bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD26 Expression Correlates with a Reduced Sensitivity to 2′-Deoxycoformycin-Induced Growth Inhibition and Apoptosis in T-Cell Leukemia/Lymphomas
Authors: Aldinucci Donatella , Poletto Dalisa , Lorenzon Debora , Nanni Paola , Degan Massimo , Olivo Karin , Rapanà Barbara , Pinto Antonio , Gattei Valter 
Published: September 2005

AbstractPurpose and Experimental Design: dCF (2′-deoxycoformycin) is a potent inhibitor of ADA (adenosine deaminase), an enzyme regulating intra- and extracellular concentrations of purine metabolites. ADA exists as cytosolic and extracellular forms, the latter colocalized on the cell surface with CD26. Once the surface expression of CD26 and ADA in a panel of cell lines and primary samples of T-cell leukemia/lymphoma was defined, we correlated this expression with the antiproliferative and apoptotic effect of dCF.Results: Surface expression of CD26 inversely correlated with the capability of dCF to inhibit cell growth and induce apoptosis both in T-cell lines and primary samples of T-cell malignancies. This conclusion was sustained by a decreased sensitivity to dCF-mediated proapoptotic and/or antiproliferative in vitro effects of: (a) leukemia/lymphoma T-cell lines expressing surface CD26/ADA complex; (b) primary CD26+ T cell malignancies; and (c) normal T cells (CD26+) as compared with tumor T cells (CD26−) in unpurified samples from three cases of T-cell receptor γδ+ T-cell malignancies characterized by a mixture of normal and neoplastic cells. This latter point was confirmed in vivo, in a patient affected by CD26− T-cell receptor γδ+ hepatosplenic γδ+ T-cell lymphomas treated on a compassionate basis with dCF. The inverse correlation between CD26 expression and sensitivity to dCF was also demonstrated in a lymphoblastic lymphoma case in which CD26 was expressed on circulating blasts at relapse but not at diagnosis, as well as in two H9 T-cell clones expressing or not expressing CD26 mRNA and protein.Conclusions: This study corroborates the notion of CD26 as a marker of poor prognosis for T-cell malignancies and delineates a role for CD26 as a predictor of poor response to dCF.
Expression of Transforming Growth Factor β Isoforms and Their Receptors in Malignant Fibrous Histiocytoma of Soft Tissues
Authors: Yamamoto Tetsuji , Akisue Toshihiro , Marui Takashi , Fujita Ikuo , Matsumoto Keiji , Hitora Toshiaki , Kawamoto Teruya , Nagira Keiko , Nakatani Tetsuya , Kurosaka Masahiro 
Published: September 2005

Abstract
Purpose: Transforming growth factor β (TGF-β) is a multifunctional growth factor that variably affects proliferation, differentiation, and extracellular matrix formation. Little information is currently available on the TGF-β expression in malignant fibrous histiocytoma (MFH). The aims of the present study were to investigate the expression of TGF-β isoforms and their receptors in human MFH specimens.
Experimental Design: The expression of TGF isoforms, and TGF-β receptors (TGF-βR1 and -βR2) were immunohistochemically evaluated in 43 paraffin-embedded MFH specimens. Furthermore, the correlation of the TGF-β and receptor expression with tumor proliferative activity assessed by MIB-1 indices was analyzed.
Results: Positive immunoreactivity for TGF-β1, -β2, and -β3 was identified in tumor cells of 42, 40, and 38 of the 43 MFHs, respectively. In each TGF-β isoform immunostaining, the specimens were divided into two groups based on the number of positive tumor cells: those with low (&lt;25%) and those with high (≧25%) immunoreactivity. There were no statistically significant differences in the MIB-1 indices between the two groups. Positive immunoreactivity for TGF-βR1 and -βR2 was identified in tumor cells of 36 and 24 of the MFHs, respectively. The specimens were divided into two groups based on their receptor expression patterns: those with both TGF-βR1- and -βR2-positive immunoreactivity (n = 23), and those with both or either TGF-βR1- and -βR2-negative immunoreactivity (n = 20). The MIB-1 indices in the both-TGF-βR1- and -βR2-positive group were significantly higher than those in the other group (P = 0.0102). There was no significant difference in pulmonary metastasis ratios between the two groups.
Conclusions: These findings strongly suggest an association of the TGF-β ligand/receptor system with a significantly higher MIB-1 index in human MFHs. Investigation of the TGF-βR1 and -βR2 coexpression might be useful in predicting tumor behavior of MFHs.
Pharmacogenomic Analysis of Cytogenetic Response in Chronic Myeloid Leukemia Patients Treated with Imatinib
Authors: McLean Lee Anne , Gathmann Insa , Capdeville Renaud , Polymeropoulos Mihael H. , Dressman Marlene 
Published: September 2005

