bluuebunny/crossref_metadata_2025_split huggingface dataset:
PRDM5 Identified as a Target of Epigenetic Silencing in Colorectal and Gastric Cancer
Authors: Watanabe Yoshiyuki , Toyota Minoru , Kondo Yutaka , Suzuki Hiromu , Imai Takashi , Ohe-Toyota Mutsumi , Maruyama Reo , Nojima Masanori , Sasaki Yasushi , Sekido Yoshitaka , Hiratsuka Hiroyoshi , Shinomura Yasuhisa , Imai Kohzoh , Itoh Fumio , Tokino Takashi 
Published: August 2007

AbstractPurpose: PR (PRDI-BF1 and RIZ) domain proteins (PRDM) are a subfamily of the kruppel-like zinc finger gene products that play key roles during cell differentiation and malignant transformation. The aim of the present study was to begin to examine the involvement of epigenetic alteration of PRDM expression in gastric and colorectal cancer.Experimental Design: We used real-time PCR to assess expression of PRDM1-17. In addition, we used bisulfite PCR to assess DNA methylation and chromatin immunoprecipitation to assess histone modification in colorectal and gastric cancer cell lines lacking PRDM5 expression.Results: Among the 17 PRDM family genes tested, we found that PRDM5 is the most frequently silenced in colorectal and gastric cancer cell lines. Silencing of PRDM5 was mediated by either DNA methylation or trimethylation of Lys27 of histone H3. Introduction of PRDM5 into cancer cells suppressed cell growth, suggesting that it acts as a tumor suppressor in gastrointestinal cancers. Methylation of PRDM5 was detected in 6.6% (4 of 61) of primary colorectal and 50.0% (39 of 78) of primary gastric cancers but not in noncancerous tissue samples collected from areas adjacent to the tumors.Conclusions: Our data suggest that epigenetic alteration of PRDM5 (e.g., methylation of its 5′-CpG island or trimethylation of Lys27 of histone H3) likely plays a key role in the progression of gastrointestinal cancers and may be a useful molecular marker.
Oxaliplatin Pharmacokinetics and Pharmacodynamics in Adult Cancer Patients with Impaired Renal Function
Authors: Takimoto Chris H. , Graham Martin A. , Lockwood Graham , Ng Chee M. , Goetz Andrew , Greenslade Dennis , Remick Scot C. , Sharma Sunil , Mani Sridhar , Ramanathan Ramesh K. , Synold Timothy W. , Doroshow James H. , Hamilton Anne , Mulkerin Daniel L. , Ivy Percy , Egorin Merrill J. , Grem Jean L. 
Published: August 2007

AbstractPurpose: To characterize the pharmacokinetics and pharmacodynamics of oxaliplatin in cancer patients with impaired renal function.Experimental Design: Thirty-four patients were stratified by 24-h urinary creatinine clearance (CrCL) into four renal dysfunction groups: group A (control, CrCL, ≥60 mL/min), B (mild, CrCL, 40-59 mL/min), C (moderate, CrCL, 20-39 mL/min), and D (severe, CrCL, &lt;20 mL/min). Patients were treated with 60 to 130 mg/m2 oxaliplatin infused over 2 h every 3 weeks. Pharmacokinetic monitoring of platinum in plasma, plasma ultrafiltrates, and urine was done during cycles 1 and 2.Results: Plasma ultrafiltrate platinum clearance strongly correlated with CrCL (r2 = 0.712). Platinum elimination from plasma was triphasic, and maximal platinum concentrations (Cmax) were consistent across all renal impairment groups. However, only the β-half-life was significantly prolonged by renal impairment, with values of 14.0 ± 4.3, 20.3 ± 17.7, 29.2 ± 29.6, and 68.1 h in groups A, B, C, and D, respectively (P = 0.002). At a dose level of 130 mg/m2, the area under the concentration time curve increased in with the degree of renal impairment, with values of 16.4 ± 5.03, 39.7 ± 11.5, and 44.6 ± 14.6 μg·h/mL, in groups A, B, and C, respectively. However, there was no increase in pharmacodynamic drug-related toxicities. Estimated CrCL using the Cockcroft-Gault method approximated the measured 24-h urinary CrCL (mean prediction error, −5.0 mL/min).Conclusions: Oxaliplatin pharmacokinetics are altered in patients with renal impairment, but a corresponding increase in oxaliplatin-related toxicities is not observed.
High-Resolution Single Nucleotide Polymorphism Array Analysis of Epithelial Ovarian Cancer Reveals Numerous Microdeletions and Amplifications
Authors: Gorringe Kylie L. , Jacobs Sharoni , Thompson Ella R. , Sridhar Anita , Qiu Wen , Choong David Y.H. , Campbell Ian G. 
Published: August 2007

