bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intermittent Exposure of Primitive Quiescent Chronic Myeloid Leukemia Cells to Granulocyte-Colony Stimulating Factor In vitro Promotes their Elimination by Imatinib Mesylate
Authors: Jørgensen Heather G. , Copland Mhairi , Allan Elaine K. , Jiang Xiaoyan , Eaves Allen , Eaves Connie , Holyoake Tessa L. 
Published: March 2006

Abstract
Purpose: Primitive quiescent chronic myeloid leukemia (CML) cells are biologically resistant to imatinib mesylate, an inhibitor of the p210BCR-ABL kinase. The present study was designed to investigate whether either continuous or intermittent exposure of these cells to granulocyte-colony stimulating factor (G-CSF) in vitro can overcome this limitation to the effectiveness of imatinib mesylate therapy.
Experimental Design: CD34+ leukemic cells were isolated from six newly diagnosed chronic phase CML patients and cultured for 12 days in serum-free medium with or without G-CSF and/or imatinib mesylate present either continuously or intermittently (three cycles of G-CSF for 0, 1, or 4 days ± imatinib mesylate for 0, 3, or 4 days). Every 4 days, the number of residual undivided viable cells and the total number of viable cells present were measured.
Results: Intermittent but not continuous exposure to G-CSF significantly accelerated the disappearance in vitro of initially quiescent CD34+ CML cells. This resulted in 3- and 5-fold fewer of these cells remaining after 8 and 12 days, respectively, relative to continuous imatinib mesylate alone (P &lt; 0.04). Cultures containing imatinib mesylate and intermittently added G-CSF also showed the greatest reduction in the total number of cells present after 12 days (5-fold more than imatinib mesylate alone).
Conclusion: Intermittent exposure to G-CSF can enhance the effect of imatinib mesylate on CML cells by specifically targeting the primitive quiescent leukemic elements. A protocol for treating chronic-phase CML patients with imatinib mesylate that incorporates intermittent G-CSF exposure may offer a novel strategy for obtaining improved responses in vivo.
Clinicopathologic Significance of the Mutations of theEpidermal Growth Factor ReceptorGene in Patients with Non–Small Cell Lung Cancer
Authors: Tomizawa Yoshio , Iijima Hironobu , Sunaga Noriaki , Sato Koji , Takise Atsushi , Otani Yoshimi , Tanaka Shigefumi , Suga Tatsuo , Saito Ryusei , Ishizuka Tamotsu , Dobashi Kunio , Minna John D. , Nakajima Takashi , Mori Masatomo 
Published: March 2006

AbstractPurpose: It has been reported that the mutations of epidermal growth factor receptor (EGFR) are detected in lung cancers. Studies of EGFR mutations in large numbers of patients' tumors with clinical data including response to EGFR tyrosine kinase directed therapy are needed to develop a robust database for clinical use. The purpose of the present study is to gain further insights into the significance of EGFR mutation in non–small cell lung cancer (NSCLC).Experimental Design: We investigated the clinicopathologic significance of tyrosine kinase domain (exons 18-21) EGFR mutations in 120 patients with primary NSCLC and the correlation between EGFR mutation and sensitivity to gefitinib in an additional 20 NSCLC patients treated with gefitinib. In addition, onocogenic KRAS mutations and RASSF1A promoter methylation were determined in the same samples.Results: EGFR mutation was detected in 29 of 120 (24%) tumors. All of the 29 (40%) mutations occurred in 72 adenocarcinomas. EGFR mutation was significantly more frequent in females (47%) than males (12%, P &lt; 0.0001), in younger patients (38%) than older patients (10%, P = 0.0005), in nonsmokers (47%) than smokers (13%, P &lt; 0.0001), and in well-differentiated tumors (39%) than moderately and poorly differentiated tumors (7%, P &lt; 0.0001). Mutation of the EGFR gene was preferentially observed in advanced disease. Furthermore, EGFR mutations were detected in 11 of 14 (79%) responders, whereas none of six (0%) nonresponders had the mutation (P = 0.0022).Conclusions: These results in Japanese (East Asian) patients indicated that EGFR mutation plays an important role in pathogenesis of lung adenocarcinoma.
Ghrelin and a Novel Preproghrelin Isoform Are Highly Expressed in Prostate Cancer and Ghrelin Activates Mitogen-Activated Protein Kinase in Prostate Cancer
Authors: Yeh Anthony H. , Jeffery Penelope L. , Duncan Russell P. , Herington Adrian C. , Chopin Lisa K. 
Published: March 2006

