bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kit Inhibitor APcK110 Induces Apoptosis and Inhibits Proliferation of Acute Myeloid Leukemia Cells
Authors: Faderl Stefan , Pal Ashutosh , Bornmann William , Albitar Maher , Maxwell David , Van Quin , Peng Zhenghong , Harris David , Liu Zhiming , Hazan-Halevy Inbal , Kantarjian Hagop M. , Estrov Zeev 
Published: April 2009

Abstract
Kit is a membrane-bound tyrosine kinase and receptor for stem cell factor (SCF) with a crucial role in hematopoiesis. Mutations of KIT occur in almost half of patients with core-binding factor leukemias, in which they have been associated with worse outcome. Development of new compounds targeting Kit may therefore hold promise for therapy. We investigated the activity and mechanism of action of APcK110, a novel Kit inhibitor, in the mastocytosis cell line HMC1.2 (KITV560G and KITD816V), acute myeloid leukemia (AML) lines OCIM2 and OCI/AML3 (both wild-type), and primary samples from patients with AML. We show that (a) APcK110 inhibits proliferation of the mastocytosis cell line HMC1.2 and the SCF-responsive cell line OCI/AML3 in a dose-dependent manner; (b) APcK110 is a more potent inhibitor of OCI/AML3 proliferation than the clinically used Kit inhibitors imatinib and dasatinib and at least as potent as cytarabine; (c) APcK110 inhibits the phosphorylation of Kit, Stat3, Stat5, and Akt in a dose-dependent fashion, showing activity of APcK110 on Kit and its downstream signaling pathways; (d) APcK110 induces apoptosis by cleavage of caspase-3 and poly(ADP-ribose) polymerase; and (e) APcK110 inhibits proliferation of primary AML blasts in a clonogenic assay but does not affect proliferation of normal colony-forming cells. Although APcK110 activity may partly depend on cytokine responsiveness (e.g., SCF) and not exclusively KIT mutation status, it remains a potent inhibitor of AML and mastocytosis cell lines and primary AML samples. APcK110 and similar compounds should be evaluated in clinical trials of patients with AML. [Cancer Res 2009;69(9):3910–7]
Synergistic Activity of the Src Family Kinase Inhibitor Dasatinib and Oxaliplatin in Colon Carcinoma Cells Is Mediated by Oxidative Stress
Authors: Kopetz Scott , Lesslie Donald P. , Dallas Nikolas A. , Park Serk I. , Johnson Marjorie , Parikh Nila U. , Kim Michael P. , Abbruzzese James L. , Ellis Lee M. , Chandra Joya , Gallick Gary E. 
Published: April 2009

AbstractChemotherapeutic regimens for the treatment of colorectal cancer generally include oxaliplatin, although inherent and acquired resistance is common. One potential mediator of oxaliplatin sensitivity is the nonreceptor protein tyrosine kinase, Src, the activity of which correlates with disease stage and patient survival. Therefore, we investigated the effects of Src inhibition using the tyrosine kinase inhibitor dasatinib on oxaliplatin sensitivity. We show that oxaliplatin acutely activates Src and that combination treatment with dasatinib is synergistic in a cell-line dependent manner, with the level of Src activation correlating with extent of synergy in a panel of six cell lines. Intracellular reactive oxygen species (ROS) are generated after oxaliplatin treatment, and ROS potently activates Src. Pretreatment with antioxidants inhibits oxaliplatin-induced Src activation. In oxaliplatin-resistant cell lines, Src activity is constitutively increased. In a mouse model of colorectal liver metastases, treatment with oxaliplatin also results in chronic Src activation. The combination of dasatinib and oxaliplatin results in significantly smaller tumors compared with single-agent treatment, corresponding with reduced proliferation and angiogenesis. Therefore, we conclude that oxaliplatin activates Src through a ROS-dependent mechanism. Src inhibition increases oxaliplatin activity both in vitro and in vivo. These results suggest that Src inhibitors combined with oxaliplatin may have efficacy in metastatic colon cancer and may provide the first indication of a molecular phenotype that might be susceptible to such combinations. [Cancer Res 2009;69(9):3842–9]
Poly(ADP-Ribose) Polymerase-1 Inhibitor Treatment Regresses Autochthonous Brca2/p53-Mutant Mammary Tumors In vivo and Delays Tumor Relapse in Combination with Carboplatin
Authors: Hay Trevor , Matthews James R. , Pietzka Lucie , Lau Alan , Cranston Aaron , Nygren Anders O.H. , Douglas-Jones Anthony , Smith Graeme C.M. , Martin Niall M.B. , O’Connor Mark , Clarke Alan R. 
Published: April 2009