Abstract
Purpose: Genetic changes in sporadic ovarian cancer are relatively poorly characterized compared with other tumor types. We have evaluated the use of high-resolution whole genome arrays for the genetic profiling of epithelial ovarian cancer.
Experimental Design: We have evaluated 31 primary ovarian cancers and matched normal DNA for loss of heterozygosity and copy number alterations using 500K single nucleotide polymorphism arrays.
Results: In addition to identifying the expected large-scale genomic copy number changes, &gt;380 small regions of copy number gain or loss (&lt;500 kb) were identified among the 31 tumors, including 33 regions of high-level gain (&gt;5 copies) and 27 homozygous deletions. The existence of such a high frequency of small regions exhibiting copy number alterations had not been previously suspected because earlier genomic array platforms lacked comparable resolution. Interestingly, many of these regions harbor known cancer genes. For example, one tumor harbored a 350-kb high-level amplification centered on FGFR1 and three tumors showed regions of homozygous loss 109 to 216 kb in size involving the RB1 tumor suppressor gene only.
Conclusions: These data suggest that novel cancer genes may be located within the other identified small regions of copy number alteration. Analysis of the number of copy number breakpoints and the distribution of the small regions of copy number change indicate high levels of structural chromosomal genetic instability in ovarian cancer.
The Cancer/Testis Antigen Melanoma-Associated Antigen-A3/A6 Is a Novel Target of Fibroblast Growth Factor Receptor 2-IIIb through Histone H3 Modifications in Thyroid Cancer
Authors: Kondo Tetsuo , Zhu Xuegong , Asa Sylvia L. , Ezzat Shereen 
Published: August 2007

Abstract
Purpose: Fibroblast growth factor (FGF) signals play fundamental roles in development and tumorigenesis. Thyroid cancer is an example of a tumor with nonoverlapping genetic mutations that up-regulate mitogen-activated protein kinase. We reported recently that FGF receptor 2 (FGFR2) is down-regulated through extensive DNA promoter methylation in thyroid cancer. Reexpression of the FGFR2-IIIb isoform impedes signaling upstream of the BRAF/mitogen-activated protein kinase pathway to interrupt tumor progression. In this analysis, we examined a novel target of FGFR2-IIIb signaling, melanoma-associated antigen-A3 and A6 (MAGE-A3/6).
Experimental Design: cDNA microarray analysis was done on human WRO thyroid cancer cells transfected with FGFR2-IIIb or empty vector. Identified gene target was confirmed by reverse transcription-PCR and Western blotting. Gene regulation was examined by treatment of WRO cells with the methylation inhibitor 5′-azacytidine followed by methylation-specific PCR and reverse transcription-PCR and by chromatin immunoprecipitation.
Results: Gene expression profiling identified the cancer/testis antigen MAGE-A3/6 as a novel target of FGFR2-IIIb signaling. MAGE-A3/6 regulation was mediated through DNA methylation and chromatin modifications. In particular, FGF7/FGFR2-IIIb activation resulted in histone 3 methylation and deacetylation associated with the MAGE-A3/6 promoter to down-regulate gene expression.
Conclusions: These data unmask a complex repertoire of epigenetically controlled signals that govern FGFR2-IIIb and MAGE-A3/6 expression. Our findings provide insights into the interrelationship between novel tumor markers that may also represent overlapping therapeutic targets.
Activated Mammalian Target of Rapamycin Is an Adverse Prognostic Factor in Patients with Biliary Tract Adenocarcinoma
Authors: Herberger Beata , Puhalla Harald , Lehnert Martina , Wrba Fritz , Novak Sabine , Brandstetter Anita , Gruenberger Birgit , Gruenberger Thomas , Pirker Robert , Filipits Martin 
Published: August 2007

