bluuebunny/crossref_metadata_2025 huggingface dataset:
Definition of Functionally Important Mechanistic Differences among Selective Estrogen Receptor Down-regulators
Authors: Wittmann Bryan M. , Sherk Andrea , McDonnell Donald P.
Published: October 2007

One subclass of antiestrogens, the selective estrogen receptor down-regulators (SERDs), have received considerable attention of late as they competitively inhibit estrogen binding and induce a rapid, proteasome-dependent degradation of the receptor. Contained within this class of molecules is the steroidal antiestrogen ICI182,780 (faslodex), recently approved for the treatment of metastatic cancer, and GW5638/DPC974, a SERD that is currently being evaluated in the clinic. Given that mechanistic differences between different selective estrogen receptor modulators have been translated into important clinical profiles, it was of interest to determine if the SERD subclass of ligands were likewise functionally or mechanistically distinguishable. In this study, we show that although the steroidal and nonsteroidal SERDs target ERα for degradation, the underlying mechanism(s) are different. Of note was the identification of a specific protein-protein interaction surface presented on ERα in the presence of the ICI182,780-activated receptor which is required for degradation. Interestingly, this surface is also presented on ERα in the presence of RU58,668, a SERD that is chemically distinct from ICI182,780. This surface is not required for GW5638-mediated degradation, and thus, this SERD seems to affect ERα down-regulation by a different mechanism. These data suggest that sequencing of therapies using drugs of this class is likely to be possible. Finally, because of the unmet need for orally active SERDS that function similarly to ICI182,780, we have used the insights from these mechanistic studies to develop and validate a high-throughput screen for compounds of this class with improved pharmaceutical properties. [Cancer Res 2007;67(19):9549–60]
Tumor Necrosis Factor α Mediates Homogeneous Distribution of Liposomes in Murine Melanoma that Contributes to a Better Tumor Response
Authors: Seynhaeve Ann L.B. , Hoving Saske , Schipper Debby , Vermeulen Cindy E. , aan de Wiel-Ambagtsheer Gisela , van Tiel Sandra T. , Eggermont Alexander M.M. , ten Hagen Timo L.M.
Published: October 2007

Successful treatment of solid tumors with chemotherapeutics requires that adequate levels reach the tumor cells. Tumor vascular normalization has been proposed to enhance drug delivery and improve tumor response to chemotherapy. Differently, augmenting leakage of the tumor-associated vasculature, and as such enhance vascular abnormality, may improve tumor response as well. In the present study, we show that addition of low-dose tumor necrosis factor α (TNF) to systemic injections with pegylated long circulating liposomes augmented the tumor accumulation of these liposomes 5- to 6-fold, which strongly correlated with enhanced tumor response. Using intravital microscopy, we could study the liposomal distribution inside the tumor in more detail. Especially 100 nm liposomes effectively extravasate in the surrounding tumor tissue in the presence of TNF and this occurred without any effect on tumor vascular density, branching, and diameter. Next to that, we observed in living animals that tumor cells take up the liposomes intact, followed by intracellular degradation. To our knowledge, this is an unprecedented observation. Taken together, TNF renders more tumor vessels permeable, leading to a more homogeneous distribution of the liposomes throughout the tumor, which is crucial for an optimal tumor response. We conclude that delivery of nanoparticulate drug formulations to solid tumor benefits from augmenting the vascular leakage through vascular manipulation with vasoactive drugs like TNF. [Cancer Res 2007;67(19):9455–62]
Trastuzumab-Resistant HER2-Driven Breast Cancer Cells Are Sensitive to Epigallocatechin-3 Gallate
Authors: Eddy Sean F. , Kane Susan E. , Sonenshein Gail E.
Published: October 2007

Overexpression of the epidermal growth factor receptor family member HER2 is found in ∼30% of breast cancers and is a target for immunotherapy. Trastuzumab, a humanized monoclonal antibody against HER2, is cytostatic when added alone and highly successful in clinical settings when used in combination with other chemotherapeutic agents. Unfortunately, HER2 tumors in patients develop resistance to trastuzumab or metastasize to the brain, which is inaccessible to antibody therapy. Previously, we showed that the green tea polyphenol epigallocatechin-3 gallate (EGCG) inhibits growth and transformed phenotype of Her-2/neu–driven mouse mammary tumor cells. The different modes of action of EGCG and trastuzumab led us to hypothesize that EGCG will inhibit HER2-driven breast cancer cells resistant to trastuzumab. We studied trastuzumab-resistant BT474 human breast cancer cells, isolated by chronic trastuzumab exposure, and JIMT-1 breast cancer cells, derived from a pleural effusion in a patient who displayed clinical resistance to trastuzumab therapy. EGCG treatment caused a dose-dependent decrease in growth and cellular ATP production, and apoptosis at high concentrations. Akt activity was suppressed by EGCG leading to the induction of FOXO3a and target cyclin-dependent kinase inhibitor p27Kip1 levels. Thus, EGCG in combination with trastuzumab may provide a novel strategy for treatment of HER2-overexpressing breast cancers, given that EGCG can cross the blood-brain barrier. [Cancer Res 2007;67(19):9018–23]
The Alternative Reading Frame Tumor Suppressor Antagonizes Hypoxia-Induced Cancer Cell Migration via Interaction with the COOH-Terminal Binding Protein Corepressor
Authors: Paliwal Seema , Kovi Ramesh C. , Nath Bharath , Chen Ya-Wen , Lewis Brian C. , Grossman Steven R.
Published: October 2007