Abstract
Germ-line heterozygosity of the BRCA2 gene in women predisposes to breast and ovarian cancers. Successful therapies targeted specifically at these neoplasms have thus far remained elusive. Recent studies in mice have shown that inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) targets cells lacking Brca2 and xenografts derived from BRCA2-deficient ES cells or Chinese hamster ovary cells. We set out to develop a more relevant preclinical model that will inform and accelerate translation into the clinic. As such, we conditionally deleted Brca2 and p53 within murine mammary epithelium and treated the resulting tumors in situ with a highly potent PARP-1 inhibitor (AZD2281) alone or in combination with carboplatin. Daily exposure to AZD2281 for 28 days caused significant regression or growth inhibition in 46 of 52 tumors. This response was shown to be specific to tumors lacking both Brca2and p53. AZD2281/carboplatin combination therapy for 28 days showed no advantage over carboplatin monotherapy. However, if PARP inhibitor treatment was continued, this significantly increased the time to tumor relapse and death in these mice. This preclinical study is the first to show in vivo hypersensitivity of spontaneously arising Brca2-deficient mammary tumors to PARP-1 inhibition monotherapy or combination therapy. As such, our data add substantial weight to the argument for the use of PARP inhibitors as therapeutic agents against human breast cancers in which BRCA2 is mutated. Moreover, the specificity that we have shown further suggests that PARP inhibitors will be generally effective against tumors caused by dysregulation of components of the homologous recombination pathway. [Cancer Res 2009;69(9):3850–55]
Prevention of Spontaneous Tumor Development in aretTransgenic Mouse Model by Ret Peptide Vaccination with Indoleamine 2,3-Dioxygenase Inhibitor 1-Methyl Tryptophan
Authors: Zeng Jun , Cai Shaohui , Yi Yanmei , He Yuwen , Wang Zhen , Jiang Guangmin , Li Xiaokun , Du Jun 
Published: April 2009

AbstractThe present study investigated an immunotherapeutic strategy for rearranged during transfection proto-oncogene (ret)–associated carcinomas in a transgenic MT/ret 304/B6 mouse model in which spontaneous tumors develop due to overexpression of the ret gene. A Ret peptide vaccine comprising an extracellular fragment of Ret protein and Th1-polarized immunoregulator CpG oligonucleotide (1826) induced strong and specific cellular and humoral immune responses in wild-type C57BL/6 mice, showing that the Ret peptide has a strong immunogenic potential as part of an antitumor vaccine. In MT/ret 304/B6 mice, however, the vaccine was only modestly effective as an inducer of the humoral immune response, and it failed to elicit a T-cell response. An immunohistochemical analysis revealed marked indoleamine 2,3-dioxygenase expression after immunization with Ret peptide vaccine in the lymph nodes and spleens of MT/ret 304/B6 mice. The systemic administration of the potent inhibitor of indoleamine 2,3-dioxygenase 1-methyl tryptophan (1MT) along with Ret vaccine produced a significant increase in tumor-specific cytotoxic activity. A delay in spontaneous tumor development was also observed in the MT/ret 304/B6 mice to which the Ret vaccine and 1MT were administered. These results indicate that an improved Ret vaccine composed of Ret peptide plus CpG oligonucleotide plus 1MT is a potential therapeutic strategy for treatment of ret-associated carcinomas. [Cancer Res 2009;69(9):3963–70]
Species-Specific In vivo Engraftment of the Human BL Melanoma Cell Line Results in an Invasive Dedifferentiated Phenotype Not Present in Xenografts
Authors: Cedervall Jessica , Jamil Seema , Prasmickaite Lina , Cheng YenFu , Eskandarpour Malihe , Hansson Johan , Mælandsmo Gunhild M. , Ringborg Ulrik , Gulyas Miklos , Zhen He Suo , Kanter Lena , Ährlund-Richter Lars 
Published: April 2009

