bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of a Gemcitabine-Resistant Murine Leukemic Cell Line
Authors: Jordheim Lars Petter , Cros Emeline , Gouy Marie-Hélène , Galmarini Carlos M. , Peyrottes Suzanne , Mackey John , Perigaud Christian , Dumontet Charles 
Published: September 2005

Abstract
Resistance to cytotoxic nucleoside analogues is a major problem in cancer treatment. The cellular mechanisms involved in this phenomenon have been studied for several years, and some factors have been identified. Various strategies to overcome resistance have been suggested, but none has yet shown efficacy in vivo. We developed a gemcitabine-resistant cell line (L1210 10K) from the murine leukemic L1210 strain (L1210 wt) by continuous exposure to increasing concentrations of gemcitabine. L1210 10K is highly resistant to gemcitabine (14,833-fold), 1-β-d-arabinofuranosylcytosine (ara-C; 2,100-fold), troxacitabine (&gt;200-fold), and cladribine (160-fold) and slightly resistant to trimidox (7.22-fold), but does not display cross-resistance to fludarabine or nonnucleoside anticancer drugs. Deoxycytidine kinase mRNA was not detected by quantitative real-time reverse transcription-PCR in L1210 10K cells, whereas expression of thymidine kinase 1 and ribonucleotide reductase subunit R2 gene was moderately reduced. L1210 10K cells also demonstrated in vivo resistance to nucleoside analogues: gemcitabine- or ara-C-treated mice carrying L1210 10K had significantly shorter survival than gemcitabine- or ara-C-treated mice carrying L1210 wt (P &lt; 0.05). UA911, a mononucleotide prodrug (pronucleotide) of ara-C was found to significantly sensitize L1210 10K cells in vitro. These results suggest that reduced deoxycytidine kinase expression is a mechanism of resistance to gemcitabine that is relevant in vivo and can be circumvented by a prodrug approach.
Overexpression of G1-S Cyclins and Cyclin-Dependent Kinases during Multistage Human Pancreatic Duct Cell Carcinogenesis
Authors: Al-Aynati Maamoun M. , Radulovich Nikolina , Ho James , Tsao Ming-Sound 
Published: September 2005

Abstract
Purpose: Molecular analysis of pancreatic intraepithelial neoplasia lesions and ductal adenocarcinoma suggested a multistage paradigm for pancreatic duct cell carcinogenesis. This study investigated the molecular basis for the neoplastic duct cells in this pancreatic intraepithelial neoplasia–carcinoma sequence to acquire progressive enhancement of their proliferative potential.
Experimental Design: Using tissue microarray blocks containing 15 to 40 pancreatic intraepithelial neoplasia lesions and ductal adenocarcinoma of pancreas, we studied by immunohistochemistry the expression profiles of cyclins and cyclin dependent kinases (CDKs) that regulate the G1-S cell cycle checkpoints. The role of cyclins D3 and D1 in three pancreatic cancer cell lines was investigated using specific short interfering RNA technique.
Results: Cyclin D3 overexpression was noted the earliest in pancreatic intraepithelial neoplasia-1A and was prevalent in 90% to 100% of high-grade pancreatic intraepithelial neoplasias and ductal cancer. Cyclin A overexpression was also noted early and reached 50% to 100% of high-grade pancreatic intraepithelial neoplasias and cancer, but the percentage of abnormal duct cells showing overexpression of cyclin A was significantly lower than cyclin D3. Cyclin E overexpression occurred in 20% to 25% of high-grade pancreatic intraepithelial neoplasias and in 75% of ductal carcinoma. Cyclin D1 demonstrated the lowest frequency of overexpression that occurred late. CDK2 and CDK4 overexpression was also noted in early pancreatic intraepithelial neoplasias and progressively increased to reach 60% to 75% in carcinoma. The down-regulation of cyclin D3 mRNA and protein levels using specific short interfering RNA resulted in growth inhibition of pancreatic cancer cell lines.
Conclusion: The results provide additional insight into the mechanism of G1-S cell cycle checkpoints deregulation during stepwise pancreatic duct cell carcinogenesis, and suggest a p16-independent role for cyclin D3 in deregulating the G1 cell cycle checkpoints during early stages of pancreatic duct cell carcinogenesis.
No Long-Term Increase in Sperm Aneuploidy Rates after Anticancer Therapy
Authors: Thomas Claire , Cans Christine , Pelletier Roberte , De Robertis Christine , Hazzouri Mira , Sele Bernard , Rousseaux Sophie , Hennebicq Sylviane 
Published: September 2005

