activity during growth factor deprivation stress (GFDS), whereas PI3K activity decayed rapidly in the wild-type cells. Importantly, constitutively active PI3K rendered the mutant cells resistant to GFDS-induced apoptosis relative to the wild-type cells, indicating a biological advantage under stress conditions that is imparted by the mutant enzymes. Compared with the wild-type cells, the mutant cells were hypersensitive to the apoptosis induced by the PI3K inhibitor LY294002. In addition, PIK3CA small interfering RNA significantly decreased DNA synthesis and/or induced apoptosis in the mutant cells but not in the wild-type cells. Furthermore, ecotopic expression of a mutant PIK3CA in a nontumorigenic PIK3CA wild-type cell line resulted in resistance to GFDS-induced apoptosis, whereas transfection of wild-type PIK3CA or empty vector had little effect. Taken together, our studies show that mutant PIK3CA increases the capacity for proliferation and survival under environmental stresses, such as GFDS while also imparting greater dependency on the PI3K pathway for proliferation and survival. [Mol Cancer Ther 2007;6(3):1143–50]
Bortezomib, but not cisplatin, induces mitochondria-dependent apoptosis accompanied by up-regulation of noxa in the non–small cell lung cancer cell line NCI-H460
Authors: Voortman Jens , Checinska Agnieszka , Giaccone Giuseppe , Rodriguez Jose A. , Kruyt Frank A.E. 
Published: March 2007

Abstract
Defects in the apoptotic machinery may contribute to chemoresistance of non–small cell lung cancer (NSCLC) cells. We have previously showed a deficiency in mitochondria-dependent caspase-9 activation in NSCLC H460 cells after exposure to cisplatin, a drug widely used to treat NSCLC. Here we show that, unlike cisplatin, the novel anticancer agent bortezomib efficiently induces caspase-9 activation and apoptosis in H460 cells. A comparative analysis of molecular events underlying cell death in bortezomib-treated versus cisplatin-treated H460 cells revealed that bortezomib, but not cisplatin, caused a rapid and abundant release of cytochrome c and Smac/DIABLO from mitochondria. This was associated with a marked increase in levels of the BH3-only proapoptotic protein Noxa and the antiapoptotic protein Mcl-1. Taken together, our data show that bortezomib, by promoting a proapoptotic shift in the levels of proteins involved in mitochondrial outer-membrane permeabilization, is a potent activator of the mitochondrial pathway of apoptosis in NSCLC cells. Our preclinical results support further investigation of bortezomib-based therapies as a possible new treatment modality for NSCLC. [Mol Cancer Ther 2007;6(3):1046–53]