bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patupilone Acts as Radiosensitizing Agent in Multidrug-Resistant Cancer Cells In vitro and In vivo
Authors: Hofstetter Barbara , Vuong Van , Broggini-Tenzer Angela , Bodis Stephan , Ciernik Ilja F. , Fabbro Doriano , Wartmann Markus , Folkers Gerd , Pruschy Martin 
Published: September 2005

Abstract
Interference with microtubule function is a promising antitumoral concept. Paclitaxel is a clinically validated tubulin-targeting agent; however, treatment with paclitaxel is often limited by taxane-related toxicities and is ineffective in tumors with multidrug-resistant cells. Patupilone (EPO906, epothilone B) is a novel non-taxane-related microtubule-stabilizing natural compound that retains full activity in multidrug-resistant tumors and is clinically less toxic than paclitaxel. Here we have investigated the effect of combined treatment with ionizing radiation and patupilone or paclitaxel in the P-glycoprotein-overexpressing, p53-mutated human colon adenocarcinoma cell line SW480 and in murine, genetically defined E1A/ras-transformed paclitaxel-sensitive embryo fibroblasts. Patupilone and paclitaxel alone and in combination with ionizing radiation reduced the proliferative activity of the E1A/ras-transformed cell line with similar potency in the sub and low nanomolar range. SW480 cells were only sensitive to patupilone, and combined treatment with low-dose patupilone (0.1 nmol/L) followed by clinically relevant doses of ionizing radiation (2 and 5 Gy) resulted in a supra-additive cytotoxic effect. Inhibition of the drug efflux protein P-glycoprotein with verapamil resensitized SW480 cells to treatment with low doses of paclitaxel alone and in combination with IR. In tumor xenografts derived from SW480 cells a minimal treatment regimen with patupilone and fractionated irradiation (1 × 2 mg/kg plus 4 × 3 Gy) resulted in an at least additive tumor response with extended tumor growth arrest. Analysis by flow cytometry in vitro revealed an apoptosis- and G2-M-independent mode of radiosensitization by patupilone. Interestingly though, a transient accumulation of cells in S phase was observed on combined treatment.Overall, patupilone might be a promising alternative in paclitaxel-resistant, P-glycoprotein-overexpressing tumors for a combined treatment regimen using ionizing radiation and a microtubule inhibitor.
Diagnostic and Prognostic Information in Prostate Cancer with the Help of a Small Set of Hypermethylated Gene Loci
Authors: Bastian Patrick J. , Ellinger Jörg , Wellmann Axel , Wernert Nicolas , Heukamp Lukas C. , Müller Stefan C. , von Ruecker Alexander 
Published: September 2005

Abstract
Purpose: Our study was designed to evaluate promoter CpG island hypermethylation in the diagnosis and prognosis of prostate cancer.
Experimental Design: Primary prostate cancers from 53 patients, pelvic lymph nodes, noncancerous prostate tissues, and prostate cell lines were analyzed. Real-time methylation-specific PCR was used to identify CpG island hypermethylation at five promising gene loci (i.e., GSTP1, APC, PTGS2, MDR1, and RASSF1a).
Results: At three gene loci (GSTP1, APC, and PTGS1) and CpG island, hypermethylation was highly prevalent in prostate cancers (71-91%), and analysis of receiver operator curves showed that hypermethylation at these three gene loci can distinguish between prostate cancer and noncancerous prostatic tissue (i.e., benign hyperplasia) with a sensitivity of 71.1% to 96.2% and a specificity of 92.9% to 100%. Using sensitive SYBR green methylation-specific PCR technology, we observed a respective 28% and 71% hypermethylation rate at the RASSF1a and MDR1 loci in benign prostate hyperplasia, which may represent early nonaggressive carcinogenesis. Methylation characteristics in prostate cancer metastases (i.e., pelvic lymph nodes) were comparable to the respective primary cancer. Statistical analysis showed no correlation between the methylation status of a single gene locus and clinicopathologic variables (e.g., preoperative prostate specific antigen levels, Gleason score, capsular penetration, involvement of seminal vesicle, and age). In contrast, the methylation of two (GSTP1/APC; GSTP1/PTGS2) or three (GSTP1/APC/PTGS2) gene loci correlated with prognostic indicators (i.e., pathologic stage, extraprostatic extension, and Gleason score, but not with prostate specific antigen levels).
Conclusions: Our data suggest that the evaluation of DNA hypermethylation at three gene loci (i.e., GSTP1, APC, and PTGS2) is of diagnostic and prognostic value in prostate cancer.
Inhibition of Phosphatidylinositol 3′-Kinase/AKT Signaling Promotes Apoptosis of Primary Effusion Lymphoma Cells
Authors: Uddin Shahab , Hussain Azhar R. , Al-Hussein Khaled A. , Manogaran Pulicat S. , Wickrema Amitha , Gutierrez Marina I. , Bhatia Kishor G. 
Published: September 2005