The alternative reading frame (ARF) tumor suppressor exerts both p53-dependent and p53-independent activities critical to the prevention of cancer in mice and humans. Recent evidence from mouse models suggests that when p53 is absent, further loss of ARF can widen the tumor spectrum, and potentiate invasion and metastasis. A major target of the p53-independent activity of ARF is the COOH-terminal binding protein (CtBP) family of metabolically regulated transcriptional corepressors, which are degraded upon acute exposure to the ARF protein. CtBPs are activated under conditions of metabolic stress, such as hypoxia, to repress epithelial and proapoptotic genes, and can mediate hypoxia-induced migration of cancer cells. The possibility that ARF could suppress tumor cell migration as part of its p53-independent activities was thus explored. Small-interfering RNA (siRNA)–mediated knockdown of ARF in human lung carcinoma cells led to increased cell migration, especially during hypoxia, and this effect was blocked by concomitant treatment with CtBP2 siRNA. Introduction of ARF into p53 and ARF-null human colon cancer cells inhibited hypoxia-induced migration. Furthermore, overexpression of CtBP2 in ARF-expressing cells enhanced cell migration, and an ARF mutant defective in CtBP-family binding was impaired in its ability to inhibit cell migration induced by CtBP2. ARF depletion or CtBP2 overexpression was associated with decreased PTEN expression and activation of the phosphatidylinositol 3-kinase pathway, and a phosphatidylinositol 3-kinase inhibitor blocked CtBP2-mediated cell migration. Thus, ARF can suppress cell migration by antagonizing CtBP2 and the phosphatidylinositol 3-kinase pathway, and these data may explain the increased aggressiveness of ARF-null tumors in mouse models. [Cancer Res 2007;67(19):9322–9]
The Fuzzy Math of Solid Tumor Stem Cells: A Perspective
Authors: Kern Scott E. , Shibata Darryl
Published: October 2007

Apparently effective therapeutic agents very often fail to cure cancer patients. It is therefore attractive to wonder whether a specific resistant cell subset should be recognized and separately targeted. In solid tumors, such as carcinomas, a minor population of “cancer stem cells” has been proposed and sought experimentally in human tumors and isolated cell populations. It is often overlooked that the rationale and supportive data are essentially numerical and can be evaluated as such. A reevaluation of the published studies and related claims within awarded U.S. patents suggests that the mathematical support for the concept of therapeutically useful stem cells is weak and may even invalidate the foundations of these publications and patent claims. Mathematical arguments should be used more consistently, because they can serve as a guide for interpreting studies into cancer stem cells of solid tumors. [Cancer Res 2007;67(19):8985–8]
Autocrine Glutamate Signaling Promotes Glioma Cell Invasion
Authors: Lyons Susan A. , Chung W. Joon , Weaver Amy K. , Ogunrinu Toyin , Sontheimer Harald
Published: October 2007

Malignant gliomas have been shown to release glutamate, which kills surrounding brain cells, creating room for tumor expansion. This glutamate release occurs primarily via system xC−, a Na+-independent cystine-glutamate exchanger. We show here, in addition, that the released glutamate acts as an essential autocrine/paracrine signal that promotes cell invasion. Specifically, chemotactic invasion and scrape motility assays each show dose-dependent inhibition of cell migration when glutamate release was inhibited using either S-(4)-CPG or sulfasalazine, both potent blockers of system xC−. This inhibition could be overcome by the addition of exogenous glutamate (100 μmol/L) in the continued presence of the inhibitors. Migration/invasion was also inhibited when Ca2+-permeable α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPA-R) were blocked using GYKI or Joro spider toxin, whereas CNQX was ineffective. Ca2+ imaging experiments show that the released glutamate activates Ca2+-permeable AMPA-R and induces intracellular Ca2+ oscillations that are essential for cell migration. Importantly, glioma cells release glutamate in sufficient quantities to activate AMPA-Rs on themselves or neighboring cells, thus acting in an autocrine and/or paracrine fashion. System xC− and the appropriate AMPA-R subunits are expressed in all glioma cell lines, patient-derived glioma cells, and acute patient biopsies investigated. Furthermore, animal studies in which human gliomas were xenographed into scid mice show that chronic inhibition of system xC−–mediated glutamate release leads to smaller and less invasive tumors compared with saline-treated controls. These data suggest that glioma invasion is effectively disrupted by inhibiting an autocrine glutamate signaling loop with a clinically approved candidate drug, sulfasalazine, already in hand. [Cancer Res 2007;67(19):9463–71]
Nitric Oxide Inactivates the Retinoblastoma Pathway in Chronic Inflammation
Authors: Ying Lei , Hofseth Anne B. , Browning Darren D. , Nagarkatti Mitzi , Nagarkatti Prakash S. , Hofseth Lorne J.
Published: October 2007

Patients with chronic inflammatory bowel disease have a high risk of colon cancer. The molecules that initiate and promote colon cancer and the cancer pathways altered remain undefined. Here, using in vitro models and a mouse model of colitis, we show that nitric oxide (NO) species induce retinoblastoma protein (pRb) hyperphosphorylation and inactivation, resulting in increased proliferation through the pRb-E2F1 pathway. NO-driven pRb hyperphosphorylation occurs through soluble guanylyl cyclase/guanosine 3′,5′-cyclic monophosphate signaling and is dependent on the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase MEK/ERK and phosphatidylinositol 3-kinase/AKT pathways. Our results reveal a link between NO and pRb inactivation and provide insight into molecules that can be targeted in the prevention of the inflammation-to-cancer sequence. [Cancer Res 2007;67(19):9286–93]
A Phase II Study of Gefitinib Monotherapy in Advanced Esophageal Adenocarcinoma: Evidence of Gene Expression, Cellular, and Clinical Response
Authors: Ferry David R. , Anderson Mark , Beddard Kate , Tomlinson Simon , Atherfold Paul , Obszynska Jolanta , Harrison Rebecca , Jankowski Janusz
Published: October 2007

Purpose: At presentation, most cases of adenocarcinoma of the esophagus (ACE) are inoperable. Although chemotherapy can prolong survival, patients eventually die as a result of refractory disease. Epidermal growth factor receptor (EGFR) is almost universally expressed in ACE and is a negative prognostic factor.