Abstract
Purpose: There is evidence that the hormone ghrelin stimulates proliferation in the PC3 prostate cancer cell line although the underlying mechanism(s) remain to be determined. A novel, exon 3–deleted preproghrelin isoform has previously been detected in breast and prostate cancer cells; however, its characterization, expression, and potential function in prostate cancer tissues are unknown.
Experimental Design: Expression of ghrelin and exon 3–deleted preproghrelin was investigated in prostate cancer cell lines and tissues by reverse transcription-PCR and immunohistochemistry. Proliferation and apoptosis assays were done in the LNCaP prostate cancer cell line to determine if ghrelin stimulates proliferation and/or cell survival. Stimulation of mitogen-activated protein kinase (MAPK) pathway activation by ghrelin was determined in PC3 and LNCaP cells by immunoblotting with antibodies specific for phosphorylated MAPKs.
Results: Prostate cancer tissues display greater immunoreactivity for ghrelin and exon 3–deleted preproghrelin than normal prostate tissues, and prostate cancer cell lines secrete mature ghrelin into conditioned medium. Treatment with ghrelin (10 nmol/L), but not the unique COOH-terminal peptide derived from exon 3–deleted preproghrelin, stimulates proliferation in the LNCaP cells (45.0 ± 1.7% above control, P &lt; 0.01) and rapidly activates the extracellular signal-regulated kinase-1/2 MAPK pathway in both PC3 and LNCaP cell lines. Ghrelin, however, does not protect prostate cancer cells from apoptosis induced by actinomycin D (1 μg/mL). The MAPK inhibitors PD98059 and U0126 blocked ghrelin-induced MAPK activation, as well as proliferation, in both cell lines.
Conclusions: These data suggest that these components of the ghrelin axis may have potential as novel biomarkers and/or adjunctive therapeutic targets for prostate cancer.
FTY720: A Promising Agent for Treatment of Metastatic Hepatocellular Carcinoma
Authors: Lee Terence K. , Man Kwan , Ho Joanna W. , Wang Xiang Hong , Poon Ronnie T.P. , Xu Yang , Ng Kevin T. , Chu Alan C. , Sun Chris K. , Ng Irene O. , Sun Hui Chuan , Tang Zao You , Xu Ray , Fan Sheung Tat 
Published: March 2006

Abstract
Purpose: Recurrence after resection and metastasis are common in hepatocellular carcinoma and are associated with poor prognosis. Therefore, effective treatment is urgently needed for improvement of patients' survival. Previously, we reported that FTY720 has an antimetastatic effect on hepatocellular carcinoma cell line through down-regulation of Rac signaling pathway. This study aims to investigate the in vivo antimetastatic potential of FTY720 in an orthotopic nude mice model using metastatic human hepatocellular carcinoma cell lines MHCC-97L (lower metastatic potential) and MHCC-97H (higher metastatic potential).
Experimental Design: The nude mice bearing liver tumors were randomized into a treatment group and a control group, each with 12 mice. FTY720 was administered at a dosage of 5 or 10 mg/kg via i.p. injection after 7 days of tumor inoculation. Thirty-five days later, the mice were sacrificed for record of intrahepatic and pulmonary metastases.
Results: After 35 days of FTY720 treatment at the dosages of 5 and 10 mg/kg, all 12 mice in the treatment group were alive and well. FTY720 at the dosages of 5 and 10 mg/kg significantly suppressed the tumor volume and intrahepatic and pulmonary metastases in the metastatic nude mice model. FTY720 suppressed intrahepatic and pulmonary metastases by inhibition of Rac expression, which at least in part down-regulated the vascular endothelial growth factor expression and CD34 staining in a dose-dependent manner.
Conclusion: FTY720 is a promising novel therapeutic drug for treatment of hepatocellular carcinoma metastasis.
Stable Suppression of Tumorigenicity by Pin1-Targeted RNA Interference in Prostate Cancer
Authors: Ryo Akihide , Uemura Hiroji , Ishiguro Hitoshi , Saitoh Tatsuya , Yamaguchi Akira , Perrem Kilian , Kubota Yoshinobu , Lu Kun Ping , Aoki Ichiro 
Published: March 2006