AbstractPurpose: Lymphomas and testicular cancers are the most frequent malignancies among young men. With recent improvement of survival rates, for many patients, the question is raised of the consequences of the anticancer treatments on their fertility and more specifically of a potential genetic risk for the offspring. This article presents the study of sperm aneuploidy rates in the largest population of cancer-treated patients studied thus far.Experimental Design: In the present study, 38 patients were initially included 7 months to 5 years after a cancer treatment by chemotherapy and/or radiotherapy for testicular cancer (n = 19) or lymphoma (n = 19). Twelve of them were azoospermic. Sperm aneuploidy rates of chromosomes X, Y, 13, 18, and 21 were analyzed by multicolor fluorescent in situ hybridization in the 26 other patients.Results: In most cases, the disomy/diploidy rates after cancer therapy did not significantly differ from those observed in the group of control healthy donors. Only five patients (one lymphoma and four testicular cancer) showed significant but still moderate increases in disomic and/or diploid sperm. For the lymphoma patient, the short posttherapeutic delay after the treatment could explain the elevated aneuploidy rates, whereas no risk factor in the clinical, biological, or therapeutic records could be identified in any of the four testicular cancer patients with elevated sperm aneuploidy rates.Conclusions: These data suggest an absence of long-term effect of anticancer therapy on sperm aneuploidy rates, and therefore, no long-term increased risk of aneuploidy for the offspring obtained either spontaneously or after assisted reproductive techniques.
Abrogation of Head and Neck Squamous Cell Carcinoma Growth by Epidermal Growth Factor Receptor Ligand Fused to
Pseudomonas
Exotoxin Transforming Growth Factor α-PE38
Authors: Thomas Sufi M. , Zeng Qing , Epperly Michael W. , Gooding William E. , Pastan Ira , Wang Qing Cheng , Greenberger Joel , Grandis Jennifer Rubin 
Published: September 2005

Abstract
Purpose: This study was undertaken to determine whether low intratumoral doses of the epidermal growth factor receptor ligand-transforming growth factor α (TGF-α) fused to Pseudomonas exotoxin (TGF-α–PE38)-abrogated head and neck squamous cell carcinoma (HNSCC) tumor growth in vitro and in vivo.
Experimental Design: In vitro cytotoxicity assays were carried out to determine the sensitivity of HNSCC cells to TGF-α–PE38. TGF-α–PE38-treated HNSCC cells were examined by immunoblotting for cleaved poly(ADP-ribose) polymerase to evaluate apoptosis. Nude mice bearing established HNSCC xenografts were treated with several doses of TGF-α–PE38 to evaluate the antitumor efficacy in vivo. Tumor sections were stained with terminal deoxynucleotidyl transferase-mediated nick end labeling for apoptosis. To determine the effect of oral administration of TGF-α–PE38, gavage injections of TGF-α–PE38 were administered, and the esophagus and surrounding soft tissue were then stained for apoptotic cells.
Results: HNSCC cell lines examined were sensitive to low doses of TGF-α–PE38 (EC50 in the range of 1.6 to 10 ng/mL). HNSCC cells treated with TGF-α–PE38 undergo apoptosis. Antitumor effects were observed using 0.1 and 0.03 μg of TGF-α–PE38 administered intratumorally. At these doses, the treatment was well tolerated. Tumors treated with the toxin had a higher number of apoptotic cells compared with the control tumors. No apoptotic cells were observed in the pharyngoesophageal tissues of the mice after gavage administration of the toxin suggesting that the toxin could be orally administered without toxicity.
Conclusions: These results indicate that topical or intratumoral administration of low doses of TGF-α–PE38 may demonstrate antitumor effects in HNSCC without associated systemic toxicity.
CD34+ Cells from Acute Myeloid Leukemia, Myelodysplastic Syndromes, and Normal Bone Marrow Display Different Apoptosis and Drug Resistance–Associated Phenotypes
Authors: Suárez Lilia , Vidriales María-Belén , García-Laraña José , Sanz Guillermo , Moreno María-José , López Antonio , Barrena Susana , Martínez Rafael , Tormo Mar , Palomera Luis , Lavilla Esperanza , López-Berges Ma Consuelo , de Santiago María , de Equiza M. Encarnación Pérez , Miguel Jesús F. San , Orfao Alberto ,   for the PETHEMA Cooperative Group
Published: September 2005