Experimental Design: This open-label, two-center, noncomparative, two-part phase II trial assessed the EGFR tyrosine kinase inhibitor gefitinib (500 mg/d) in patients with advanced, inoperable ACE. The primary end point was tumor response. The effect of EGFR inhibition was also evaluated by gene expression analysis of tumor biopsies taken before gefitinib treatment and 28 days after.

Results: Twenty-seven patients were recruited and evaluable for tumor response and safety. Three patients had a partial response and seven had stable disease, giving a disease control rate (partial response + stable disease) of 37%. Drug-related adverse events were generally mild: diarrhea in 19 (grade 3 in three) and rash in 19 (grade 3 in five) patients, and there were no grade 4 drug-related adverse events. Microarray experiments on tumor biopsies showed that gefitinib also down-regulated oncogenes associated with tumor progression. Ki67 (a marker of tumor growth) expression decreased in five of seven biopsies taken before and after treatment.

Conclusion: Gefitinib (500 mg/d) is an active and generally well-tolerated treatment for ACE. Studies on endoscopic biopsies are feasible and indicate that gefitinib inhibits both gene expression and cellular biology at 500 mg/d, and these may provide surrogate end points for predictive biomarkers. Further trials of gefitinib are warranted, particularly as patient response seems to be durable and current second-line chemotherapy options have no proven ability to prolong life.
Phase I Trial of Poly-l-Glutamate Camptothecin (CT-2106) Administered Weekly in Patients with Advanced Solid Malignancies
Authors: Homsi Jade , Simon George R. , Garrett Chris R. , Springett Gregory , De Conti Ronald , Chiappori Alberto A. , Munster Pamela N. , Burton Michelle K. , Stromatt Scott , Allievi Claudia , Angiuli Patrizia , Eisenfeld Amy , Sullivan Daniel M. , Daud Adil I.
Published: October 2007

Purpose: CT-2106 is a 20(S)-camptothecin poly-l-glutamate conjugate. This linkage stabilizes the active lactone form of camptothecin and enhances aqueous solubility. In addition, poly-l-glutamate is postulated to increase tumor delivery of the active compound through enhanced permeability and retention effect in tumor. We studied a weekly schedule of CT-2106 in patients with refractory solid tumor malignancies.

Experimental Design: CT-2106 was infused (10 min i.v. infusion) on days 1, 8, and 15 of each 28-day cycle. Plasma and urine were analyzed for total and unconjugated camptothecin by high-performance liquid chromatography equipped with a fluorescence detector. Toxicity and response assessments were done with Common Toxicity Criteria for Adverse Events version 3 and Response Evaluation Criteria in Solid Tumors, respectively.

Results: Twenty-six patients were enrolled. Median age was 58 years (range, 36-83) and median number of doses was 6 (range, 1-9). The most frequent tumor type (50%) was melanoma. Dose limiting toxicities were thrombocytopenia and fatigue. A weekly dose of 25 mg/m2 given every 3 of 4 weeks was the maximum tolerated dose. The majority of grade 3 and 4 toxicities were hematologic. The pharmacokinetic profile of conjugated and unconjugated camptothecin showed a polyexponential decline with similar terminal half life (t1/2 range was 44-63 and 31-48 h for conjugated and unconjugated, respectively). Pharmacokinetics of conjugated and unconjugated camptothecin were dose and time independent in the tested dose range. Urinary excretion of conjugated and unconjugated camptothecin accounted for about 30% and 4% of the administered dose, respectively.

Conclusions: CT-2106 has a more manageable toxicity profile compared with unconjugated camptothecin. The maximum tolerated dose is 25 mg/m2 weekly given 3 of 4 weeks. This compound results in prolonged release of unconjugated camptothecin.
Amplification of PVT1 Contributes to the Pathophysiology of Ovarian and Breast Cancer
Authors: Guan Yinghui , Kuo Wen-Lin , Stilwell Jackie L. , Takano Hirokuni , Lapuk Anna V. , Fridlyand Jane , Mao Jian-Hua , Yu Mamie , Miller Melinda A. , Santos Jennifer L. , Kalloger Steve E. , Carlson Joseph W. , Ginzinger David G. , Celniker Susan E. , Mills Gordon B. , Huntsman David G. , Gray Joe W.
Published: October 2007

Purpose: This study was designed to elucidate the role of amplification at 8q24 in the pathophysiology of ovarian and breast cancer because increased copy number at this locus is one of the most frequent genomic abnormalities in these cancers.

Experimental Design: To accomplish this, we assessed the association of amplification at 8q24 with outcome in ovarian cancers using fluorescence in situ hybridization to tissue microarrays and measured responses of ovarian and breast cancer cell lines to specific small interfering RNAs against the oncogene MYC and a putative noncoding RNA, PVT1, both of which map to 8q24.

Results: Amplification of 8q24 was associated with significantly reduced survival duration. In addition, small interfering RNA–mediated reduction in either PVT1 or MYC expression inhibited proliferation in breast and ovarian cancer cell lines in which they were both amplified and overexpressed but not in lines in which they were not amplified/overexpressed. Inhibition of PVT1 expression also induced a strong apoptotic response in cell lines in which it was overexpressed but not in lines in which it was not amplified/overexpressed. Inhibition of MYC, on the other hand, did not induce an apoptotic response in cell lines in which MYC was amplified and overexpressed.