Abstract
Purpose: To better understand the molecular basis of cytogenetic response in chronic myeloid leukemia patients treated with imatinib, we studied gene expression profiles from a total of 100 patients from a large, multinational Phase III clinical trial (International Randomized Study of IFN-α versus STI571).
Experimental Design: Gene expression data for &gt;12,000 genes were generated from whole blood samples collected at baseline (before imatinib treatment) using Affymetrix oligonucleotide microarrays. Cytogenetic response was determined based on the percentage of Ph+ cells from bone marrow following a median of 13 months of treatment.
Results: A genomic profile of response was developed using a subset of individuals that exhibited the greatest divergence in cytogenetic response; those with complete response (0% Ph+ cells; n = 53) and those with minimal or no response (&gt;65% Ph+ cells; n = 13). A total of 55 genes was identified that were differentially expressed between these two groups. Using a “leave-one-out” strategy, we identified the optimum 31 genes from this list to use as our genomic profile of response. Using this genomic profile, we were able to distinguish between individuals that achieved major cytogenetic response (0–35% Ph+ cells) and those that did not, with a sensitivity of 93.4% (71 of 76 patients), specificity of 58.3% (14 of 24 patients), positive predictive value of 87.7%, and negative predictive value of 73.7%.
Conclusions: Interestingly, many of the genes identified appear to be strongly related to reported mechanisms of BCR-ABL transformation and warrant additional research as potential drug targets. The validity and clinical implications of these results should be explored in future studies.
Chemosensitization of Androgen-Independent Prostate Cancer with Neutral Endopeptidase
Authors: Sumitomo Makoto , Asano Tomohiko , Asakuma Junichi , Asano Takako , Nanus David M. , Hayakawa Masamichi 
Published: September 2005

Abstract
Purpose: We investigated whether neutral endopeptidase (NEP) could augment chemosensitivity to anticancer drugs by promoting protein kinase C (PKC)δ-mediated mitochondrial apoptosis in prostate cancer (PC) cells.
Experimental Design: Human PC cell lines LNCaP and PC-3, and a normal prostate epithelial cell line (PrEC) were used. The protein expression was detected by Western blot analysis, and the protein turnover was determined by pulse-chase assay. Apoptotic ratio was measured by annexin V staining.
Results: Western blot analyses and pulse-chase assays showed that the specific NEP inhibitor CGS24592 decreased PKCδ protein expression by promoting PKCδ protein degradation in NEP-expressing LNCaP cells. Conversely, recombinant NEP (rNEP) increased PKCδ protein expression by delaying PKCδ protein degradation in NEP-negative PC-3 cells. Apoptosis assays showed that rNEP promoted anticancer drug-induced apoptosis in PC-3 cells specifically through PKCδ activity that mediated anticancer drug-induced mitochondrial change such as cytochrome-c release and caspase-9 activation. Of note, rNEP was able to increase PKCδ protein expression predominantly in PC-3 cells rather than in PrEC cells. Treatment with rNEP before subtoxic concentrations of etoposide (0.1 μm) significantly promoted mitochondrial apoptosis compared with only etoposide in PC-3 cells (P &lt; 0.01) but not in PrEC cells.
Conclusions: These results suggest that NEP enzyme activity contributes to anticancer drug-induced PC cell apoptosis dependent on PKCδ-mediated mitochondrial events. More importantly, the combination of NEP with anticancer drugs may be a promising therapeutic modality because rNEP is able to augment chemosensitivity in androgen-independent PC with minimal toxicity in normal tissues.
DNA Methylation in Serum and Tumors of Cervical Cancer Patients
Authors: Widschwendter Andreas , Müller Hannes M. , Fiegl Heidi , Ivarsson Lennart , Wiedemair Annemarie , Müller-Holzner Elisabeth , Goebel Georg , Marth Christian , Widschwendter Martin 
Published: September 2005