AbstractPurpose: Phosphatidylinositol 3′-kinase (PI3′-kinase) can be activated by the K1 protein of Kaposi sarcoma–associated herpes virus (KSHV). However, the role of PI3′-kinase in KSHV-associated primary effusion lymphoma (PEL) is not known. To assess this, we studied survival and apoptosis in PEL cell lines following inhibition of PI3′-kinase.Experimental Design: Constitutive activation of several targets of PI3-kinase and apoptotic proteins were determined by Western blot analysis using specific antibodies. We used LY294002 to block PI3′-kinase/AKT activation and assess apoptosis by flow cytometric analysis.Results: Blocking PI3′-kinase induced apoptosis in PEL cells, including BC1, BC3, BCBL1, and HBL6, whereas BCP1 was refractory to LY294002-induced apoptosis. LY294002-induced apoptosis did not seem to involve Fas/Fas-L but had an additive effect to CH11-mediated apoptosis. We also show that AKT/PKB is constitutively activated in all PELs and treatment with LY294002 causes complete dephosphorylation in all cell lines except BCP1 where a residual AKT phosphorylation remained after 24 hours of treatment. FKHR and GSK3 were also constitutively phosphorylated in PELs and treatment with LY294002 caused their dephosphorylation. Although inhibition of PI3′-kinase induced cleavage of BID in all cell lines, cytochrome c was released from the mitochondria and caspase-9 and caspase-3 were activated in LY294002-induced apoptotic BC1 but not in resistant BCP1. Similarly, XIAP, a target of AKT, was down-regulated after LY294002 treatment only in sensitive PEL cells.Conclusions: Our data show that the PI3′-kinase pathway plays a major role in survival of PEL cells and suggest that this cascade may be a promising target for therapeutic intervention in primary effusion lymphomas.
Cure of Mammary Carcinomas in Her-2 Transgenic Mice through Sequential Stimulation of Innate (Neoadjuvant Interleukin-12) and Adaptive (DNA Vaccine Electroporation) Immunity
Authors: Spadaro Michela , Ambrosino Elena , Iezzi Manuela , Di Carlo Emma , Sacchetti Pamela , Curcio Claudia , Amici Augusto , Wei Wei-Zen , Musiani Piero , Lollini Pier-Luigi , Cavallo Federica , Forni Guido 
Published: September 2005

AbstractPurpose: Whereas neoadjuvant therapy is emerging as a treatment option in early primary breast cancer, no data are available on the use of antiangiogenic and immunomodulatory agents in a neoadjuvant setting. In a model of Her-2 spontaneous mammary cancer, we investigated the efficacy of neoadjuvant interleukin 12 (IL-12) followed by “immune-surgery” of the residual tumor.Experimental Design: Female BALB/c mice transgenic for the rat Her-2 oncogene inexorably develop invasive carcinomas in all their mammary glands by the 23rd week of age. Mice with multifocal in situ carcinomas received four weekly i.p. injections of 100 ng IL-12 followed by a 3-week rest. This course was given four times. A few mice additionally received DNA plasmids encoding portions of the Her-2 receptor electroporated through transcutaneous electric pulses.Results: The protection elicited by IL-12 in combination with two DNA vaccine electroporations kept 63% of mice tumor-free. Complete protection of all 1-year-old mice was achieved when IL-12-treated mice received four vaccine electroporations. Pathologic findings, in vitro tests, and the results from immunization of both IFN-γ and immunoglobulin gene knockout transgenic mice and of adoptive transfer experiments all show that IL-12 augments the B- and T-cell response elicited by vaccination and slightly decreases the number of regulatory T cells. In addition, IL-12 strongly inhibits tumor angiogenesis.Conclusions: In Her-2 transgenic mice, IL-12 impairs tumor progression and triggers innate immunity so markedly that DNA vaccination becomes effective at late points in time when it is ineffective on its own.
Influence of CD80, Interleukin-2, and Interleukin-7 Expression in Human Renal Cell Carcinoma on the Expansion, Function, and Survival of Tumor-Specific CTLs
Authors: Frankenberger Bernhard , Pohla Heike , Noessner Elfriede , Willimsky Gerald , Papier Britta , Pezzutto Antonio , Kopp Joachim , Oberneder Ralph , Blankenstein Thomas , Schendel Dolores J. 
Published: September 2005