Abstract
Purpose: The mammalian target of rapamycin (mTOR) is a protein kinase that plays a key role in cellular growth and homeostasis. Because its regulation is frequently altered in tumors, mTOR is currently under investigation as a potential target for anticancer therapy. The purpose of our study was to determine the prognostic value of activated mTOR (p-mTOR) in patients with biliary tract adenocarcinoma (BTA), in order to strengthen the rationale for targeted therapy of BTA using mTOR inhibitors.
Experimental Design: We determined expression of p-mTOR in paraffin-embedded surgical specimens of BTA by immunohistochemistry with a monoclonal antibody to phosphorylated mTOR. Overall survival was analyzed with a Cox model adjusted for clinical and pathologic factors.
Results: Immunostaining for p-mTOR was positive in 56 of 88 (64%) tumors. Activated mTOR was not associated with any of the clinical or pathologic variables of the patients but predicted overall survival of the patients. Overall survival was significantly shorter in patients with p-mTOR–positive tumors as compared with patients with p-mTOR–negative tumors (hazard ratio for death 2.57; 95% confidence interval, 1.35-4.89; P = 0.004). Multivariate Cox proportional hazards regression analyses identified p-mTOR to be an independent prognostic factor for death (adjusted hazard ratio for death, 2.44; 95% confidence interval, 1.24-4.80; P = 0.01).
Conclusions: Patients with BTA and p-mTOR–positive tumors have a significantly shorter overall survival than patients with p-mTOR–negative tumors and may benefit from targeted therapy with mTOR inhibitors in the future.
Interleukin-12: Biological Properties and Clinical Application
Authors: Del Vecchio Michele , Bajetta Emilio , Canova Stefania , Lotze Michael T. , Wesa Amy , Parmiani Giorgio , Anichini Andrea 
Published: August 2007

AbstractInterleukin-12 (IL-12) is a heterodimeric protein, first recovered from EBV-transformed B cell lines. It is a multifunctional cytokine, the properties of which bridge innate and adaptive immunity, acting as a key regulator of cell-mediated immune responses through the induction of T helper 1 differentiation. By promoting IFN-γ production, proliferation, and cytolytic activity of natural killer and T cells, IL-12 induces cellular immunity. In addition, IL-12 induces an antiangiogenic program mediated by IFN-γ–inducible genes and by lymphocyte-endothelial cell cross-talk. The immunomodulating and antiangiogenic functions of IL-12 have provided the rationale for exploiting this cytokine as an anticancer agent. In contrast with the significant antitumor and antimetastatic activity of IL-12, documented in several preclinical studies, clinical trials with IL-12, used as a single agent, or as a vaccine adjuvant, have shown limited efficacy in most instances. More effective application of this cytokine, and of newly identified IL-12 family members (IL-23 and IL-27), should be evaluated as therapeutic agents with considerable potential in cancer patients.
Alteration of dihydropyrimidine dehydrogenase expression by IFN-α affects the antiproliferative effects of 5-fluorouracil in human hepatocellular carcinoma cells
Authors: Oie Shinji , Ono Mayumi , Fukushima Hiroto , Hosoi Fumihito , Yano Hirohisa , Maruyama Yuichiro , Kojiro Masamichi , Terada Tadafumi , Hirano Kazuyuki , Kuwano Michihiko , Yamada Yuji 
Published: August 2007