Abstract
For clinically relevant studies on melanoma progression and invasiveness, in vivo experimental systems with a human cellular microenvironment would be advantageous. We have compared tumor formation from a human cutaneous malignant melanoma cell line (BL), after injection as conventional xenografts in the mouse, or when injected into a predominantly species-specific environment of human embryonic stem cell–derived teratoma induced in the mouse (the hEST model). The resulting melanoma histology was generally analogous, both systems showing delimited densely packed areas with pleomorphic cells of malignant appearance. A specificity of the integration process into the human embryonic teratoma tissues was indicated by the melanoma exclusively being found in areas compatible with condensed mesenchyme, similar to neural crest development. Here, also enhanced neovascularization was seen within the human mesenchymal tissues facing the BL melanoma growth. Furthermore, in the hEST model an additional melanoma cell phenotype occurred, located at the border of, or infiltrating into, the surrounding human loose mesenchymal fibrous stroma. This BL population had a desmoplastic spindle-like appearance, with markers indicative of dedifferentiation and migration. The appearance of this apparently more aggressive phenotype, as well as the induction of human angiogenesis, shows specific interactions with the human embryonic microenvironment in the hEST model. In conclusion, these data provide exciting options for using the hEST model in molecular in vivo studies on differentiation, invasiveness, and malignancy of human melanoma, while analyzing species-specific reactions in vivo. [Cancer Res 2009;69(9):3746–54]
Caspase-8 Association with the Focal Adhesion Complex Promotes Tumor Cell Migration and Metastasis
Authors: Barbero Simone , Mielgo Ainhoa , Torres Vicente , Teitz Tal , Shields David J. , Mikolon David , Bogyo Matthew , Barilà Daniela , Lahti Jill M. , Schlaepfer David , Stupack Dwayne G. 
Published: April 2009

Abstract
Caspase-8 is a proapoptotic protease that suppresses neuroblastoma metastasis by inducing programmed cell death. Paradoxically, caspase-8 can also promote cell migration among nonapoptotic cells; here, we show that caspase-8 can promote metastasis when apoptosis is compromised. Migration is enhanced by caspase-8 recruitment to the cellular migration machinery following integrin ligation. Caspase-8 catalytic activity is not required for caspase-8–enhanced cell migration; rather, caspase-8 interacts with a multiprotein complex that can include focal adhesion kinase and calpain 2 (CPN2), enhancing cleavage of focal adhesion substrates and cell migration. Caspase-8 association with CPN2/calpastatin disrupts calpastatin-mediated inhibition of CPN2. In vivo, knockdown of either caspase-8 or CPN2 disrupts metastasis among apoptosis-resistant tumors. This unexpected molecular collaboration provides an explanation for the continued or elevated expression of caspase-8 observed in many tumors. [Cancer Res 2009;69(9):3755–63]
B-MYB Is Required for Recovery from the DNA Damage–Induced G2 Checkpoint in p53 Mutant Cells
Authors: Mannefeld Mirijam , Klassen Elena , Gaubatz Stefan 
Published: April 2009

Abstract
In response to DNA damage, several signaling pathways that arrest the cell cycle in G1 and G2 are activated. The down-regulation of mitotic genes contributes to the stable maintenance of the G2 arrest. The human LINC or DREAM complex, together with the B-MYB transcription factor, plays an essential role in the expression of G2-M genes. Here, we show that DNA damage results in the p53-dependent binding of p130 and E2F4 to LINC and the dissociation of B-MYB from LINC. We find that B-MYB fails to dissociate from LINC in p53 mutant cells, that this contributes to increased G2-M gene expression in response to DNA damage in these cells, and, importantly, that B-MYB is required for recovery from the G2 DNA damage checkpoint in p53-negative cells. Reanalysis of microarray expression data sets revealed that high levels of B-MYB correlate with a p53 mutant status and an advanced tumor stage in primary human breast cancer. Taken together, these data suggest that B-MYB/LINC plays an important role in the DNA damage response downstream of p53. [Cancer Res 2009;69(9):4073–80]
Catecholamines Regulate Tumor Angiogenesis
Authors: Chakroborty Debanjan , Sarkar Chandrani , Basu Biswarup , Dasgupta Partha Sarathi , Basu Sujit 
Published: April 2009

Abstract
Among the regulators of angiogenesis, catecholamine neurotransmitters are of recent interest because of their opposite roles in the regulation of tumor neovascularization. Norepinephrine and epinephrine by acting through specific adrenoceptors increase the synthesis of proangiogenic factors, and thereby, promote tumor growth. In contrast, dopamine acting via its specific D2 receptors inhibits tumor growth by suppressing the actions of vascular permeability factor/vascular endothelial growth factor-A on both tumor endothelial and bone marrow-derived endothelial progenitor cells. These reports identify novel endogenous regulators of tumor angiogenesis and also indicate a new and an inexpensive class of antiangiogenic drugs for the treatment of cancer. [Cancer Res 2009;69(9):3727–30]
Wnt/β-Catenin Signaling Regulates Cytokine-Induced Human Inducible Nitric Oxide Synthase Expression by Inhibiting Nuclear Factor-κB Activation in Cancer Cells
Authors: Du Qiang , Zhang Xinglu , Cardinal Jon , Cao Zongxian , Guo Zhong , Shao Lifang , Geller David A. 
Published: April 2009