Abstract
Myelodysplastic syndromes and acute myeloid leukemia (AML) are heterogeneous disorders in which conflicting results in apoptosis and multidrug resistance (MDR) have been reported. We have evaluated by multiparameter flow cytometry the expression of apoptosis- (APO2.7, bcl-2, and bax) and MDR-related proteins [P-glycoprotein (P-gp), multidrug resistance protein (MRP), and lung resistance protein (LRP)] specifically on bone marrow (BM) CD34+ cells, and their major CD32−/dim and CD32+ subsets, in de novo AML (n = 90), high-risk myelodysplastic syndrome (n = 9), and low-risk myelodysplastic syndrome (n = 21) patients at diagnosis, and compared with normal BM CD34+ cells (n = 6). CD34+ myeloid cells from AML and high-risk myelodysplastic syndrome patients displayed higher expression of bcl-2 (P &lt; 0.0001) and lower reactivity for APO2.7 (P = 0.002) compared with low-risk myelodysplastic syndrome and normal controls. Similar results applied to the two predefined CD34+ myeloid cell subsets. No significant differences were found in the expression of P-gp, MRP, and LRP between low-risk myelodysplastic syndrome patients and normal BM, but decreased expression of MRP (P &lt; 0.03) in AML and high-risk myelodysplastic syndromes and P-gp (P = 0.008) in high-risk myelodysplastic syndromes were detected. Hierarchical clustering analysis showed that low-risk myelodysplastic syndrome patients were clustered next to normal BM samples, whereas high-risk myelodysplastic syndromes were clustered together and mixed with the de novo AML patients. In summary, increased resistance to chemotherapy of CD34+ cells from both AML and high-risk myelodysplastic syndromes would be explained more appropriately in terms of an increased antiapoptotic phenotype rather than a MDR phenotype. In low-risk myelodysplastic syndromes abnormally high apoptotic rates would be restricted to the CD34− cell compartments.
Identification of the Fenretinide Metabolite 4-Oxo-Fenretinide Present in Human Plasma and Formed in Human Ovarian Carcinoma Cells through Induction of Cytochrome P450 26A1
Authors: Villani Maria Grazia , Appierto Valentina , Cavadini Elena , Valsecchi Manuela , Sonnino Sandro , Curley Robert W. , Formelli Franca 
Published: September 2005

Abstract
Purpose: The synthetic retinoid fenretinide (4-HPR) exhibits preventive and therapeutic activity against ovarian tumors. An unidentified polar metabolite was previously found in 4-HPR-treated subjects and in A2780 human ovarian carcinoma cells continuously treated with 4-HPR (A2780/HPR). The metabolite and the enzyme involved in its formation in tumor cells are herein identified.
Experimental Design: The metabolite was identified by mass spectrometry in A2780/HPR cell extracts and in plasma from 11 women participating in a phase III trial and treated with 200 mg/d 4-HPR for 5 years. The expression of proteins involved in retinoid metabolism and transport, cytochrome P450 26A1 (CYP26A1), cellular retinol-binding protein I (CRBP-I), and cellular retinoic acid-binding protein I and II (CRABP-I, CRABP-II) were evaluated in tumor cells by reverse transcription-PCR and Western blot analyses. Overexpression of CYP26A1 and retinoic acid receptors (RARs) in A2780 cells were obtained by cDNAs transfection.
Results: The polar metabolite was 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) i.e., an oxidized form of 4-HPR with modification in position 4 of the cyclohexene ring. 4-oxo-4-HPR plasma levels were slightly lower (0.52 ± 0.17 μmol/L) than those of the parent drug (0.84 ± 0.53 μmol/L) and of the already identified metabolite N-(4-methoxyphenyl)retinamide (1.13 ± 0.85 μmol/L). In A2780/HPR cells continuously treated with 4-HPR and producing 4-oxo-4-HPR, CYP26A1 and CRBP-I were markedly up-regulated compared with A2780 untreated cells. In A2780 cells, not producing 4-oxo-4-HPR, overexpression of CYP26A1 caused formation of 4-oxo-4-HPR, which was associated with no change in 4-HPR sensitivity. Moreover, the addition of 4-oxo-4-HPR to A2780 cells inhibited cell proliferation. Elevated levels of CYP26A1 protein and metabolism of 4-HPR to 4-oxo-4-HPR were found in A2780 cells transfected with RARβ and to a lesser extent in those transfected with RARγ.
Conclusions: A new metabolite of 4-HPR, 4-oxo-4-HPR, present in human plasma and in tumor cells, has been identified. The formation of this biologically active metabolite in tumor cells was due to CYP26A1 induction and was influenced by RAR expression. Moreover evidence was provided that 4-HPR up-modulates the expression of CRBP-I transcript, which is lost during ovarian carcinogenesis.
Overexpression of Matrix Metalloproteinase-1 and -9 mRNA Is Associated with Progression of Oral Dysplasia to Cancer
Authors: Jordan Richard C. K. , Macabeo-Ong Maricris , Shiboski Caroline H. , Dekker Nusi , Ginzinger David G. , Wong David T. W. , Schmidt Brian L. 
Published: September 2005