Abstract
Purpose: The peptidyl-prolyl isomrase Pin1 plays a catalytic role in oncogenesis in solid cancers, including prostate cancer. In the present study, we sought to determine the potential of Pin1-targeted gene silencing in inhibiting cellular growth and tumorigenicity in prostate cancer.
Experimental Design: A retrovirus-mediated RNA interference targeting Pin1 was expressed in PC3 and LNCaP cells, and cell growth and several transformed properties were investigated.
Results: The stable expression of Pin1-specific small interfering RNA constructs in PC3 and LNCaP cells significantly reduced cellular proliferation, colony formation, migration, and invasion but strongly enhanced the apoptotic response induced by serum depletion or treatment with anticancer agents. Furthermore, Pin1 depletion significantly suppressed tumorigenic potential in athymic mice, resulting in the inhibition of both tumor growth and angiogeneisis.
Conclusions: These results strongly suggest that Pin1 plays an important role not only in tumorigenesis but also in the maintenance of the transformed phenotype in prostate cancer cells. Hence, Pin1 may serve as a promising therapeutic target, particularly for recurrent prostate tumors.
Pharmacokinetic-Pharmacodynamic Relationships for the Heat Shock Protein 90 Molecular Chaperone Inhibitor 17-Allylamino, 17-Demethoxygeldanamycin in Human Ovarian Cancer Xenograft Models
Authors: Banerji Udai , Walton Michael , Raynaud Florence , Grimshaw Rachel , Kelland Lloyd , Valenti Melani , Judson Ian , Workman Paul 
Published: March 2006

Abstract
Purpose: To establish the pharmacokinetic and pharmacodynamic profile of the heat shock protein 90 (HSP90) inhibitor 17-allylamino, 17-demethoxygeldanamycin (17-AAG) in ovarian cancer xenograft models.
Experimental Design: The effects of 17-AAG on growth inhibition and the expression of pharmacodynamic biomarkers c-RAF-1, CDK4, and HSP70 were studied in human ovarian cancer cell lines A2780 and CH1. Corresponding experiments were conducted with established tumor xenografts. The variability and specificity of pharmacodynamic markers in human peripheral blood lymphocytes (PBL) were studied.
Results: The IC50 values of 17-AAG in A2780 and CH1 cells were 18.3 nmol/L (SD, 2.3) and 410.1 nmol/L (SD, 9.4), respectively. Pharmacodynamic changes indicative of HSP90 inhibition were demonstrable at greater than or equal the IC50 concentration in both cell lines. Xenograft experiments confirmed tumor growth inhibition in vivo. Peak concentrations of 17-AAG achieved in A2780 and CH1 tumors were 15.6 and 16.5 μmol/L, respectively, and there was no significant difference between day 1 and 11 pharmacokinetic profiles. Reversible changes in pharmacodynamic biomarkers were shown in tumor and murine PBLs in both xenograft models. Expression of pharmacodynamic markers varied between human PBLs from different human volunteers but not within the same individual. Pharmacodynamic biomarker changes consistent with HSP90 inhibition were shown in human PBLs exposed ex vivo to 17-AAG but not to selected cytotoxic drugs.
Conclusion: Pharmacokinetic-pharmacodynamic relationships were established for 17-AAG. This information formed the basis of a pharmacokinetic-pharmacodynamic-driven phase I trial.
Feasibility and Tolerability of Sequential Doxorubicin/Paclitaxel Followed by Cyclophosphamide, Methotrexate, and Fluorouracil and Its Effects on Tumor Response as Preoperative Therapy
Authors: Gianni Luca , Baselga José , Eiermann Wolfgang , Guillem Porta Vicente , Semiglazov Vladimir , Lluch Aña , Zambetti Milvia , Sabadell Dolores , Raab Günther , Llombart Cussac Antonio , Bozhok Alla , Martinez-Agulló Angel , Greco Marco , Byakhov Mikhail , Lopez Lopez Juan Josè , Mansutti Mauro , Valagussa Pinuccia , Bonadonna Gianni ,   European Cooperative Trial in Operable Breast Cancer Study Group
Published: March 2006