Abstract
Purpose: Promoter hypermethylation has been recognized to play an important role in carcinogenesis. Numerous studies have demonstrated tumor-specific alterations, such as aberrant promoter hypermethylation, in DNA recovered from plasma or serum of patients with various malignancies. The aim of this study was to investigate the methylation status of various genes in cervical cancer patients and their association with clinicopathological characteristics and outcome of the disease.
Experimental Design: The methylation status of CALCA, hTERT, MYOD1, PGR (progesterone receptor), and TIMP3 was investigated in serum samples from 93 cervical cancer patients and 19 corresponding tissue samples using the MethyLight technique.
Results: Aberrant promoter hypermethylation was detected in any of these genes in 87% (81 of 93) of the serum samples studied. Methylation of MYOD1 was detected more frequently in advanced stage. All of the genes found to be methylated in serum samples were also methylated in the corresponding tissue sample, except in one patient. Patients with unmethylated MYOD1 serum DNA had significantly better disease-free (P = 0.04) and overall survival (P = 0.02) in comparison with patients with methylated MYOD1.
Conclusions: To the best of our knowledge, this is, thus far, the largest study investigating aberrant promoter hypermethylation in serum samples from cancer patients and the first study investigating methylation patterns in sera of cervical cancer patients. Our results suggest that serological detection of MYOD1 promoter hypermethylation may be of potential use as a prognostic marker for discriminating cervical cancer patients at high risk for lymph node metastasis or relapse. Additional studies, including a panel of additional genes, are necessary to elucidate the role of aberrant methylation in serum as a tool for surveillance of cervical cancer.
In Vivo
Assessment of Antiangiogenic Activity of SU6668 in an Experimental Colon Carcinoma Model
Authors: Marzola Pasquina , Degrassi Anna , Calderan Laura , Farace Paolo , Crescimanno Caterina , Nicolato Elena , Giusti Anna , Pesenti Enrico , Terron Andrea , Sbarbati Andrea , Abrams Tinya , Murray Lesley , Osculati Francesco 
Published: September 2005

Abstract
Purpose: The purpose of this research was to assess in vivo by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) the antiangiogenic effect of SU6668, an oral, small molecule inhibitor of the angiogenic receptor tyrosine kinases vascular endothelial growth factor receptor 2 (Flk-1/KDR), platelet-derived growth factor receptor, and fibroblast growth factor receptor 1.
Experimental Design: A s.c. tumor model of HT29 human colon carcinoma in athymic mice was used. DCE-MRI with a macromolecular contrast agent was used to measure transendothelial permeability and fractional plasma volume, accepted surrogate markers of tumor angiogenesis. CD31 immunohistochemical staining was used for assessing microvessels density and vessels area. Experiments were performed after 24 h, and 3, 7, and 14 days of treatment.
Results: DCE-MRI clearly detected the early effect (after 24 h of treatment) of SU6668 on tumor vasculature as a 51% and 26% decrease in the average vessel permeability measured in the tumor rim and core (respectively). A substantial decrease was also observed in average fractional plasma volume in the rim (59%) and core (35%) of the tumor. Histological results confirmed magnetic resonance imaging findings. After 3, 7, and 14 days of treatment, postcontrast magnetic resonant images presented a thin strip of strongly enhanced tissue at the tumor periphery; histology examination showed that this hyperenhanced ring corresponded to strongly vascularized tissue adjacent but external to the tumor. Histology also revealed a strong decrease in the thickness of peripheral viable tissue, with a greatly reduced vessel count. SU6668 greatly inhibited tumor growth, with 60% inhibition at 14 days of treatment.
Conclusions: DCE-MRI detected in vivo the antiangiogenic efficacy of SU6668.
VX-710 (Biricodar) Increases Drug Retention and Enhances Chemosensitivity in Resistant Cells Overexpressing P-Glycoprotein, Multidrug Resistance Protein, and Breast Cancer Resistance Protein
Authors: Minderman Hans , O’Loughlin Kieran L. , Pendyala Lakshmi , Baer Maria R. 
Published: September 2005