Conclusions: These results suggest that MYC and PVT1 contribute independently to ovarian and breast pathogenesis when overexpressed because of genomic abnormalities. They also suggest that PVT1-mediated inhibition of apoptosis may explain why amplification of 8q24 is associated with reduced survival duration in patients treated with agents that act through apoptotic mechanisms.
p66 Shc Tumor Levels Show a Strong Prognostic Correlation with Disease Outcome in Stage IIA Colon Cancer
Authors: Grossman Steven R. , Lyle Stephen , Resnick Murray B. , Sabo Edmond , Lis Rosina T. , Rosinha Elizabeth , Liu Qin , Hsieh Chung-Cheng , Bhat Gajanan , Frackelton A. Raymond , Hafer Laurie J.
Published: October 2007

Purpose: Most stage IIA colon cancer patients receive no adjuvant therapy despite an estimated 15% risk of disease-related death within 5 years of resection. Prognostication of disease outcome would benefit the clinician by categorizing patients with stage IIA disease by risk. The abundance of the signal transduction proteins p66 Shc and tyrosine-phosphorylated (PY)-Shc in tumor cells is a prognostic indicator of disease outcome in breast cancer, suggesting that Shc analysis may provide prognostic information in stage IIA colon cancer.

Experimental Design: Immunohistochemical staining of p66 Shc and PY-Shc was examined in resection specimens from 240 chemotherapy-naïve patients with stage IIA (T3N0M0) colon cancer from two independent (130 and 110 cases, respectively) retrospective cohorts. Staining was scored on a 0 to 5 scale and correlated with relapse-free survival and disease-specific survival in a multivariate analysis to obtain hazard ratios (HR) for both outcomes.

Results: In a pooled analysis of both cohorts, p66 Shc score was a significant prognostic indicator of relapse-free survival (full-range HR, 13.0; P = 0.012) and disease-specific survival (full-range HR, 36.6; P = 0.004) when analyzed as a continuous variable in a multivariate Cox proportional hazards model stratified by study site and adjusted for age, sex, grade, and lymphovascular involvement. PY-Shc in this multivariate Cox model, however, did not achieve statistical significance for either outcome.

Conclusions: Measuring p66 Shc tumor levels provides a unique and simple tool for stratifying stage IIA colon cancer patients by risk of recurrence and disease-specific death and may assist in determining treatment strategies for these patients.
Genetic Variants in Cell Cycle Control Pathway Confer Susceptibility to Lung Cancer
Authors: Wang Wei , Spitz Margaret R. , Yang Hushan , Lu Charles , Stewart David J. , Wu Xifeng
Published: October 2007

Purpose: To test the hypothesis that common sequence variants of cell cycle control genes may affect lung cancer predisposition.

Experimental Design: We explored lung cancer risk associations of 11 polymorphisms in seven cell cycle genes in a large case-control study including 1,518 Caucasian lung cancer patients and 1,518 controls.

Results: When individuals with variant-containing genotypes were compared with homozygous wild-type carriers, a significantly increased lung cancer risk was identified for polymorphisms in p53 intron 6 [rs1625895; odds ratio (OR), 1.29; 95% confidence interval (95% CI), 1.08-1.55] and in p27 5′ untranslated region (UTR; rs34330; OR, 1.27; 95% CI, 1.01-1.60). Compared with homozygous wild-types, the homozygous variant genotypes of STK15 F31I and CCND1 G870A were associated with a significantly altered lung cancer risk with ORs of 0.58 (95% CI, 0.37-0.90) and 1.26 (95% CI, 1.03-1.53), respectively. To assess the cumulative effects of all the investigated polymorphisms on lung carcinogenesis, we conducted a combined analysis and found that compared with low-risk individuals with few adverse alleles, individuals with more adverse alleles had an increased risk in a significant dose-dependent manner (Ptrend = 0.041). This pattern was more evident in ever smokers (Ptrend = 0.037), heavy smokers (Ptrend = 0.020), and older subjects (Ptrend = 0.011). Higher-order gene-gene interactions were evaluated using the classification and regression tree analysis, which indicated that STK15 F31I and p53 intron 6 polymorphisms might be associated with lung carcinogenesis in never/light-smokers and heavy smokers, respectively.

Conclusions: Our results suggest that cell cycle gene polymorphisms and smoking may function collectively to modulate the risk of lung cancer.
Adjuvant Adenovirus-Mediated Delivery of Herpes Simplex Virus Thymidine Kinase Administration Improves Outcome of Liver Transplantation in Patients with Advanced Hepatocellular Carcinoma
Authors: Li Ning , Zhou Jianfeng , Weng Danhui , Zhang Chenghua , Li Lixin , Wang Beibei , Song Yang , He Qiang , Lin Dongdong , Chen Dazhi , Chen Gang , Gao Qinglei , Wang Shixuan , Xu Gang , Meng Li , Lu YunPing , Ma Ding
Published: October 2007

Purpose: Previous poor results of liver transplantation (LT) have been confirmed in patients with advanced hepatocellular carcinoma (HCC). Adenovirus-mediated delivery of herpes simplex virus thymidine kinase (ADV-TK) therapy is an established adjuvant treatment in cancer, and we evaluated its potential as an adjuvant treatment for HCC patients who underwent LT.

Experimental Design: Forty-five HCC patients with tumors >5 cm in diameter participated in the study over a follow-up period of 50 months. Among these patients, 22 received LT only, and 23 received LT combined with ADV-TK therapy. All HCC patients enrolled in this study had tumors >5 cm in diameter and no metastasis in lungs or bones was detected by computed tomography or magnetic resonance imaging scans.

