bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Trans-2,3-Dimethoxycinnamoyl Azide on Enhancing Antitumor Activity of Romidepsin on Human Bladder Cancer
Authors: Fan Jinhai , Stanfield Jennifer , Guo Yi , Karam Jose A. , Frenkel Eugene , Sun Xiankai , Hsieh Jer-Tsong 
Published: February 2008

Abstract
Purpose: Romidepsin (FK228, depsipeptide, FR901228), a unique cyclic depsipeptide with a histone deacetylase inhibitor (HDACI) activity, is a potential cancer therapeutic agent and currently under clinical trials for several types of cancer. For bladder cancer, romidepsin seems to be a potent antitumor agent from our recent study. In this study, we further delineate a new agent that can enhance both HDACI and antitumor activity of romidepsin.
Experimental Design: We screened a chemical library to identify candidate(s) that could enhance romidepsin activity. Chemical synthesis and purification were carried out to produce pure compound to examine its biochemical and antitumor effect on bladder cancer cell lines both in vitro and in vivo.
Results: Tranilast, N-(acetoacetyl) anthranilic acid, was first identified as a lead compound from screening, and then, one of the analogues, 2,3-dimethoxycinnamoyl azide (DMCA), seems to be more potent than tranilast. Our data indicate that DMCA can potentiate the HDACI activity of romidepsin and other biological activities, such as cell cycle arrest and apoptosis; these effects were accompanied with the expression of various key cell cycle regulators in different bladder cancer cells. Consistently, DMCA can enhance the in vivo antitumor effect of romidepsin without causing any more weight loss than romidepsin alone.
Conclusion: DMCA is able to enhance the antitumor effect of romidepsin on bladder cancer from in vitro and in vivo.
Yeast-Derived β-Glucan Augments the Therapeutic Efficacy Mediated by Anti–Vascular Endothelial Growth Factor Monoclonal Antibody in Human Carcinoma Xenograft Models
Authors: Salvador Carolina , Li Bing , Hansen Richard , Cramer Daniel E. , Kong Maiying , Yan Jun 
Published: February 2008

AbstractPurpose: Bevacizumab is a recombinant IgG1 humanized monoclonal antibody against vascular endothelial growth factor (VEGF). Its proposed mechanism of action is independent of immune effector functions. Many human carcinomas not only secrete VEGF but also express membrane-bound VEGF. In addition, VEGF receptors are expressed on tumor cells. It is hypothesized that bevacizumab could bind membrane-bound VEGF or VEGF-VEGF receptor complexes on tumors, thereby initiating potential immunologic consequences. We previously showed that yeast-derived β-glucan functions with antitumor antibodies that activate complement to recruit complement receptor 3–expressing leukocytes capable of mediating complement receptor 3–dependent cellular cytotoxicity of tumors opsonized with iC3b. In the current study, the therapeutic efficacy mediated by combining bevacizumab with yeast-derived β-glucan was studied in human carcinoma xenograft models.Experimental Design: Human tumor cell lines were screened for membrane-bound VEGF expression both in vitro and in vivo. Complement activation mediated by bevacizumab was examined. Tumor cell lines positive or negative for membrane-bound VEGF expression were implanted in severe combined immunodeficient mice to establish xenograft models. Tumor-bearing mice were treated with different regimens. Tumor regression and long-term survival were recorded.Results: Human ovarian carcinoma SKOV-3 cells expressed membrane-bound VEGF both in vitro and in vivo. Bevacizumab was bound to membrane-bound VEGF, activated complement, and synergized with β-glucan to elicit cellular cytotoxicity in vitro. In vivo study showed that β-glucan could significantly augment the therapeutic efficacy mediated by bevacizumab.Conclusions: Yeast-derived β-glucan can synergize with anti-VEGF monoclonal antibody bevacizumab for the treatment of cancer with membrane-bound VEGF expression.
Suppression of Peutz-Jeghers Polyposis by Targeting Mammalian Target of Rapamycin Signaling
Authors: Wei Chongjuan , Amos Christopher I. , Zhang Nianxiang , Wang Xiaopei , Rashid Asif , Walker Cheryl L. , Behringer Richard R. , Frazier Marsha L. 
Published: February 2008