Abstract
Purpose: The European Cooperative Trial in Operable breast cancer (ECTO) randomly tested whether efficacy of adjuvant doxorubicin followed by i.v. cyclophosphamide, methotrexate, and fluorouracil (CMF; doxorubicin → CMF, arm A) could be improved by adding paclitaxel (doxorubicin/paclitaxel → CMF) as adjuvant (arm B) or primary systemic therapy (PST, arm C). We report here feasibility, tolerability, locoregional antitumor activity, and breast conservation rate.
Methods: A total of 1,355 women entered the study. Feasibility and safety were compared in arm A versus arms B plus C. Surgical findings were compared in arms A plus B versus arm C.
Results: Grade 3 or 4 National Cancer Institute toxicities were low (&lt;5%) in all arms. Neuropathy was more frequent in the paclitaxel-containing arms (grade 2, 20.5% versus 5.0%; grade 3, 1.3% versus 0.2%). At 31 months of follow-up, asymptomatic drop of left ventricular ejection fraction was similar in all arms, whereas symptomatic cardiotoxicity was recorded in three patients (0.5%) in A and in three patients (0.3%) in B plus C. PST induced clinical complete plus partial remission in 78%, with an in-breast pathologic complete response rate of 23% and an in-breast plus axilla pathologic complete response rate of 20%. In the multivariate analysis, only estrogen receptor (ER) status was significantly associated with pathologic complete response (odds ratio for ER negative, 5.77; 95% confidence interval, 3.49-9.52; P &lt; 0.0001). PTS induced a significant axillary downstaging (P &lt; 0.001), and breast sparing surgery was feasible in 65% versus 34% (P &lt; 0.001).
Conclusions: Doxorubicin/paclitaxel → CMF is feasible, safe, and well tolerated. Given as PST, it is markedly active, allowing for breast-sparing surgery in a large fraction of patients.
Serum Markers in Patients with Resectable Pancreatic Adenocarcinoma: Macrophage Inhibitory Cytokine 1 versus CA19-9
Authors: Koopmann Jens , Rosenzweig C. Nicole White , Zhang Zhen , Canto Marcia I. , Brown David A. , Hunter Mark , Yeo Charles , Chan Daniel W. , Breit Samuel N. , Goggins Michael 
Published: March 2006

Abstract
Purpose: More accurate serum markers of pancreatic cancer could improve the early detection and prognosis of this deadly disease. We compared the diagnostic utility of a panel of candidate serum markers of pancreatic cancer.
Experimental Design: We collected preoperative serum from 50 patients with resectable pancreatic adenocarcinoma, as well as sera from 50 patients with chronic pancreatitis and 50 age/sex-matched healthy controls from our institution. Sera were analyzed for the following candidate markers of pancreatic cancer: CA19-9, macrophage inhibitory cytokine 1 (MIC-1), osteopontin, tissue inhibitor of metalloproteinase 1, and hepatocarcinoma-intestine-pancreas protein levels.
Results: By logistic regression analysis, MIC-1 and CA19-9 were significant independent predictors of diagnosis. Receiver operating characteristic curve analysis showed that MIC-1 was significantly better than CA19-9 in differentiating patients with pancreatic cancer from healthy controls (area under the curve is 0.99 and 0.78, respectively; P = 0.003), but not in distinguishing pancreatic cancer from chronic pancreatitis (area under the curve of 0.81 and 0.74, respectively; P = 0.63). Hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein, osteopontin, and tissue inhibitor of metalloproteinase 1 serum levels did not provide additional diagnostic power.
Conclusion: In the differentiation of patients with resectable pancreatic cancer from controls, serum MIC-1 outperforms other markers including CA19-9.
Overexpression of Stefin A in Human Esophageal Squamous Cell Carcinoma Cells Inhibits Tumor Cell Growth, Angiogenesis, Invasion, and Metastasis
Authors: Li Wendong , Ding Fang , Zhang Liyong , Liu Zhongmin , Wu Yu , Luo Aiping , Wu Min , Wang Mingrong , Zhan Qimin , Liu Zhihua 
Published: March 2006

Abstract
Purpose: Evidence is accumulating that an inverse correlation exists between stefin A level and malignant progression. The aim of this study is to investigate the role of stefin A in human esophageal squamous cell carcinoma cells and to evaluate the possibility of stefin A for cancer therapy.
Experimental Design: We stably transfected stefin A cDNA into human EC9706 or KYSE150 esophageal squamous cell carcinoma cells. Subsequently, we evaluated the effect of stefin A overexpression on cell growth, cathepsin B activity, cell motility and invasion, tumor growth, and metastasis. Immunoanalysis was done to assess the expression of factor VIII and to support the localization of stefin A and cathepsin B. We also evaluated the effect of CA074Me, a selective membrane-permeant cathepsin B inhibitor.
Results: Both transfection of stefin A and treatment with 10 μmol/L CA074Me significantly reduced cathepsin B activity and inhibited the Matrigel invasion. Combination of both further reduced cathepsin B activity and inhibited the Matrigel invasion. Overexpression of stefin A delayed the in vitro and in vivo growth of cells and significantly inhibited lung metastasis compared with 50% of lung metastasis in xenograft mice from EC9706 or empty vector cells. Transfection with stefin A showed a dramatic reduction of factor VIII staining in the tumors of xenograft mice.
Conclusions: Our data strongly indicate that stefin A plays an important role in the growth, angiogenesis, invasion, and metastasis of human esophageal squamous cell carcinoma cells and suggest that stefin A may be useful in cancer therapy.
Carboxylesterase Isoform 2 mRNA Expression in Peripheral Blood Mononuclear Cells Is a Predictive Marker of the Irinotecan to SN38 Activation Step in Colorectal Cancer Patients
Authors: Cecchin Erika , Corona Giuseppe , Masier Sara , Biason Paola , Cattarossi Giulio , Frustaci Sergio , Buonadonna Angela , Colussi Annamaria , Toffoli Giuseppe 
Published: March 2006