AbstractPurpose: A renal cell carcinoma (RCC) line, RCC-26, has been identified as a suitable candidate for development of an allogeneic tumor cell vaccine based on its expression of a variety of tumor-associated antigens (TAA). To improve immunogenicity, RCC-26 cells were genetically engineered to express CD80 alone or in combination with interleukin (IL)-2 or IL-7. The effect of these modifications on proliferation, function, and survival of autologous and allogeneic tumor-specific CTLs was assessed.Experimental Design: RCC-26 sublines expressing different transgenes were tested for their capacity to reactivate cytokine secretion and cytotoxicity in autologous tumor-infiltrating lymphocytes, to improve proliferation and survival of tumor-associated T cells present in autologous peripheral blood, and to induce tumor-associated responses in naive allogeneic lymphocytes. The expression of several common TAA was quantitated in the RCC-26 sublines using reverse transcription-PCR to identify surrogate markers for immune monitoring in clinical trials.Results: Gene-modified RCC-26 cells showed enhanced immunogenicity. CD80 expression was necessary to induce RCC-associated CTL in blood of healthy allogeneic donors. It also improved proliferation of autologous effector-memory T cells. Further enhancement was achieved with IL-2 through induction of the antiapoptosis protein Bcl-xL. The candidate vaccine lines overexpressed several common TAA that are suitable markers for immune monitoring.Conclusions: RCC-26 cells coexpressing CD80 and cytokine transgenes display improved immunogenic characteristics, supporting their use as allogeneic tumor cell vaccines for HLA-A2-matched patients with metastatic RCC.
EGFR Mutation Status in Japanese Lung Cancer Patients: Genotyping Analysis Using LightCycler
Authors: Sasaki Hidefumi , Endo Katsuhiko , Konishi Akimitsu , Takada Minoru , Kawahara Masaaki , Iuchi Keiji , Matsumura Akihide , Okumura Meinoshin , Tanaka Hisaichi , Kawaguchi Tomoya , Shimizu Toshiki , Takeuchi Hiroshi , Yano Motoki , Fukai Ichiro , Fujii Yoshitaka 
Published: September 2005

Abstract
Purpose: Recently, somatic mutations of the epidermal growth factor receptor (EGFR) gene were found in ∼25% of Japanese lung cancer patients. These EGFR mutations are reported to be correlated with clinical response to gefitinib therapy. However, DNA sequencing using the PCR methods described to date is time-consuming and requires significant quantities of DNA; thus, this existing approach is not suitable for a routine pretherapeutic screening program.
Experimental Design: We have genotyped EGFR mutation status in Japanese lung cancer patients, including 102 surgically treated lung cancer cases from Nagoya City University Hospital and 16 gefitinib-treated lung cancer cases from Kinki-chuo Chest Medical Center. The presence or absence of three common EGFR mutations were analyzed by real-time quantitative PCR with mutation-specific sensor and anchor probes.
Results: In exon 21, EGFR mutations (CTG → CGG; L858R) were found from 8 of 102 patients from Nagoya and 1 of 16 from Kinki. We also detected the deletion mutations in exon 19 from 7 of 102 patients from Nagoya (all were deletion type 1a) and 4 of 16 patients from Kinki (one was type 1a and three were type 1b). In exon 18, one example of G719S mutation was found from both Nagoya and Kinki. The L858R mutation was significantly correlated with gender (women versus men, P &lt; 0.0001), Brinkman index (600 ≤ versus 600&gt;, P = 0.001), pathologic subtypes (adenocarcinoma versus nonadenocarcinoma, P = 0.007), and differentiation status of the lung cancers (well versus moderately or poorly, P = 0.0439), whereas the deletion mutants were not. EGFR gene status, including the type of EGFR somatic mutation, was correlated with sensitivity to gefitinib therapy. For example, some of our gefitinib-responsive patients had L858R or deletion type 1a mutations. On the other hand, one of our gefitinib-resistant patients had a G719S mutation.
Conclusions: Using the LightCycler PCR assay, the EGFR L858R mutation status might correlate with gender, pathologic subtypes, and gefitinib sensitivity of lung cancers. However, further genotyping studies are needed to confirm the mechanisms of EGFR mutations for the sensitivity or resistance of gefitinib therapy for the lung cancer.
An Orthotopic Model of Anaplastic Thyroid Carcinoma in Athymic Nude Mice
Authors: Kim Seungwon , Park Young-Wook , Schiff Bradley A. , Doan Dao D. , Yazici Yasemin , Jasser Samar A. , Younes Maher , Mandal Mahitosh , Bekele Benjamin N. , Myers Jeffrey N. 
Published: September 2005