AbstractPurpose: Peutz-Jeghers syndrome (PJS) is a unique disorder characterized by the development of hamartomas in the gastrointestinal tract as well as increased risks for variety of malignancies. Germ-line mutations of LKB1 cause PJS. We have generated Lkb1+/− mice, which model human PJS. Rapamycin and its analogues are promising preventive and therapeutic agents that specifically inhibit signaling from mammalian target of rapamycin (mTOR). Hyperactivation of mTOR signaling has been associated with PJS. The objective of the study is to investigate the efficacy of mTOR inhibition in suppressing Peutz-Jeghers polyposis in Lkb1+/− mice.Experimental Design: We initiated a trial of rapamycin in Lkb1+/− mice at 9 months of age (after the onset of polyposis) at the dose of 2 mg/kg/d for a 2-month period. We assessed the efficacy of rapamycin by measuring polyp sizes and tumor burden. To examine the effect of rapamycin on mTOR signaling, phosphorylation levels of S6 were evaluated by immunostaining.Results: We observed a significant decrease in mean tumor burden (Student's t test, P = 0.023) as well as total tumor burden in rapamycin-treated group compared with control group. Comparison of the polyp size observed in both rapamycin-treated and control groups showed that rapamycin efficiently decreased the tumor burden of large polyps (&gt;8 mm). This inhibition of rapamycin was associated with a decrease in phosphorylated S6 levels in the polyps.Conclusions: Rapamycin effectively suppresses Peutz-Jeghers polyposis in a mouse model, suggesting that rapamycin or its analogues may represent a new targeted therapy for the treatment of PJS.
Analysis of Integrin β4 Expression in Human Breast Cancer: Association with Basal-like Tumors and Prognostic Significance
Authors: Lu Shaolei , Simin Karl , Khan Ashraf , Mercurio Arthur M. 
Published: February 2008

AbstractPurpose: The β4 integrin has been implicated in functions associated with the genesis and progression of carcinomas based on data obtained from cell lines and mouse models. Data on its expression and relevance to human carcinomas, however, are relatively scant. The aim of this study was to assess its expression and prognostic significance in human breast carcinomas.Experimental Design: We integrated data on β4 expression from multiple gene profiling studies of breast tumors of known clinical outcome with immunohistochemical analysis of 105 breast carcinomas, and we identified genes whose expression correlates with that of β4.Results: The expression of both β4 mRNA and protein is not homogeneous in breast cancer and it associates most significantly with the “basal-like” subtype of breast tumors (P = 0.008). No association between β4 and HER2 expression was evident from either gene profiling or immunohistochemical analysis. To gain insight into the relevance of β4 expression to human breast carcinomas, we generated a 65-gene “β4 signature” based on integration of four published gene profiling studies that included the top 0.1% of genes that correlated with β4, either positively or negatively. This β4 signature predicted decreased time to tumor recurrence and survival of patients when applied to four data sets including two independent ones.Conclusions: These observations indicate that β4 expression in human breast cancer is restricted and associated with basal-like cancers, and they support the hypothesis that β4 may function in concert with a discrete set of proteins to facilitate the aggressive behavior of a subset of tumors.
Reduced hGC-1 Protein Expression Is Associated with Malignant Progression of Colon Carcinoma
Authors: Liu Wenli , Liu Yueqin , Zhu Jianqiong , Wright Elizabeth , Ding Ivan , Rodgers Griffin P. 
Published: February 2008

Abstract
Purpose: hGC-1 (human granulocyte colony–stimulating factor–stimulated clone 1) is a gastrointestinal protein that is a member of the olfactomedin glycoprotein family. Its biological function remains poorly understood. Aberrant expression of hGC-1 in some human carcinomas has been recently reported. The purpose of this study was to examine hGC-1 expression in colon carcinoma and explore the relationship between hGC-1 expression and the clinicopathologic features of patients with colon cancer.
Experimental Design: The expression of hGC-1 in colon adenocarcinoma tissues was examined by dot-blot analysis, in situ hybridization, and immunohistochemistry. The association of hGC-1 expression pattern with patient differentiation grade, tumor stage, metastasis, and survival were examined. To further investigate the involvement of hGC-1 in colon cancer progression, human colon carcinoma (HT-29) cells overexpressing hGC-1 were established and cell proliferation, adhesion, and migration were studied.
Results: Compared with normal colon mucosa, the up-regulation of hGC-1 was more frequently detected in more differentiated colon cancers, whereas down-regulation or no expression was associated with poorly differentiated colon cancers. Interestingly, hGC-1 down-regulation was also found in late tumor-node-metastasis stage, metastasis, and in patients with shorter survival. The morphology and cortical actin distribution of HT-29 cells were altered by hGC-1 overexpression. However, this did not change cell proliferation, but decreased cell adhesion and migration.
Conclusion: Our findings indicate that hGC-1 is involved in colon cancer adhesion and metastasis, and that hGC-1 may be a useful marker for tumor differentiation and progression of human colon carcinoma.
Phase I Trial of VNP40101M (Cloretazine) in Children with Recurrent Brain Tumors: A Pediatric Brain Tumor Consortium Study
Authors: Gururangan Sridharan , Turner Christopher D. , Stewart Clinton F. , O'Shaughnessy Melinda , Kocak Mehmet , Poussaint Tina Young , Phillips Peter C. , Goldman Stewart , Packer Roger , Pollack Ian F. , Blaney Susan M. , Karsten Verena , Gerson Stanton L. , Boyett James M. , Friedman Henry S. , Kun Larry E. 
Published: February 2008