AbstractThe human inducible nitric oxide synthase (hiNOS) gene is regulated by nuclear factor κB (NF-κB) and has recently been shown to be a target of the Wnt/β-catenin pathway. In this study, we tested the hypothesis that Wnt/β-catenin signaling might regulate cytokine- or tumor necrosis factor α (TNFα)–induced hiNOS expression through interaction with NF-κB. A cytokine mixture of TNFα + interleukin (IL)-1β + IFNγ induced a 2- to 3-fold increase in hiNOS promoter activity in HCT116 and DLD1 colon cells, but produced a 2-fold decrease in SW480 colon cancer cells. A similar differential activity was seen in liver cancer cells (HepG2, Huh7, and Hep3B). Overexpression of β-catenin produced a dose-dependent decrease in NF-κB reporter activity and decreased cytokine mixture–induced hiNOS promoter activity. Gel shift for TNFα-induced hiNOS NF-κB activation showed decreased p50 binding and decreased NF-κB reporter activity in the β-catenin–mutant HAβ18 cells. Conversely, enhanced p50 binding and increased NF-κB reporter activity were seen in HAβ85 cells, which lack β-catenin signaling. Coimmunoprecipitation confirmed that β-catenin complexed with both p65 and p50 NF-κB proteins. NF-κB–dependent Traf1 protein expression also inversely correlated with the level of β-catenin. Furthermore, SW480 cells stably transformed with wild-type adenomatous polyposis coli showed decreased β-catenin protein and increased TNFα-induced p65 NF-κB binding as well as iNOS and Traf1 expression. Finally, β-catenin inversely correlated with iNOS and Fas expression in vivo in hepatocellular carcinoma tumor samples. Our in vitro and in vivo data show that β-catenin signaling inversely correlates with cytokine-induced hiNOS and other NF-κB–dependent gene expression. These findings underscore the complex role of Wnt/β-catenin, NF-κB, and iNOS signaling in the pathophysiology of inflammation-associated carcinogenesis. [Cancer Res 2009;69(9):3764–71]
When the Sphingosine Kinase 1/Sphingosine 1-Phosphate Pathway Meets Hypoxia Signaling: New Targets for Cancer Therapy
Authors: Ader Isabelle , Malavaud Bernard , Cuvillier Olivier 
Published: April 2009

Abstract
The reduction in the normal level of tissue oxygen tension or hypoxia is a characteristic of solid tumors that triggers the activation of signaling pathways promoting neovascularization, metastasis, increased tumor growth, and resistance to treatments. The activation of the transcription factor hypoxia-inducible factor 1α (HIF-1α) has been identified as the master mechanism of adaptation to hypoxia. In a recent study, we identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway, which elicits various cellular processes including cell proliferation, cell survival, or angiogenesis, as a new modulator of HIF-1α activity under hypoxic conditions. Here, we consider how the SphK1/S1P signaling pathway could represent a very important target for therapeutic intervention in cancer. [Cancer Res 2009;69(9):3723–6]
Mutations in the Hepatitis C Virus core Gene Are Associated with Advanced Liver Disease and Hepatocellular Carcinoma
Authors: Fishman Sarah L. , Factor Stephanie H. , Balestrieri Cinzia , Fan Xiaofeng , DiBisceglie Adrian M. , Desai Suresh M. , Benson Gary , Branch Andrea D. 
Published: April 2009