Abstract
Purpose: Although an important risk factor for oral cancer is the presence of epithelial dysplasia, many lesions will not progress to malignancy. Matrix metalloproteinases (MMPs) are zinc-dependent proteinases capable of digesting various structural components of the extracellular matrix. Because MMPs are frequently overexpressed in oral squamous cell carcinoma (SCC), we hypothesized that they are also overexpressed in oral dysplasias; we also hypothesized that those dysplasias that progress to oral cancer express higher levels of MMPs than those lesions that do not progress.
Experimental Design: In this retrospective study, we examined changes in MMP-1, -2, and -9 mRNA expression using quantitative TaqMan reverse transcription-polymerase chain reaction in 34 routinely processed oral dysplasias and 15 SCCs obtained from 34 patients. After several years of close follow-up, 19 dysplasias progressed to oral SCC and 15 did not.
Results: Overall, MMP-1 mRNA was overexpressed (&gt;2-fold) in 24 of 34 (71%) dysplasias and 13 of 15 (87%) oral SCCs. MMP-2 overexpression was seen in 11 of 34 (32%) dysplasias and 7 of 15 (47%) cancers; for MMP-9, overexpression was identified in 29 of 34 (85%) dysplasias and 15 of 15 (100%) cancers. MMP-1 and -9 levels were significantly higher in the SCCs compared with all oral dysplasias (P = 0.004 and P = 0.01, respectively). MMP-1 and -9 mRNA levels were significantly higher in the oral dysplasias that progressed to oral cancer compared with those that did not (P = 0.04 and P = 0.002, respectively).
Conclusions: Levels of MMP-1 and -9 mRNA may be markers of malignant transformation of oral dysplasia to oral cancer.
Analysis of Antitumor Activity of an Interleukin-13 (IL-13) Receptor-Targeted Cytotoxin Composed of IL-13 Antagonist and
Pseudomonas
Exotoxin
Authors: Kioi Mitomu , Kawakami Koji , Puri Raj K. 
Published: September 2005

Abstract
We have shown previously that a chimeric fusion protein composed of human interleukin-13 (IL-13) and Pseudomonas exotoxin (PE), termed IL-13 cytotoxin (IL13-PE38), is specifically cytotoxic to various cancer cell lines and primary cell cultures derived from a variety of solid cancers. In addition, we have shown that IL-13 mutant IL-13E13K, in which glutamic acid (E) residue at position 13 of IL-13 molecule was substituted by a lysine (K), is a powerful antagonist of IL-13 and binds to IL-13 receptor with a higher affinity compared with wild-type IL-13. In this study, we have generated an IL-13 cytotoxin IL13E13K-PE38, in which IL-13 antagonist is fused to PE to determine whether this molecule has improved cytotoxicity to tumor cells compared with wild type (wt)IL13-PE38. Highly purified IL13E13K-PE38 was tested in various tumor cell lines including seven glioblastoma multiforme cell lines to compare its binding to the cells, in vitro cytotoxicity, in vivo antitumor activity, and safety in mouse model with wtIL13-PE38. IL13E13K-PE38 bound to U251MG and IL-13Rα2 chain-transfected tumor cell lines with 3 to 10 times higher affinity compared with wtIL13-PE38. However, IL13E13K-PE38 did not show higher cytotoxicity compared with wtIL13-PE38 in glioblastoma multiforme or any other cell lines tested. The antitumor activity of IL13E13K-PE38, when administered intraperitoneally to nude mice bearing U251 tumors, was also similar to wtIL13-PE38. Some improvement in antitumor activity was observed when lower doses of IL13E13K-PE38 were injected intratumorally in subcutaneous tumors. These results indicate that in general, IL13E13K-PE38 mediates similar cytotoxicity and antitumor activity to wtIL13-PE38 despite its improved binding affinity to IL-13 receptors.
Array Comparative Genomic Hybridization Identifies Genetic Subgroups in Grade 4 Human Astrocytoma
Authors: Misra Anjan , Pellarin Malgorzata , Nigro Janice , Smirnov Ivan , Moore Dan , Lamborn Kathleen R. , Pinkel Daniel , Albertson Donna G. , Feuerstein Burt G. 
Published: September 2005