Abstract
Purpose: VNP40101M (Cloretazine), a novel DNA alkylating agent, was evaluated in a phase I study in children with recurrent brain tumors.
Experimental Design: VNP40101M was given i.v. daily for 5 consecutive days every 6 weeks for up to eight cycles. Dose escalation was done independently in patients stratified based on intensity of prior therapy (moderately pretreated, stratum I; heavily pretreated, stratum II). Correlative studies included pharmacokinetics and measurement of O6-alkylguanine-DNA alkyl transferase levels in peripheral blood mononuclear cells before and after treatment.
Results: Forty-one eligible patients (stratum I, 19; stratum II, 22) were enrolled on this study. The dose-limiting toxicity in 35 evaluable patients was myelosuppression, which occurred in 4 of 16 patients in stratum I and 3 of 19 patients in stratum II. Pharmacokinetic studies showed a median terminal half-life of 30 min (range, 14-39.5). The maximum tolerated dose in stratum I and II were 45 and 30 mg/m2/d daily for 5 days every 6 weeks, respectively. Peripheral blood mononuclear cells alkylguanine alkyl transferase levels did not decrease significantly after VNP40101M treatment. Central imaging review confirmed that three patients had stable disease for a median of 45 weeks (range, 37-61+) after therapy.
Conclusions: The recommended dose of VNP40101M for phase II studies in children with brain tumors is 45 mg/m2/d in moderately pretreated and 30 mg/m2/d in heavily pretreated patients when administered for 5 consecutive days every 6 weeks.
Phase I Clinical and Pharmacokinetic Study of Kahalalide F Administered Weekly as a 1-Hour Infusion to Patients with Advanced Solid Tumors
Authors: Pardo Beatriz , Paz-Ares Luis , Tabernero Josep , Ciruelos Eva , García Margarita , Salazar Ramón , López Ana , Blanco María , Nieto Antonio , Jimeno José , Izquierdo Miguel Ángel , Trigo José Manuel 
Published: February 2008

Abstract
Purpose: A dose-escalation, phase I study evaluated the safety, pharmacokinetics, and efficacy of a weekly 1-h regimen of kahalalide F, a cyclic depsipeptide isolated from the marine mollusk Elysia rufescens, in adult patients with advanced solid tumors and no standard treatment available.
Experimental Design: Patients received an i.v. 1-h infusion of kahalalide F once weekly until disease progression or unacceptable toxicity. The starting kahalalide F dose was 266 μg/m2, and dose escalation proceeded based on the worst toxicity found in the previous cohort.
Results: Thirty-eight patients were enrolled at three Spanish institutions and received once-weekly kahalalide F 1-h infusions at doses between 266 and 1,200 μg/m2. Dose-limiting toxicities consisted of transient grade 3/4 increases in transaminase blood levels. The maximum tolerated dose for this kahalalide F schedule was 800 μg/m2, and the recommended dose for phase II studies was 650 μg/m2. No accumulated toxicity was found. One patient with malignant melanoma had unconfirmed partial response, one patient with metastatic lung adenocarcinoma had minor response, and six patients with different types of metastatic solid tumors had stable disease for 2.8 to 12.7 months. The noncompartmental pharmacokinetics of this kahalalide F schedule was linear and showed a narrow distribution and short body residence. The transaminitis associated with kahalalide F was dose dependent.
Conclusions: The maximum tolerated dose was 800 μg/m2. Dose-limiting toxicities with weekly kahalalide F 1-h i.v. infusions were transient grade 3/4 increases in blood transaminase levels, and 650 μg/m2 was declared the recommended dose for phase II studies. This schedule showed a favorable safety profile and hints of antitumor activity.
Enhancement of Antitumor Radiation Efficacy and Consistent Induction of the Abscopal Effect in Mice by ECI301, an Active Variant of Macrophage Inflammatory Protein-1α
Authors: Shiraishi Kenshiro , Ishiwata Yoshiro , Nakagawa Keiichi , Yokochi Shoji , Taruki Chiho , Akuta Teruo , Ohtomo Kuni , Matsushima Kouji , Tamatani Takuya , Kanegasaki Shiro 
Published: February 2008