Abstract
Purpose: To develop an orthotopic model of anaplastic thyroid carcinoma (ATC) in athymic nude mice.
Experimental Design: Various thyroid carcinoma cell lines were injected into the thyroid gland of athymic nude mice to determine whether such injection was technically feasible. ATC cells were then injected into the thyroid gland or the subcutis of nude mice at various concentrations, and the mice were then followed for tumor development. The tumors were examined histopathologically for local invasion or regional or distant metastasis.
Results: Injection of tumor cells into the thyroid glands of nude mice was technically feasible and resulted in the formation of thyroid tumors. The ATC cell line DRO showed significantly higher tumorigenicity in the thyroid gland than in the subcutis. In contrast, oral squamous cell carcinoma cell line TU167 shows no significantly higher tumorigenicity in the thyroid gland than in the subcutis. ATC tumors established in the thyroid gland also produced symptomatic compression of the esophagus and the trachea. Local invasion of the larynx and trachea was as well as high rates of pulmonary metastasis were also observed. Immunohistochemical staining showed higher microvessel density as well as higher expression of vascular endothelial growth factor and interleukin-8 in the orthotopic thyroid tumors than in ectopic tumors.
Conclusion: An orthotopic model of ATC in athymic nude mice was developed that closely recapitulates the clinical findings of human ATC. This model should facilitate the understanding of the pathogenesis of ATC and aid in the development of novel therapies against ATC.
Increased Expression of Insulin-Like Growth Factor I and/or Its Receptor in Gastrinomas Is Associated with Low Curability, Increased Growth, and Development of Metastases
Authors: Furukawa Masayuki , Raffeld Mark , Mateo Carmen , Sakamoto Akio , Moody Terry W. , Ito Tetsuhide , Venzon David J. , Serrano Jose , Jensen Robert T. 
Published: September 2005

Abstract
Purpose: Growth factors, particularly insulin-like growth factor I (IGF-I) and IGF-I receptor (IGF-IR) in some nonendocrine and a few endocrine tumors, are thought important in recurrence, growth, and aggressiveness. Whether this is true of neuroendocrine tumors such as gastrinomas is unclear. The aim of this study was to address this question in gastrinomas.
Experimental Design: IGF-I and IGF-IR expression in gastrinomas from 54 patients with Zollinger-Ellison syndrome were analyzed and correlated with clinical/tumor characteristics. IGF-I and IGF-IR mRNA levels were determined by competitive reverse transcription-PCR. IGF-IR expression, assessed by immunohistochemistry, was done on a subset.
Results: IGF-IR mRNA was found in 100% and IGF-I in 89%. IGF-I mRNA expression varied by &gt;254-fold, IGF-IR by 2,670-fold, and the levels correlated in a given tumor. The IGF-IR level was lower in gastrinomas of patients who were rendered disease free and increased levels correlated with tumor growth, aggressiveness, extent, and with liver metastases. Increased IGF-I levels correlated with increased growth, tumor extent, and aggressiveness. Neither IGF-IR nor IGF-I levels correlated with tumor location, size, or its clinical/functional features. The IGF-IR correlated with disease-free survival. IGF-IRβ was found in 31 of 32 tumors (97%) by immunohistochemistry.
Conclusions: These results indicate that IGF-I and IGF-IR are expressed in almost all gastrinomas. Furthermore, assessment of IGF-I/IGF-IR expression in gastrinomas may be clinically useful in identifying those patients with more aggressive tumors who might benefit from more aggressive treatment.
Chromosomal Radiosensitivity in Two Cell Lineages Derived from Clinically Radiosensitive Cancer Patients
Authors: Sprung Carl N. , Chao Michael , Leong Trevor , McKay Michael J. 
Published: September 2005