Abstract
Alterations of DNA copy number are believed to be important indicators of tumor progression in human astrocytoma. We used an array of bacterial artificial chromosomes to map relative DNA copy number in 50 primary glioblastoma multiforme tumors at ∼1.4-Mb resolution. We identified 33 candidate sites for amplification and homozygous deletion in these tumors. We identified three major genetic subgroups within these glioblastoma multiforme tumors: tumors with chromosome 7 gain and chromosome 10 loss, tumors with only chromosome 10 loss in the absence of chromosome 7 gain, and tumors without copy number change in chromosomes 7 or 10. The significance of these genetic groups to therapeutics needs further study.
Phase I Clinical Trial of Oral Curcumin
Authors: Sharma Ricky A. , Euden Stephanie A. , Platton Sharon L. , Cooke Darren N. , Shafayat Aisha , Hewitt Heather R. , Marczylo Timothy H. , Morgan Bruno , Hemingway David , Plummer Simon M. , Pirmohamed Munir , Gescher Andreas J. , Steward William P. 
Published: September 2005

Abstract
Curcumin, a polyphenolic antioxidant derived from a dietary spice, exhibits anticancer activity in rodents and in humans. Its efficacy appears to be related to induction of glutathione S-transferase enzymes, inhibition of prostaglandin E2 (PGE2) production, or suppression of oxidative DNA adduct (M1G) formation. We designed a dose-escalation study to explore the pharmacology of curcumin in humans. Fifteen patients with advanced colorectal cancer refractory to standard chemotherapies consumed capsules compatible with curcumin doses between 0.45 and 3.6 g daily for up to 4 months. Levels of curcumin and its metabolites in plasma, urine, and feces were analyzed by high-pressure liquid chromatography and mass spectrometry. Three biomarkers of the potential activity of curcumin were translated from preclinical models and measured in patient blood leukocytes: glutathione S-transferase activity, levels of M1G, and PGE2 production induced ex vivo. Dose-limiting toxicity was not observed. Curcumin and its glucuronide and sulfate metabolites were detected in plasma in the 10 nmol/L range and in urine. A daily dose of 3.6 g curcumin engendered 62% and 57% decreases in inducible PGE2 production in blood samples taken 1 hour after dose on days 1 and 29, respectively, of treatment compared with levels observed immediately predose (P &lt; 0.05). A daily oral dose of 3.6 g of curcumin is advocated for Phase II evaluation in the prevention or treatment of cancers outside the gastrointestinal tract. PGE2 production in blood and target tissue may indicate biological activity. Levels of curcumin and its metabolites in the urine can be used to assess general compliance.
Cisplatin Rapidly Down-regulates Its Own Influx Transporter hCTR1 in Cultured Human Ovarian Carcinoma Cells
Authors: Holzer Alison K. , Katano Kuniyuki , Klomp Leo W. J. , Howell Stephen B. 
Published: September 2005

Abstract
Purpose: Cisplatin (DDP)-resistant cells commonly exhibit reduced drug accumulation. Previous studies have shown that the major copper (Cu) influx transporter CTR1 controls the uptake of DDP in yeast and mammalian cells. The goal of this study was to examine the effect of Cu and DDP on the level and subcellular localization of hCTR1 protein in human ovarian carcinoma cells.
Experimental Design: Cultured human ovarian carcinoma A2780 cells were exposed to DDP and Cu, and the effect on hCTR1 was determined using Western blot analysis and confocal digital deconvolution microscopy.
Results: Loss of hCTR1 was triggered by DDP exposure in a concentration and time-dependent manner. Exposure to 0.5 μmol/L DDP for 5 minutes reduced hCTR1 levels and exposure to DDP concentrations ≥2 μmol/L caused almost complete disappearance. The loss of hCTR1 was observed within 1 minute of the start of exposure to 2 μmol/L DDP. Treatment of cells with 100 μmol/L Cu for 5 minutes produced a smaller effect. Pretreatment of cells with 2 μmol/L DDP for 5 minutes resulted in a 50% decrease in 64Cu uptake, demonstrating that the DDP-induced loss of hCTR1 detected by Western blot analysis and imaging was functionally significant.
Conclusions: DDP down-regulated the amount of its major influx transporter in cultured human ovarian carcinoma cells in a concentration- and time-dependent manner. The effect was observed at DDP concentrations within the range found in the plasma of patients being treated with DDP, and it occurred very quickly relative to the half-life of the drug.