AbstractPurpose: We studied whether i.v. administration of a chemokine after local tumor site irradiation could prevent remaining, as well as distant, nonirradiated tumor cell growth by leukocyte recruitment.Experimental Design: Tumors were implanted s.c. in the right or both flanks. After local irradiation at the right flank, ECI301, a human macrophage inflammatory protein-1α variant was injected i.v. Tumor volumes were measured every 3 days after treatment.Results: In Colon26 adenocarcinoma-bearing BALB/c mice, repeated daily administration (over 3-5 consecutive days) of 2 μg per mouse ECI301 after local irradiation of 6 Gy prolonged survival without significant toxicity, and in about half of the treated mice, the tumor was completely eradicated. Three weekly administrations of ECI301 after local irradiation also led to significant, although less effective, antitumor radiation efficacy. ECI301 also inhibited growth of other syngenic tumor grafts, including MethA fibrosarcoma (BALB/c) and Lewis lung carcinoma (C57BL/6). Importantly, tumor growth at the nonirradiated site was inhibited, indicating that ECI301 potentiated the abscopal effect of radiation. This abscopal effect observed in BALB/c and C57BL/6 mice was tumor-type independent. Leukocyte depletion studies suggest that CD8+ and CD4+ lymphocytes and NK1.1 cells were involved.Conclusions: Marked inhibition of tumor growth at the irradiated site, with complete tumor eradication and consistent induction of the abscopal effect, was potentiated by i.v. administration of ECI301. The results of this study may offer a new concept for cancer therapy, namely chemokine administration after local irradiation, leading to development of novel therapeutics for the treatment of advanced metastatic cancer.
Adrenocortical carcinoma survival rates correlated to genomic copy number variants
Authors: Stephan Elizabeth A. , Chung Tae-Hoon , Grant Clive S. , Kim Seungchan , Von Hoff Daniel D. , Trent Jeffrey M. , Demeure Michael J. 
Published: February 2008

Abstract
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy accounting for between 0.02% and 0.2% of all cancer deaths. Surgical removal offers the only current potential for cure. Unfortunately, ACC has undergone metastatic spread in 40% to 70% of patients at the time of diagnosis. Standard chemotherapy with mitotane is often ineffective with intolerable side effects. The modern molecular technology of comparative genomic hybridization allows the examination of DNA for chromosomal alterations, which can lend biological insight into cancer processes. Genomes of 25 ACC clinical samples were queried on the Agilent 44K Human Genome comparative genomic hybridization array detecting regions of chromosomal gain and loss within the tumor population. Commonly shared amplifications appearing in ≥50% of tumors at P ≤ 10−4 include regions within chromosomes 5, 7, 12, 16q, and 20. Deleted genomic regions within ACC include portions of chromosomes 1, 3p, 10q, 11, 14q, 15q, 17, and 22q. Genomic aberrations in regions associated with differential survival (P ≤ 0.05) and presence in ≥20% of tumors include amplifications of 6q, 7q, 12q, and 19p. Deletions within stratified survival groups include localized regions within 3, 8, 10p, 16q, 17q, and 19q. Statistical analysis of this genetic landscape reveals a set of chromosomal aberrations strongly associated with survival in an accumulation-dependent fashion. These regions may hold prognostic indicators and offer therapeutic targets that can be used to develop novel treatments for aggressive tumors. [Mol Cancer Ther 2008;7(2):425–31]
A new mechanism of drug resistance in breast cancer cells: fatty acid synthase overexpression-mediated palmitate overproduction
Authors: Liu Hailan , Liu Yang , Zhang Jian-Ting 
Published: February 2008