Results: The recurrence-free survival and the overall survival in the LT plus ADV-TK therapy group were 43.5% and 69.6%, respectively, at 3 years; both values were significantly higher than those in the LT-only group (9.1% and 19.9%, respectively). In the nonvascular invasion subgroup, overall survival was 100% and recurrence-free survival was 83.3% in the patients receiving LT plus ADV-TK, significantly higher than the patients receiving LT only.

Conclusions: HCC patients with no vascular invasion could be selected for LT followed by adjuvant ADV-TK therapy, regardless of intrahepatic huge or diffuse tumor. We propose that the current criteria for LT based on tumor size may be expanded if accompanied by ADV-TK therapy due to improved prognosis.
The Therapeutic Efficacy of Anti–Vascular Endothelial Growth Factor Antibody, Bevacizumab, and Pemetrexed against Orthotopically Implanted Human Pleural Mesothelioma Cells in Severe Combined Immunodeficient Mice
Authors: Li Qi , Yano Seiji , Ogino Hirokazu , Wang Wei , Uehara Hisanori , Nishioka Yasuhiko , Sone Saburo
Published: October 2007

Purpose: Malignant pleural mesothelioma (MPM) is an aggressive malignancy, which has a poor prognosis with a median survival of less than 1 year. The vascular endothelial growth factor (VEGF) has been reported to be an ideal therapeutic target, and a multitargeted antifolate, pemetrexed, has been clinically used for the treatment of MPM.

Experimental Design: We examined the therapeutic efficacy of the antihuman VEGF neutralizing antibody, bevacizumab, in combination with pemetrexed against two different human MPM cells, EHMES-10 and MSTO-211H, orthotopically inoculated into severe combined immunodeficient mice.

Results: Bevacizumab inhibited a VEGF-induced proliferation of the human endothelial cells in a dose-dependent manner, but it had no effect on the proliferation of the two MPM cell lines in vitro. The orthotopically inoculated EHMES-10 cells (VEGF high expressing) produced thoracic tumors and a large volume of bloody pleural effusion, whereas the MSTO-211H cells (VEGF low expressing) produced thoracic tumors and a small volume of bloody effusions. Treatment with bevacizumab effectively inhibited the production of thoracic tumors and dramatically prevented the production of pleural effusion by the EHMES-10 cells but not the MSTO-211H cells. Treatment with bevacizumab reduced the number of enlarged tumor-associated vessels and proliferating tumor cells. Moreover, treatment with bevacizumab in combination with pemetrexed more effectively suppressed the formation of the pleural effusion and prolonged the survival compared with the control and monotherapy in the EHMES-10 cell–bearing severe combined immunodeficient mice.

Conclusions: These results suggest that the combined use of bevacizumab and pemetrexed may therefore be promising for controlling the progression of MPM highly expressing VEGF.
Comparative Analysis of Peritoneum and Tumor Eicosanoids and Pathways in Advanced Ovarian Cancer
Authors: Freedman Ralph S. , Wang Ena , Voiculescu Sonia , Patenia Rebecca , Bassett Roland L. , Deavers Michael , Marincola Francesco M. , Yang Peiying , Newman Robert A.
Published: October 2007

Purpose: To describe the eicosanoid profile and differentially expressed eicosanoid and arachidonic acid pathway genes in tissues from patients with advanced epithelial ovarian cancer (EOC).

Experimental Design: We first employed electrospray tandem mass spectrometry to determine tissue-specific concentrations of the eicosanoids prostaglandin E2 (PGE2), the hydroxyeicosatetraenoic acids (12-HETE and 5-HETE), and leukotriene (LTB4), selected for tumor growth potential, and two other bioactive lipids (15-HETE and 13-HODE) with tumor cell proliferation interference potential. The cellular location of eicosanoid activity was identified by immunofluorescence antibody costaining and confocal microscopy. Differential analysis of eicosanoid and arachidonic pathway genes was done using a previously validated cDNA microarray platform. Tissues used included EOC tumor, tumor-free malignant peritoneum (MP), and benign peritoneum (BP) from patients with benign pelvic disease.

Results: (a) Eicosanoid products were detected in tumor, MP, and BP specimens. PGE2 levels were significantly elevated in tumors in an overall comparison with MP or BP (P < 0.001). Combined levels of PGE2, 12-HETE, 5-HETE, and LTB4 increased progressively from low to high concentrations in BP, MP, and tumors (P = 0.012). Neither 15-HETE nor 13-HODE showed a significant opposite trend toward levels found in BP. (b) Tissue specimens representing common EOC histotypes showed strong coexpressions of cyclooxygenases (COX-1) and prostaglandin E synthases (PGES-1) on tumor cells, whereas intratumoral or peritumoral MO/MA coexpressed COX-1 and COX-2 and PGES-1 and PGES-2, respectively. (c) cDNA microarray analysis of MP, BP, and tumor showed that a number of eicosanoid and arachidonic acid pathway genes were differentially expressed in MP and BP compared with tumor, except for CYP2J2, which was increased in tumors.

Conclusions: Elevated levels of eicosanoid metabolites in tumors and differential expression of eicosanoid and arachidonic acid pathway genes in the peritoneum support the involvement of bioactive lipids in the inflammatory tumor environment of EOC.
Identification of Toll-Like Receptor 3 as a Potential Therapeutic Target in Clear Cell Renal Cell Carcinoma
Authors: Morikawa Teppei , Sugiyama Akira , Kume Haruki , Ota Satoshi , Kashima Takeshi , Tomita Kyoichi , Kitamura Tadaichi , Kodama Tatsuhiko , Fukayama Masashi , Aburatani Hiroyuki
Published: October 2007

Purpose: Renal cell carcinoma (RCC) is one of the most drug-refractory cancers. The aim of this study is to discover a novel therapeutic target molecule for clear cell RCC (CCRCC), which accounts for the majority of RCC.