Abstract
Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU) and its activity is closely associated with cellular sensitivity to 5-FU. This study examines the role of DPD in the antiproliferative effects of 5-FU combined with IFN-α on hepatocellular carcinoma (HCC) cells in culture and asks whether IFN-α could affect DPD expression. The combined action of IFN-α and 5-FU on three HCC lines was quantified by a combination index method. Coadministration of IFN-α and 5-FU showed synergistic effects against HAK-1A and KYN-2 but antagonistic effects against KYN-3. The cellular expression levels of DPD mRNA and protein were markedly up-regulated in KYN-3 cells by IFN-α but were down-regulated in HAK-1A and KYN-2. The expression of thymidylate synthase mRNA and protein was down-regulated by IFN-α in all three cell lines. Coadministration of a selective DPD inhibitor, 5-chloro-2,4-dihydroxypyridine (CDHP), enhanced the antiproliferative effect of 5-FU and IFN-α on KYN-3 ∼4-fold. However, the synergistic effects of 5-FU and IFN-α on HAK-1A and KYN-2 were not affected by CDHP. The antiproliferative effect of 5-FU could thus be modulated by IFN-α, possibly through DPD expression, in HCC cells. Inhibition of DPD activity by CDHP may enhance the efficacy of IFN-α and 5-FU combination therapy in patients with HCC showing resistance to this therapy. [Mol Cancer Ther 2007;6(8):2310–8]
The antipsychotic drug trifluoperazine inhibits DNA repair and sensitizes non–small cell lung carcinoma cells to DNA double-strand break–induced cell death
Authors: Polischouk Anya G. , Holgersson Åsa , Zong Dali , Stenerlöw Bo , Karlsson Hanna L. , Möller Lennart , Viktorsson Kristina , Lewensohn Rolf 
Published: August 2007

Abstract
Trifluoperazine (TFP), a member of the phenothiazine class of antipsychotic drugs, has been shown to augment the cytotoxicity of the DNA-damaging agent bleomycin. In the present study, we investigated the effect of trifluoperazine on (a) survival of bleomycin-treated human non–small cell lung carcinoma U1810 cells, (b) induction and repair of bleomycin-induced DNA strand breaks, and (c) nonhomologous end-joining (NHEJ), the major DNA double-strand break (DSB) repair pathway in mammalian cells. By using a clonogenic survival assay, we show here that concomitant administration of trifluoperazine at a subtoxic concentration enhances the cytotoxicity of bleomycin. Moreover, trifluoperazine also increases the longevity of bleomycin-induced DNA strand breaks in U1810 cells, as shown by both comet assay and fraction of activity released (FAR)-assay. This action seems to be related to suppression of cellular DNA DSB repair activities because NHEJ–mediated rejoining of DSBs occurs with significantly lower efficiency in the presence of trifluoperazine. We propose that TFP might be capable of inhibiting one or more elements of the DNA DSB repair machinery, thereby increasing the cytotoxicity of bleomycin in lung cancer cells. [Mol Cancer Ther 2007;6(8):2303–9]
Therapeutic targeting of nuclear receptor corepressor misfolding in acute promyelocytic leukemia cells with genistein
Authors: Ng Angela Ping Ping , Nin Dawn Sijin , Fong Jek Howe , Venkataraman Divya , Chen Chien-Shing , Khan Matiullah 
Published: August 2007