Abstract
Multidrug resistance is a major problem in successful cancer chemotherapy. Various mechanisms of resistance, such as ABC transporter-mediated drug efflux, have been discovered using established model cancer cell lines. While characterizing a drug-resistant breast cancer cell line, MCF7/AdVp3000, we found that fatty acid synthase (FASN) is overexpressed. In this study, we showed that ectopic overexpression of FASN indeed causes drug resistance and that reducing the FASN expression increased the drug sensitivity in breast cancer cell lines MCF7 and MDA-MB-468 but not in the normal mammary epithelial cell line MCF10A1. Use of FASN inhibitor, Orlistat, at low concentrations also sensitized cells with FASN overexpression to anticancer drugs. The FASN-mediated drug resistance appears to be due to a decrease in drug-induced apoptosis from an overproduction of palmitic acid by FASN. Together with previous findings of FASN as a poor prognosis marker for breast cancer patients, our results suggest that FASN overexpression is a new mechanism of drug resistance and may be an ideal target for chemosensitization in breast cancer chemotherapy. [Mol Cancer Ther 2008;7(2):263–70]
Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer
Authors: Li Min , Bharadwaj Uddalak , Zhang Rongxin , Zhang Sheng , Mu Hong , Fisher William E. , Brunicardi F. Charles , Chen Changyi , Yao Qizhi 
Published: February 2008

AbstractGiven the high fatality rate of pancreatic cancer, an effective treatment for this devastating disease is urgently needed. We have shown that mesothelin expression was higher in human pancreatic cancer cells than in human pancreatic duct epithelial cells, and mesothelin mRNA was substantially overexpressed in 18 of 21 (86%) clinical pancreatic adenocarcinoma specimens when compared with the surrounding normal tissues. However, the biological functions of mesothelin in tumor progression are not clearly understood. Here we studied the effects of mesothelin overexpression in pancreatic cancer cell proliferation and migration in vitro and pancreatic cancer progression in vivo. We found that forced expression of mesothelin significantly increased tumor cell proliferation and migration by 90% and 300%, respectively, and increased tumor volume by 4-fold in the nude mice xenograft model when compared with the vector control cell line. Silencing of mesothelin inhibited cell proliferation and migration in pancreatic cancer cells and ablated tumor progression in vivo. Vaccination with chimeric virus-like particles that contain human mesothelin substantially inhibited tumor progression in C57BL/6J mice. The increases in mesothelin-specific antibodies and CTL activity and the decrease in regulatory T cells correlated with reduced tumor progression and prolonged survival. This study revealed novel functions of mesothelin and suggested a new therapeutic vaccine strategy whereby mesothelin is targeted to control pancreatic cancer progression. [Mol Cancer Ther 2008;7(2):286–96]
6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol, a specific glutathione S-transferase inhibitor, overcomes the multidrug resistance (MDR)-associated protein 1–mediated MDR in small cell lung cancer
Authors: Filomeni Giuseppe , Turella Paola , Dupuis Maria Luisa , Forini Olindo , Ciriolo Maria Rosa , Cianfriglia Maurizio , Pezzola Silvia , Federici Giorgio , Caccuri Anna Maria 
Published: February 2008

Abstract
In the present work, we have investigated the antitumor activity of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) on aggressive small cell lung cancer. NBDHEX not only is cytotoxic toward the parental small cell lung cancer H69 cell line (LC50 of 2.3 ± 0.6 μmol/L) but also overcomes the multidrug resistance of its variant, H69AR, which overexpresses the ATP-binding cassette transporter multidrug resistance–associated protein 1 (MRP1; LC50 of 4.5 ± 0.9 μmol/L). Drug efflux experiments, done in the presence of a specific inhibitor of MRP1, confirmed that NBDHEX is not a substrate for this export pump. Interestingly, NBDHEX triggers two different types of cell death: a caspase-dependent apoptosis in the H69AR cells and a necrotic phenotype in the parental H69 cells. The apoptotic pathway triggered by NBDHEX in H69AR cells is associated with c-Jun NH2-terminal kinase and c-Jun activation, whereas glutathione oxidation and activation of p38MAPK is observed in the NBDHEX-treated H69 cells. In contrast to the parental cells, the higher propensity to die through apoptosis of the H69AR cell line may be related to the lower expression of the antiapoptotic protein Bcl-2. Therefore, down-regulation of a factor crucial for cell survival makes H69AR cells more sensitive to the cytotoxic action of NBDHEX, which is not a MRP1 substrate. We have previously shown that NBDHEX is cytotoxic toward P-glycoprotein–overexpressing tumor cell lines. Therefore, NBDHEX seems a very promising compound in the search for new molecules able to overcome the ATP-binding cassette family of proteins, one of the major mechanisms of multidrug resistance in cancer cells. [Mol Cancer Ther 2008;7(2):371–9]