Experimental Design: Gene expression profiles of 27 CCRCCs and 9 normal kidney tissues as well as 15 various adult normal tissues were examined by Affymetrix U133 Plus 2.0 arrays. Among the 34 genes specifically up-regulated in CCRCC, overexpression of Toll-like receptor 3 (TLR3) mRNA and its protein was validated by quantitative reverse transcription-PCR, immunoblot, and immunohistochemistry. The effects of TLR3 signaling on in vitro cell growth were examined.

Results: TLR3 gene was highly expressed in CCRCC, with only limited expression in a panel of normal tissues. On immunohistochemical analysis using a monoclonal antibody against TLR3, overexpression of TLR3 was observed in 139 of 189 (73.5%) cases of CCRCC as well as in lung metastatic CCRCC (6 of 8), whereas TLR3 expression was entirely absent in chromophobe RCC (0 of 8). Polyinosinic-polycytidilic acid, a TLR3 ligand, exerted a growth-inhibitory effect against RCC cells in a TLR3-dependent manner. Moreover, a combination of polyinosinic-polycytidilic acid and IFNα exerted a synergistic growth-inhibitory effect against Caki-1 RCC cells.

Conclusions: This is the first report that TLR3 is overexpressed in CCRCC. These observations suggest that TLR3 pathway may represent a novel therapeutic target in CCRCC.
Inflammatory Breast Cancer as a Model Disease to Study Tumor Angiogenesis: Results of a Phase IB Trial of Combination SU5416 and Doxorubicin
Authors: Overmoyer Beth , Fu Pingfu , Hoppel Charles , Radivoyevitch Tomas , Shenk Robert , Persons Marjie , Silverman Paula , Robertson Kelly , Ziats Nicholas P. , Wasman Jay K. , Abdul-Karim Fadi W. , Jesberger John A. , Duerk Jeffrey , Hartman Paul , Hanks Shelli , Lewin Jonathan , Dowlati Afshin , McCrae Keith , Ivy Percy , Remick Scot C.
Published: October 2007

Purpose: We used inflammatory breast cancer (IBC) as a model disease to investigate biological changes associated with an antiangiogenesis agent, SU5416, combined with doxorubicin.

Experimental Design: Patients with stage IIIB or IV IBC were treated neoadjuvantly with the combination of SU5416 and doxorubicin for induction therapy. The dose of SU5416 (administered on days 1 and 4, every 3 weeks) and doxorubicin (administered on day 1 every 3 weeks) were escalated in cohorts of three patients starting at 110 and 60 mg/m2, respectively, for a total of five cycles leading up to mastectomy. Patients underwent serial assessment (pharmacokinetic sampling, biopsy of breast, tumor blood flow dynamic contrast-enhanced magnetic resonance imaging, plasma angiogenesis, and endothelial cell damage markers) prior to treatment, at the end of cycles no. 2 and no. 5, and after mastectomy.

Results: Eighteen patients were enrolled; neutropenia was dose-limiting, and overall median survival was not reached (50 months of study follow-up). Four patients (22%) experienced congestive heart failure, which resolved and were likely attributable to a smaller volume of distribution and higher Cmax of doxorubicin in combination with SU5416. We did observe a significant decline in tumor blood flow using Kep calculated by Brix (pretreatment versus post-cycle no. 5; P = 0.033), trend for a decline in tumor microvessel density after treatment, and low baseline levels of soluble intracellular adhesion molecule were associated with improved event-free survival.

Conclusions: This study showed evidence of an unfavorable cardiac interaction between SU5416 and doxorubicin, which prohibits further investigation of this combination. However, this study supports the importance of using IBC as a model for investigating angiogenesis inhibitors.
Neutralizing B-Cell–Activating Factor Antibody Improves Survival and Inhibits Osteoclastogenesis in a Severe Combined Immunodeficient Human Multiple Myeloma Model
Authors: Neri Paola , Kumar Shaji , Fulciniti Maria Teresa , Vallet Sonia , Chhetri Shweta , Mukherjee Sidhartha , Tai YuTzu , Chauhan Dharminder , Tassone Pierfrancesco , Venuta Salvatore , Munshi Nikhil C. , Hideshima Teru , Anderson Kenneth C. , Raje Noopur
Published: October 2007

Purpose: B-cell–activating factor (BAFF) is a tumor necrosis factor superfamily member critical for the maintenance and homeostasis of normal B-cell development. It has been implicated in conferring a survival advantage to B-cell malignancies, including multiple myeloma (MM).

Experimental Design: Here, we validate the role of BAFF in the in vivo pathogenesis of MM examining BAFF and its receptors in the context of patient MM cells and show activity of anti-BAFF antibody in a severe combined immunodeficient model of human MM.

Results: Gene microarrays and flow cytometry studies showed increased transcripts and the presence of all three receptors for BAFF in CD138+ patient MM cells, as well as an increase in plasma BAFF levels in 51 MM patients. Functional studies show that recombinant BAFF protects MM cells against dexamethasone-induced apoptosis accompanied by an increase in survival proteins belonging to the BCL family. These in vitro studies led to the evaluation of a clinical grade–neutralizing antibody to BAFF in a severe combined immunodeficient human MM model. Anti-BAFF–treated animals showed decreased soluble human interleukin 6 receptor levels, a surrogate marker of viable tumor, suggesting direct anti-MM activity. This translated into a survival advantage of 16 days (P < 0.05), a decrease in tartrate-resistant acid phosphatase–positive osteoclasts, and a reduction in radiologically evident lytic lesions in anti-BAFF–treated animals.