Abstract
We have recently reported that PML-RAR–induced misfolding of the N-CoR protein could be reversed by retinoic acid (RA), a therapeutic agent that promotes differentiation of acute promyelocytic leukemia (APL) cells. This finding suggests a role of misfolded N-CoR in the differentiation arrest of APL cells and highlights its significance as a potential molecular target in protein conformation–based therapy for APL. Based on this hypothesis, we investigated the therapeutic potential of several protein conformation modifiers on APL-derived cell lines NB4 and NB4-R1. Through a small-scale screening of these selected compounds, we identified genistein as a potent inhibitor of growth of both RA-sensitive and RA-resistant APL cells. Genistein inhibited the growth of NB4 cells through its collective regulatory effects on cell cycle progression, differentiation, and apoptosis. Genistein-induced apoptosis of NB4 cells was mediated by activation of caspase-9 and caspase-3 and was associated with a decrease in mitochondrial transmembrane potential and cytosolic release of cytochrome c. Genistein promoted differentiation of both RA-sensitive and RA-resistant NB4 cells and induced cell cycle arrest by blocking the G2-M transition. Genistein up-regulated the expression of PML and N-CoR proteins, promoted degradation of PML-RAR, and reorganized the microspeckled distribution of PML oncogenic domains to a normal dot-like pattern in NB4 cells. Moreover, genistein significantly reversed the PML-RAR–induced misfolding of N-CoR protein by possibly inhibiting the selective phosphorylation-dependent binding of N-CoR to PML-RAR. These findings identify genistein as a potent modifier of N-CoR protein conformation and highlights its therapeutic potential in both RA-sensitive and RA-resistant APL cells. [Mol Cancer Ther 2007;6(8):2240–8]
Context-dependent roles of mutant B-Raf signaling in melanoma and colorectal carcinoma cell growth
Authors: Hao Honglin , Muniz-Medina Vanessa M. , Mehta Heena , Thomas Nancy E. , Khazak Vladimir , Der Channing J. , Shields Janiel M. 
Published: August 2007

Abstract
Mutational activation of Ras and a key downstream effector of Ras, the B-Raf serine/threonine kinase, has been observed in melanomas and colorectal carcinomas. These observations suggest that inhibition of B-Raf activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK) and the extracellular signal-regulated kinase MAPK cascade may be an effective approach for the treatment of RAS and B-RAF mutation-positive melanomas and colon carcinomas. Although recent studies with interfering RNA (RNAi) and pharmacologic inhibitors support a critical role for B-Raf signaling in melanoma growth, whether mutant B-Raf has an equivalent role in promoting colorectal carcinoma growth has not been determined. In the present study, we used both RNAi and pharmacologic approaches to further assess the role of B-Raf activation in the growth of human melanomas and additionally determined if a similar role for mutant B-Raf is seen for colorectal carcinoma cell lines. We observed that RNAi suppression of mutant B-Raf(V600E) expression strongly suppressed the anchorage-dependent growth of B-RAF mutation-positive melanoma, but not colorectal carcinoma, cells. However, the anchorage-independent and tumorigenic growth of B-RAF mutation-positive colorectal carcinomas was dependent on mutant B-Raf function. Finally, pharmacologic inhibition of MEK and Raf was highly effective at inhibiting the growth of B-RAF mutation-positive melanomas and colorectal carcinoma cells, whereas inhibitors of other protein kinases activated by Ras (AKT, c-Jun NH2-terminal kinase, and p38 MAPK) were less effective. Our observations suggest that Raf and MEK inhibitors may be effective for the treatment of B-RAF mutation-positive colorectal carcinomas as well as melanomas. [Mol Cancer Ther 2007;6(8):2220–9]
CCG-1423: a small-molecule inhibitor of RhoA transcriptional signaling
Authors: Evelyn Chris R. , Wade Susan M. , Wang Qin , Wu Mei , Iñiguez-Lluhí Jorge A. , Merajver Sofia D. , Neubig Richard R. 
Published: August 2007