Abstract
Purpose: The pipecolinate derivative VX-710 (biricodar; Incel) is a clinically applicable modulator of P-glycoprotein (Pgp) and multidrug resistance protein (MRP-1); we studied its activity against the third multidrug resistance (MDR)-associated drug efflux protein, breast cancer resistance protein (BCRP).
Experimental Design: VX-710 modulation of uptake, retention, and cytotoxicity of mitoxantrone, daunorubicin, doxorubicin, topotecan, and SN38 was studied in cell lines overexpressing Pgp, MRP-1 and wild-type (BCRPR482) and mutant (BCRPR482T) BCRP.
Results: In 8226/Dox6 cells (Pgp), VX-710 increased mitoxantrone and daunorubicin uptake by 55 and 100%, respectively, increased their retention by 100 and 60%, respectively, and increased their cytotoxicity 3.1- and 6.9-fold, respectively. In HL60/Adr cells (MRP-1), VX-710 increased mitoxantrone and daunorubicin uptake by 43 and 130%, increased their retention by 90 and 60%, and increased their cytotoxicity 2.4- and 3.3-fold. In 8226/MR20 cells (BCRPR482), VX-710 increased mitoxantrone uptake and retention by 60 and 40%, respectively, and increased cytotoxicity 2.4-fold. VX-710 increased daunorubicin uptake and retention by only 10% in 8226/MR20 cells, consistent with the fact that daunorubicin is not a substrate for BCRPR482, but, nevertheless, it increased daunorubicin cytotoxicity 3.6-fold, and this increase was not associated with intracellular drug redistribution. VX-710 had little effect on uptake, retention, or cytotoxicity of mitoxantrone, daunorubicin, doxorubicin, topotecan, or SN38 in MCF7 AdVP3000 cells (BCRPR482T).
Conclusions: VX-710 modulates Pgp, MRP-1, and BCRPR482, and has potential as a clinical broad-spectrum MDR modulator in malignancies such as the acute leukemias in which these proteins are expressed.
Epigenetic Inactivation of
TMS1/ASC
in Ovarian Cancer
Authors: Terasawa Katsuhiko , Sagae Satoru , Toyota Minoru , Tsukada Kuniko , Ogi Kazuhiro , Satoh Ayumi , Mita Hiroaki , Imai Kohzoh , Tokino Takashi , Kudo Ryuichi 
Published: September 2005

Abstract
Purpose: The purpose of this work was to explore the role of epigenetic inactivation of apoptotic pathways in ovarian cancer by examining the DNA methylation and expression status of four proapoptotic genes in primary ovarian cancers and cancer cell lines and to correlate those findings with the clinicopathological features of ovarian cancer patients.
Experimental Design: Genomic DNA was isolated from 15 ovarian cancer cell lines, 80 primary ovarian cancer specimens, and 4 normal ovary specimens using phenol-chloroform extraction. The methylation status of the DNA was evaluated using combined bisulfite restriction analysis, gene expression was evaluated using reverse transcription-PCR, and histone acetylation was evaluated using chromatin immunoprecipitation.
Results: Of the four proapoptotic genes studied, expression of TMS1/ASC was absent in six ovarian cancer cell lines. Dense methylation of the 5′ region of TMS1/ASC was detected in cells not expressing TMS1/ASC. Treating methylated cells with 5-aza-deoxycytidine restored gene expression, confirming the role of methylation in silencing the gene. Chromatin immunoprecipitation revealed histone to be deacetylated in cells not expressing TMS1/ASC, indicating that histone deacetylation is also involved in silencing TMS1/ASC. Aberrant methylation of TMS1/ASC was detected in 15 of 80 ovarian cancer tissues (19%) but in none of the normal ovary specimens. Aberrant methylation of TMS1/ASC was observed significantly more often in clear cell-type ovarian cancers than in other tumor types (P &lt; 0.0001).
Conclusions: Methylation-mediated silencing of TMS1/ASC confers a survival advantage to tumor cells by enabling them to escape apoptosis. The role for aberrant methylation in human ovarian tumorigenesis may be particularly important for ovarian cancers with the clear cell phenotype.
Phase I Clinical Trial of the Farnesyltransferase Inhibitor BMS-214662 Given as a 1-Hour Intravenous Infusion in Patients with Advanced Solid Tumors
Authors: Ryan David P. , Eder Joseph P. , Puchlaski Thomas , Seiden Michael V. , Lynch Thomas J. , Fuchs Charles S. , Amrein Philip C. , Sonnichsen Darrell , Supko Jeffrey G. , Clark Jeffrey W. 
Published: September 2005