Conclusions: Our data show a role for BAFF as a survival factor in MM. Importantly, the in vivo antitumor activity of neutralizing anti-BAFF antibody provide the preclinical rationale for its evaluation in the treatment of MM.
Phase I and Pharmacokinetic Study of Imatinib Mesylate (Gleevec) and Gemcitabine in Patients with Refractory Solid Tumors
Authors: Ali Yaqoob , Lin Yong , Gharibo Mecide M. , Gounder Murugesan K. , Stein Mark N. , Lagattuta Theodore F. , Egorin Merrill J. , Rubin Eric H. , Poplin Elizabeth A.
Published: October 2007

Purpose: Preclinical data shows improvements in response for the combination of imatinib mesylate (IM, Gleevec) and gemcitabine (GEM) therapy compared with GEM alone. Our goals were to determine the maximum tolerated dose of GEM and IM in combination, the pharmacokinetics of GEM in the absence and in the presence of IM, and IM pharmacokinetics in this combination.

Patients and Methods: Patients with refractory malignancy, intact intestinal absorption, measurable/evaluable disease, adequate organ function, Eastern Cooperative Oncology Group PS 0-2, and signed informed consent were eligible. Initially, treatment consisted of 600 mg/m2 of GEM (10 mg/m2/min) on days 1, 8, and 15, and 300 mg of IM daily every 28 days. Due to excessive toxicity, the schedule was altered to IM on days 1 to 5 and 8 to 12, and GEM on days 3 and 10 every 21 days. Two final cohorts received IM on days 1 to 5, 8 to 12, and 15 to 19.

Results: Fifty-four patients were treated. IM and GEM given daily at 500 to 600 mg/m2 on days 1, 8, and 15 produced frequent dose-limiting toxicities. With the modified scheduling, GEM given at 1,500 mg/m2/150 min was deliverable, along with 400 mg of IM, without dose-limiting toxicities. Three partial (laryngeal, renal, and mesothelioma) and two minor (renal and pancreatic) responses were noted at GEM doses of 450 to 1,500 mg/m2. Stable disease >24 weeks was seen in 17 patients. CA19-9 in 7 of 10 patients with pancreatic cancer was reduced by ∼90%. IM did not significantly alter GEM pharmacokinetics.

Conclusion: The addition of intermittently dosed IM to GEM at low to full dose was associated with broad antitumor activity and little increase in toxicity.
Molecular Alterations in Prostate Carcinomas that Associate with In vivo Exposure to Chemotherapy: Identification of a Cytoprotective Mechanism Involving Growth Differentiation Factor 15
Authors: Huang Chung-Ying , Beer Tomasz M. , Higano Celestia S. , True Lawrence D. , Vessella Robert , Lange Paul H. , Garzotto Mark , Nelson Peter S.
Published: October 2007

Purpose: To identify molecular alterations associating with in vivo exposure of prostate carcinoma to chemotherapy and assess functional roles modulating tumor response and resistance.

Experimental Design: Patients with high-risk localized prostate cancer (tumor-node-metastasis ≥ T2b or prostate-specific antigen ≥ 15 ng/mL or Gleason glade ≥ 4+3) were enrolled into a phase II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone followed by prostatectomy. Pretreatment prostate tissue was acquired by needle biopsy and posttreatment tissue was acquired by prostatectomy. Prostate epithelium was captured by microdissection, and transcript levels were quantitated by cDNA microarray hybridization. Gene expression changes associated with chemotherapy were determined by a random variance t test. Several were verified by quantitative reverse transcription PCR. In vitro analyses determining the influence of growth differentiation factor 15 (GDF15) on chemotherapy resistance were done.

Results: Gene expression changes after chemotherapy were measured in 31 patients who completed four cycles of neoadjuvant chemotherapy. After excluding genes shown previously to be influenced by the radical prostatectomy procedure, we identified 51 genes with significant transcript level alterations following chemotherapy. This group included several cytokines, including GDF15, chemokine (C-X-C motif) ligand 10, and interleukin receptor 1β. Overexpression of GDF15 or exposure of prostate cancer cell lines to exogenous recombinant GDF15 conferred resistance to docetaxel and mitoxantrone.

Conclusions: Consistent molecular alterations were identified in prostate cancer cells exposed to docetaxel and mitoxantrone chemotherapy. These alterations include transcripts encoding cytokines known to be regulated through the nuclear factor-κB pathway. Chemotherapy-induced cytokines and growth factors, such as GDF15, contribute to tumor cell therapy resistance and may serve as targets to improve responses.
Phase I Dose Escalation Study of the Anti–Insulin-Like Growth Factor-I Receptor Monoclonal Antibody CP-751,871 in Patients with Refractory Solid Tumors
Authors: Haluska Paul , Shaw Heather M. , Batzel Gretchen N. , Yin Donghua , Molina Julian R. , Molife L. Rhoda , Yap Timothy A. , Roberts M. Luisa , Sharma Amarnath , Gualberto Antonio , Adjei Alex A. , de Bono Johann S.
Published: October 2007

Purpose: This phase I study was undertaken to define the maximum tolerated dose, safety, and pharmacokinetic profile of CP-751,871.

Experimental Design: Using a rapid dose escalation design, patients with advanced nonhematologic malignancies were treated with CP-751,871 in four dose escalation cohorts. CP-751,871 was administered i.v. on day 1 of each 21-day cycle. Pharmacokinetic evaluation was done in all treatment cohorts during cycles 1 and 4.