AbstractLysophosphatidic acid receptors stimulate a Gα12/13/RhoA-dependent gene transcription program involving the serum response factor (SRF) and its coactivator and oncogene, megakaryoblastic leukemia 1 (MKL1). Inhibitors of this pathway could serve as useful biological probes and potential cancer therapeutic agents. Through a transcription-based high-throughput serum response element-luciferase screening assay, we identified two small-molecule inhibitors of this pathway. Mechanistic studies on the more potent CCG-1423 show that it acts downstream of Rho because it blocks SRE.L-driven transcription stimulated by Gα12Q231L, Gα13Q226L, RhoA-G14V, and RhoC-G14V. The ability of CCG-1423 to block transcription activated by MKL1, but not that induced by SRF-VP16 or GAL4-VP16, suggests a mechanism targeting MKL/SRF-dependent transcriptional activation that does not involve alterations in DNA binding. Consistent with its role as a Rho/SRF pathway inhibitor, CCG-1423 displays activity in several in vitro cancer cell functional assays. CCG-1423 potently (&lt;1 μmol/L) inhibits lysophosphatidic acid–induced DNA synthesis in PC-3 prostate cancer cells, and whereas it inhibits the growth of RhoC-overexpressing melanoma lines (A375M2 and SK-Mel-147) at nanomolar concentrations, it is less active on related lines (A375 and SK-Mel-28) that express lower levels of Rho. Similarly, CCG-1423 selectively stimulates apoptosis of the metastasis-prone, RhoC-overexpressing melanoma cell line (A375M2) compared with the parental cell line (A375). CCG-1423 inhibited Rho-dependent invasion by PC-3 prostate cancer cells, whereas it did not affect the Gαi-dependent invasion by the SKOV-3 ovarian cancer cell line. Thus, based on its profile, CCG-1423 is a promising lead compound for the development of novel pharmacologic tools to disrupt transcriptional responses of the Rho pathway in cancer. [Mol Cancer Ther 2007;6(8):2249–60]
Anticancer medicines in development: assessment of bioactivity profiles within the National Cancer Institute anticancer screening data
Authors: Covell David G. , Huang Ruili , Wallqvist Anders 
Published: August 2007

AbstractWe present an analysis of current anticancer compounds that are in phase I, II, or III clinical trials and their structural analogues that have been screened in the National Cancer Institute (NCI) anticancer screening program. Bioactivity profiles, measured across the NCI 60 cell lines, were examined for a correspondence between the type of cancer proposed for clinical testing and selective sensitivity to appropriately matched tumor subpanels in the NCI screen. These results find strongest support for using the NCI anticancer screen to select analogue compounds with selective sensitivity to the leukemia, colon, central nervous system, melanoma, and ovarian panels, but not for renal, prostate, and breast panels. These results are extended to applications of two-dimensional structural features to further refine compound selections based on tumor panel sensitivity obtained from tumor screening results. [Mol Cancer Ther 2007;6(8):2261–70]
Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo
Authors: Hagos Ghenet K. , Carroll Robert E. , Kouznetsova Tatiana , Li Qian , Toader Violeta , Fernandez Patricia A. , Swanson Steven M. , Thatcher Gregory R.J. 
Published: August 2007

Abstract
Chemopreventive agents in colorectal cancer possess either antiproliferative or anti-inflammatory actions. Nonsteroidal anti-inflammatory drugs (NSAID) and cyclooxygenase-2 inhibitors have shown promise, but are compromised by side effects. Nitric oxide donor NSAIDs are organic nitrates conjugated via a labile linker to an NSAID, originally designed for use in pain relief, that have shown efficacy in colorectal cancer chemoprevention. The NO chimera, GT-094, is a novel nitrate containing an NSAID and disulfide pharmacophores, a lead compound for the design of agents specifically for colorectal cancer. GT-094 is the first nitrate reported to reduce aberrant crypt foci (by 45%) when administered after carcinogen in the standard azoxymethane rat model of colorectal cancer. Analysis of proximal and distal colon tissue from 8- and 28-week rat/azoxymethane studies showed that GT-094 treatment reduced colon crypt proliferation by 30% to 69%, reduced inducible NO synthase (iNOS) levels by 33% to 67%, reduced poly(ADP-ribose)polymerase-1 expression and cleavage 2- to 4-fold, and elevated levels of p27 in the distal colon 3-fold. Studies in cancer cell cultures recapitulated actions of GT-094: antiproliferative activity and transient G2-M phase cell cycle block were measured in Caco-2 cells; apoptotic activity was examined but not observed; anti-inflammatory activity was seen in the inhibition of up-regulation of iNOS and endogenous NO production in lipopolysaccharide (LPS)-induced RAW 264.7 cells. In summary, antiproliferative, anti-inflammatory, and cytoprotective activity observed in vivo and in vitro support GT-094 as a lead compound for the design of NO chimeras for colorectal cancer chemoprevention. [Mol Cancer Ther 2007;6(8):2230–9]