Abstract
Purpose: BMS-214662 is a nonsedating benzodiazepine derivative that exhibits broad spectrum cytotoxicity against human solid tumor cell lines and potently inhibits farnesylation of the H-ras and K-ras oncogenic proteins. This report describes the initial Phase I clinical trial of the compound. The main objective of the study was to determine the dose-limiting toxicities and the maximum tolerated dose of BMS-214662 when administered as a single dose i.v. over 1 h every 21 days to patients with advanced solid tumors.
Experimental Design: Patients with advanced solid tumors and adequate organ function were eligible for the study. The dose was escalated according to a modified Fibonacci schedule after evaluating groups of at least three patients for toxicity during the first cycle of therapy at each dose level. Pharmacokinetic and pharmacodynamic studies were performed after administration of the two initial doses.
Results: The dose of BMS-214662 was escalated from 36 to 225 mg/m2 through 5 intermediate dose levels in a total of 44 patients. Dose-limiting toxicities occurred in 3 of the 13 (23%) patients during the first cycle of treatment with 225 mg/m2, consisting of grade 3 nausea/vomiting in 2 patients and grade 3 diarrhea in another patient. In addition, four of these patients experienced reversible grade 3 transaminitis, which was not considered to be dose-limiting. At the recommended dose for Phase II studies, 200 mg/m2, the most common side effects were reversible transaminitis, nausea, and vomiting. Although there were no objective responses, one patient with pancreatic cancer continues to receive treatment more than 3.5 years after entering the study. BMS-214662 exhibited linear pharmacokinetics and had a mean biological half-life of 1.55 ± 0.27 h and a total body clearance of 21.8 ± 10.8 liters/h/m2, with a low apparent volume of distribution at steady state (31.5 ± 12.9 liters/m2). In patients treated with the recommended Phase II dose, the mean maximum plasma concentration of the drug was 6.57 ± 2.94 μg/ml, and farnesyltransferase activity in peripheral blood mononuclear cells decreased to a nadir of 10.5 ± 6.4% of baseline at the end of the infusion but fully recovered within 24 h.
Conclusions: BMS-214662 can be delivered safely as a single 1-h i.v. infusion at a dose that results in pronounced inhibition of farnesyltransferase activity in peripheral blood mononuclear cells. However, the duration of enzyme inhibition was transient, recovering in parallel with the decline in plasma concentrations of this rapidly eliminated drug. Because indications of anticancer activity were observed in several patients, further optimization of the administration schedule for this promising new compound is warranted.
Phase I and Pharmacokinetic Study of Prinomastat, a Matrix Metalloprotease Inhibitor
Authors: Hande Kenneth R. , Collier Mary , Paradiso Linda , Stuart-Smith Jill , Dixon Mary , Clendeninn Neil , Yeun Geoff , Alberti Donna , Binger Kim , Wilding George 
Published: September 2005

Abstract
Purpose: Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these MMPs has been postulated to block tumor invasion and metastasis. This Phase I, dose-escalation study was designed to evaluate the acute and chronic toxicities of various doses of prinomastat and to determine prinomastat pharmacokinetics.
Experimental Design: Seventy-five patients with advanced cancer were given 1, 2, 5, 10, 25, 50, or 100 mg prinomastat orally twice daily until tumor progression or development of significant toxicities. Prinomastat pharmacokinetics were measured on day 29 of therapy.
Results: The primary toxicities identified were joint and muscle-related pain, which were generally reversible with treatment rest and/or dose reduction. No dose-limiting toxicities were noted within the first 4 weeks of treatment, but grade 2–3 arthralgias and myalgias were noted 2–3 months after initiation of therapy in &gt;25% of patients at doses &gt;25 mg twice a day. The frequency and severity of symptoms were dose related. Plasma prinomastat concentrations greater than the Ki for MMPs 2 and 9 were achieved at all of the dose levels.
Conclusions: Doses of 5–10 mg bid were recommended for additional trials, because this dose range was well tolerated for a treatment duration of at least 3 months and achieves trough plasma concentrations 10–100-fold greater than the Ki (in vitro inhibition constant) for the targeted MMPs (2 and 9).