Results: Twenty-four patients received 110 cycles at four dose levels. The maximum tolerated dose exceeded the maximal feasible dose of 20 mg/kg and, thus, was not identified. Treatment-related toxicities were generally mild. The most common adverse events were hyperglycemia, anorexia, nausea, elevated aspartate aminotransferase, elevated γ-glutamyltransferase, diarrhea, hyperuracemia, and fatigue. At 20 mg/kg, 10 of 15 patients experienced stability of disease. Two of these patients experienced long-term stability. There were no objective responses. Pharmacokinetic analysis revealed a dose-dependent increase in CP-751,871 exposure and ∼2-fold accumulation on repeated dosing in 21-day cycles. Plasma concentrations of CP-751,871 attained were several log-fold greater than the biologically active concentration. Treatment with CP-751,871 increased serum insulin and human growth hormone levels, with modest increases in serum glucose levels.

Conclusions: CP-751,871 has a favorable safety profile and was well tolerated when given in continuous cycles. At the maximal feasible dose of 20 mg/kg, there was a moderate accumulation in plasma exposure, and most of the treated patients experienced stability of disease.
Phase I Dose-Finding Study of Weekly Docetaxel Followed by Flavopiridol for Patients with Advanced Solid Tumors
Authors: Fornier M.N. , Rathkopf D. , Shah M. , Patil S. , O'Reilly E. , Tse A.N. , Hudis C. , Lefkowitz R. , Kelsen D.P. , Schwartz G.K.
Published: October 2007

Purpose: Flavopiridol is a cyclin-dependent kinase inhibitor that enhances docetaxel-induced apoptosis in a sequence-specific manner. In vivo, docetaxel must precede flavopiridol by at least 4 h to induce this effect. We conducted a phase I trial of weekly, sequential docetaxel followed 4 h later by flavopiridol in patients with advanced solid tumors.

Experimental Design: Docetaxel at a fixed dose of 35 mg/m2 was administered over 30 min, followed 4 h later by escalating doses of flavopiridol, ranging from 20 to 80 mg/m2 in successive cohorts, administered weekly over 1 h. This schedule was repeated for 3 weeks of each 4-week cycle.

Results: Twenty-seven evaluable patients were enrolled. The combination was well tolerated, with one dose-limiting toxicity occurring at flavopiridol 70 mg/m2 (grade 3 mucositis) and one dose-limiting toxicity at 80 mg/m2 (grade 4 neutropenia). We observed 1 complete response in a patient with pancreatic carcinoma and 4 partial responses in pancreatic (1), breast (2), and ovarian (1) cancer patients. Stable disease was seen in 10 patients. Pharmacokinetic studies showed Cmax ranging from 1.49 ± 0.69 μmol/L (flavopiridol 20 mg/m2) to 4.54 ± 0.08 μmol/L (flavopiridol 60 mg/m2) in cycle 1.

Conclusions: Treatment with weekly, sequential docetaxel followed by flavopiridol is an effective and safe regimen at all flavopiridol dose levels. The pharmacokinetic data indicate that concentrations of flavopiridol that enhance the effects of docetaxel both in vitro and in vivo can be achieved. Clinical activity is encouraging, even in patients who have received a prior taxane and in patients with gemcitabine-refractory metastatic pancreatic cancer.
The Role of Traditionalists and Modernists on the Development of the Saudi Legal System
Authors: Al-Jarbou Ayoub
Published: October 2007

This article deals with the issue of the role of traditionalists and modernists on the development of the Saudi legal system. It presents and defines the two movements and evaluates their backgrounds and approaches. It also explores their impacts on the development of the Saudi legal system through evaluating their approaches on the following areas: legislative process, people's perspective toward applied laws, the judicial system, and legal education.

The article concludes that it is clear from this evidentiary demonstration that the development of the Saudi legal system has been affected by the concurrent influences of traditionalist and modernist movements. The substance of enacted laws, legal education, the judicial systems, and people's attitude toward both Shariah and enacted laws has been negatively affected by the approaches of both movements. The paper provides for various approaches and solutions that address the problems of the system of legal education, judicial system, and legislative process. The paper suggests that these various approaches and solutions have to be adopted jointly; otherwise the confusion in the legal system will continue.
Positive Organizational Behavior in the Workplace
Authors: Youssef Carolyn M. , Luthans Fred
Published: October 2007

Drawing from the foundation of positive psychology and the recently emerging positive organizational behavior, two studies (N = 1,032 and N = 232) test hypotheses on the impact that the selected positive psychological resource capacities of hope, optimism, and resilience have on desired work-related employee outcomes. These outcomes include performance (self-reported in Study 1 and organizational performance appraisals in Study 2), job satisfaction, work happiness, and organizational commitment. The findings generally support that employees' positive psychological resource capacities relate to, and contribute unique variance to, the outcomes. However, hope, and, to a lesser extent, optimism and resilience, do differentially contribute to the various outcomes. Utility analysis supports the practical implications of the study results.
Onset of Offending and Life Course Among Men Convicted of Murder
Authors: Dobash Russell P. , Emerson Dobash R. , Cavanagh Kate , Smith Duncan , Medina-Ariza Juanjo
Published: October 2007

Although the developmental perspective has become a leading paradigm in criminology, little attention has been paid to the onset of offending and life course of murderers within this tradition. We use bivariate and Multiple Correspondence Analysis to investigate the life course and criminal careers of three onset groups among a UK sample of 786 men convicted of murder. The early-onset group (20% of the sample) is more likely to have experienced significant problems in childhood and adulthood. The no-offending group (10% of the sample) is the least likely to have had problematic backgrounds. The childhoods of the late-onset group (67% of the sample) resemble the no-offending group (with few problems) but in adulthood they more closely resemble the early-onset group (with many problems). The implications of these findings for developmental criminology and homicide research are discussed.