Abstract
Purpose: Despite its prominent contribution to cancer cure and palliation, around 1% to 5% of cancer patients suffer serious side effects from radiotherapy. A cardinal goal in the fields of radiobiology and oncology is to predict normal tissue radiosensitivity of a cancer patient before radiotherapy. Higher tumor control rates are likely if radiotherapy individualization could be achieved by applying predictive approaches.
Experimental Design: Here, we make use of the cytokinesis block micronucleus assay to assess radiosensitivity in cell lines derived from two different cell lineages obtained from clinically radiosensitive patients. We determined the micronucleus frequency after graded doses of ionizing radiation to primary fibroblasts and lymphoblast cell lines derived from 36 highly radiosensitive cancer patients.
Results: Many cell lines, following exposure to ionizing radiation, from patients with severe clinical reactions to radiotherapy showed statistically significantly higher frequencies of micronuclei than those from patients who had normal reactions to radiotherapy. One individual revealed significantly higher micronucleus frequencies in both cell lineages. Interestingly, lymphoblast cell lines from one patient showed micronucleus frequencies similar to ataxia telangiectasia mutated–deficient cells.
Conclusions: These results indicate that the micronucleus assay may have use for identifying predisposition to clinical radiosensitivity, at least in a subset of patients as a component of a pretreatment radiosensitivity assay for use in the clinic.
Growth Inhibition of Multiple Myeloma Cells by a Novel IκB Kinase Inhibitor
Authors: Sanda Takaomi , Iida Shinsuke , Ogura Hiroka , Asamitsu Kaori , Murata Toshiki , Bacon Kevin B. , Ueda Ryuzo , Okamoto Takashi 
Published: September 2005

Abstract
Involvement of nuclear factor-κB (NF-κB) in cell survival and proliferation of multiple myeloma has been well established. In this study we observed that NF-κB is constitutively activated in all human myeloma cell lines, thus confirming the previous studies. In addition, we found the phosphorylation of p65 subunit of NF-κB in addition to the phosphorylation of IκBα and the activation of NF-κB DNA binding and that various target genes of NF-κB including bcl-xL, XIAP, c-IAP1, cyclin D1, and IL-6 are up-regulated. We then examined the effect of a novel IκB kinase inhibitor, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile (ACHP). When myeloma cells were treated with ACHP, the cell growth was efficiently inhibited with IC50 values ranging from 18 to 35 μmol/L concomitantly with inhibition of the phosphorylation of IκBα/p65 and NF-κB DNA-binding, down-regulation of the NF-κB target genes, and induction of apoptosis. In addition, we observed the treatment of ACHP augmented the cytotoxic effects of vincristine and melphalan (l-phenylalanine mustard), conventional antimyeloma drugs. These findings indicate that IκB kinase inhibitors such as ACHP can sensitize myeloma cells to the cytotoxic effects of chemotherapeutic agents by blocking the antiapoptotic nature of myeloma cells endowed by the constitutive activation of NF-κB.
Phase I and Pharmacokinetic Study of the Dolastatin 10 Analogue TZT-1027, Given on Days 1 and 8 of a 3-Week Cycle in Patients with Advanced Solid Tumors
Authors: de Jonge Maja J.A. , van der Gaast Ate , Planting André S.T. , van Doorn Leny , Lems Aletta , Boot Inge , Wanders Jantien , Satomi Masahiko , Verweij Jaap 
Published: September 2005

AbstractPurpose: TZT-1027 {N2-(N,N-dimethyl-l-valyl)-N-[(1S,2R)-2-methoxy-4-[(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-[(2-phenylethyl)]amino]propyl]-1-pyrrolidinyl]-1-[(S)-1-methylpropyl]-4-oxobutyl]-N-methyl-l-valinamide} is a cytotoxic dolastatin 10 derivative inhibiting microtubule assembly through the binding to tubulins. The objectives of this phase I study was to assess the dose-limiting toxicities (DLT), to determine the maximum tolerated dose, and to study the pharmacokinetics of TZT-1027 when given i.v. over 60 minutes on days 1 and 8 every 3 weeks to patients with advanced solid tumors.Experimental Design: Patients were treated with escalating doses of TZT-1027 at doses ranging from 1.35 to 2.7 mg/m2. For pharmacokinetic analysis, plasma sampling was done during the first and second course and assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection.Results: Seventeen patients received a total of &gt;70 courses. The stopping dose was reached at 2.7 mg/m2, with neutropenia and infusion arm pain as DLT. Neutropenia was not complicated by fever. Over all dose levels, eight patients experienced pain in the infusion arm 1 to 2 days after administration of the drug, which seemed ameliorated by adding additional flushing after drug administration. Other side effects included nausea, vomiting, diarrhea, and fatigue. One partial response lasting &gt;54 weeks was observed in an extensively pretreated patient with metastatic liposarcoma. The pharmacokinetics of TZT-1027 suggested linearity over the dose ranges. No correlation between body surface area and absolute CL of TZT-1027 was established, vindicating that a flat dosing regimen might be used in the future. A correlation was observed between the percentage decrease in neutrophil count and the AUC of TZT-1027.Conclusions: In this study, the DLT of TZT-1027 was neutropenia and infusion arm pain. The recommended dose for phase II studies of TZT-1027 is 2.4 mg/m2 given i.v. over 60 minutes, on days 1 and 8 every 21 days. Phase II studies have recently started.