Abstract
Purpose: Hepatitis C virus (HCV) infection can promote the development of hepatocellular carcinoma (HCC). Published data implicate the HCV core gene in oncogenesis. We tested the hypothesis that core gene sequences from HCC patients differ from those of patients without cirrhosis/HCC.
Experimental Design: Full-length HCV sequences from HCC patients and controls were obtained from the investigators and GenBank and compared with each other. A logistic regression model was developed to predict the HCC risk of individual point mutations and other sequence features. Mutations in partial sequences (bases 36-288) from HCC patients and controls were also analyzed. The first base of the AUG start codon was designated position 1.
Results: A logistic regression model developed through analysis of full-length core gene sequences identified seven polymorphisms significantly associated with increased HCC risk (36G/C, 209A, 271U/C, 309A/C, 435A/C, 481A, and 546A/C) and an interaction term (for 209A-271U/C) that had an odds ratio &lt;1.0. Three of these polymorphisms could be analyzed in the partial sequences. Two of them, 36G/C and 209A, were again associated with increased HCC risk, but 271U/C was not. The odds ratio of 209A-271U/C was not significant.
Conclusions: HCV core genes from patients with and without HCC differ at several positions. Of interest, 209A has been associated with IFN resistance and HCC in previous studies. Our findings suggest that HCV core gene sequence data might provide useful information about HCC risk. Prospective investigation is needed to establish the temporal relationship between appearance of the viral mutations and development of HCC.
Phase I Study of MG98, an Oligonucleotide Antisense Inhibitor of Human DNA Methyltransferase 1, Given as a 7-Day Infusion in Patients with Advanced Solid Tumors
Authors: Plummer Ruth , Vidal Laura , Griffin Melanie , Lesley Mark , de Bono Johann , Coulthard Sally , Sludden Julieann , Siu Lillian L. , Chen Eric X. , Oza Amit M. , Reid Gregory K. , McLeod A. Robert , Besterman Jeffrey M. , Lee Chooi , Judson Ian , Calvert Hilary , Boddy Alan V. 
Published: April 2009

AbstractPurpose: To assess the safety and tolerability, pharmacokinetics, and early evidence of antitumor activity of escalating doses of MG98, an antisense oligonucleotide to DNA methyltransferase 1 (DNMT1), which has been shown to reduce CpG island methylation and allow reexpression of tumor suppressor genes in vitro.Experimental Design: In this phase I, open-label study, patients with advanced solid malignancies were treated with escalating doses of MG98 administered as a continuous i.v. infusion over 7 days repeated every 14 days. Cohorts of three patients, which could be expanded to six patients, were studied. The maximum tolerated dose was defined as the highest dose at which no more than 33% of subjects experienced dose-limiting toxicity. Pharmacokinetic and pharmacodynamic parameters of MG98 were also characterized.Results: Thirty-three patients were treated at doses of 100 to 250 mg/m2/d MG98. MG98 was well tolerated with mild fatigue and myalgia, dose-limiting toxicity was asymptomatic transaminitis, and the maximum tolerated dose was 200 mg/m2/d. One patient achieved a partial response and another prolonged disease stabilization. Plasma half-life of MG98 was short (2 hours), drug concentrations reaching a dose-dependent steady state during infusion with a volume of distribution equivalent to plasma volume. Suppression of DNMT1 expression was observed in 26 of 32 patients studied.Conclusions: MG98 was well tolerated with early evidence of clinical activity. Proof of mechanism was observed and measurement of DNMT1 expression in peripheral blood mononuclear cells may be useful in future phase II development.
Rectal Mucosal Microvascular Blood Supply Increase Is Associated with Colonic Neoplasia
Authors: Gomes Andrew J. , Roy Hemant K. , Turzhitsky Vladimir , Kim Young , Rogers Jeremy D. , Ruderman Sarah , Stoyneva Valentina , Goldberg Michael J. , Bianchi Laura K. , Yen Eugene , Kromine Alexey , Jameel Mohammed , Backman Vadim 
Published: April 2009

Abstract
Purpose: Endoscopic examination has proven effective in both detecting and preventing colorectal cancer; however, only about a quarter of eligible patients undergo screening. Even if the compliance rate increased, limited endoscopic capacity and cost would be prohibitive. There is a need for an accurate method to target colonoscopy to those most at risk of harboring colonic neoplasia. Exploiting field carcinogenesis seems to be a promising avenue. Our group recently reported that an early increase in blood supply (EIBS) is a reliable marker of field carcinogenesis in experimental models. We now investigate whether in situ detection of EIBS in the rectum can predict neoplasia elsewhere in the colon.
Experimental Design: We developed a novel polarization-gated spectroscopy fiber-optic probe that allows depth-selective interrogation of microvascular blood content. Using the probe, we examined the blood content in vivo from the rectal mucosa of 216 patients undergoing screening colonoscopy.
Results: Microvascular blood content was increased by ∼50% in the endoscopically normal rectal mucosa of patients harboring advanced adenomas when compared with neoplasia-free patients irrespective of lesion location. Demographic factors and nonneoplastic lesions did not confound this observation. Logistic regression using mucosal oxyhemoglobin concentration and patient age resulted in a sensitivity of 83%, a specificity of 82%, and an area under the receiver operating characteristic curve of 0.88 for the detection of advanced adenomas.
Conclusions: Increased microvascular blood supply in the normal rectal mucosa is associated with the presence of clinically significant neoplasia elsewhere in the colon, supporting the development of rectal EIBS as a colon cancer risk-stratification tool.