AbstractPurpose: Irinotecan (CPT11) is a prodrug activated in humans mainly by carboxylesterase 2 (CES2) generating the SN38 metabolite responsible for the drug efficacy and toxicity. The interpatients variability in CPT11 activation step could cause unpredictable toxicity. To identify a predictive molecular marker for CPT11 activation in cancer patients, we investigated the CES2 mRNA expression in peripheral blood mononuclear cells (PBMC) and correlated it to CPT11 activation rate, toxic effects, and response.Experimental Design: Forty-five colorectal cancer patients were treated with a CPT11-including regimen (FOLFIRI). CES2 mRNA expression in PBMC was quantified by reverse transcription-PCR in real time. Plasma concentrations of CPT11, SN38, and SN38-glucuronide were determined by high-performance liquid chromatography and the pharmacokinetic variables calculated adopting the noncompartmental model. Toxicity was evaluated by the National Cancer Institute Common Toxicity Criteria scale and response by the WHO criteria.Results: A high interindividual variability in CES2 mRNA relative expression was observed (median, 1.45; range, 0.01-28.21). CES2 mRNA expression level was significantly associated with CPT11 activation ratio [(AUCSN38 + AUCSN38G)/AUCCPT11]. Patients with CES2 mRNA expression above the median cutoff value presented an activation ratio higher (median, 0.25; range, 0.15-0.42) than those with CES2 mRNA below the median (median, 0.20; range, 0.10-0.40; P = 0.013). This was associated with a nonsignificant trend of 1.34-fold increase of SN38 AUC in the group of patients with high CES2 mRNA expression (mean, 1.03 ± 0.62 versus 0.77 ± 0.32 μmol/L hour). Eight of 23 high CES2 mRNA–expressing patients (34.8%) developed grade 3 to 4 neutropenia or diarrhea compared with 2 of 22 (9.1%) in the low CES2-expressing group (P = 0.071).Conclusion: Our data support a predictive power of CES2 mRNA expression in PBMC for the activation rate of CPT11.
Combined Abl Inhibitor Therapy for Minimizing Drug Resistance in Chronic Myeloid Leukemia: Src/Abl Inhibitors Are Compatible with Imatinib
Authors: O'Hare Thomas , Walters Denise K. , Stoffregen Eric P. , Sherbenou Daniel W. , Heinrich Michael C. , Deininger Michael W.N. , Druker Brian J. 
Published: March 2006

Abstract
Purpose: Chronic myeloid leukemia (CML) is effectively treated with imatinib. However, reactivation of Bcr-Abl via kinase domain mutations that reduce sensitivity to imatinib can cause relapse. As combination therapy is frequently used to prevent emergence of resistance, the combination of imatinib with an inhibitor of imatinib-resistant Bcr-Abl mutants (e.g., Src/Abl inhibitors AP23848 and BMS-354825) was investigated.
Experimental Design: To test this approach, cellular proliferation and Bcr-Abl tyrosine phosphorylation assays were done on Ba/F3 cells expressing wild-type (WT) Bcr-Abl and four common imatinib-resistant mutants (Y253F, E255K, T315I, and M351T). Colony-forming assays with primary CML cells were also done.
Results: Both Src/Abl inhibitors retained full inhibitory capacity when coadministered with imatinib at concentrations above typical clinical levels. For cells expressing WT Bcr-Abl or the marginally imatinib-resistant mutant M351T, inclusion of imatinib at therapeutic levels enhanced the effects of the Src/Abl inhibitors. By comparison, for the highly imatinib-resistant mutants Y253F and E255K, inclusion of imatinib at clinical levels resulted in only a slight enhancement beyond the effects of the Src/Abl inhibitors. None of the inhibitors affected Bcr-Abl T315I cells. Colony-forming assays with primary CML cells yielded analogous results.
Conclusions: Our results indicate that Src/Abl inhibitors are compatible with imatinib and suggest that combined Abl inhibitor therapy is a feasible treatment strategy for patients with CML.