bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Pharmacokinetic-Pharmacodynamic Study of 17-(Allylamino)-17-Demethoxygeldanamycin (17AAG, NSC 330507), a Novel Inhibitor of Heat Shock Protein 90, in Patients with Refractory Advanced Cancers
Authors: Ramanathan Ramesh K. , Trump Donald L. , Eiseman Julie L. , Belani Chandra P. , Agarwala Sanjiv S. , Zuhowski Eleanor G. , Lan Jing , Potter Douglas M. , Ivy S. Percy , Ramalingam Sakkaraiappan , Brufsky Adam M. , Wong Michael K.K. , Tutchko Susan , Egorin Merrill J. 
Published: September 2005

Abstract
Purpose: 17-(Allylamino)-17-demethoxygeldanamycin (17AAG), a benzoquinone antibiotic, down-regulates oncoproteins by binding specifically to heat shock protein 90 (HSP90). We did a phase I study of 17AAG to establish the dose-limiting toxicity and maximum tolerated dose and to characterize 17AAG pharmacokinetics and pharmacodynamics.
Experimental Design: Escalating doses of 17AAG were given i.v. over 1 or 2 hours on a weekly × 3 schedule every 4 weeks to cohorts of three to six patients. Plasma pharmacokinetics of 17AAG and 17-(amino)-17-demethoxygeldanamycin (17AG) were assessed by high-performance liquid chromatography. Expression of HSP70 and HSP90 in peripheral blood mononuclear cells was measured by Western blot.
Results: Forty-five patients were enrolled to 11 dose levels between 10 and 395 mg/m2. The maximum tolerated dose was 295 mg/m2. Dose-limiting toxicity occurred in both patients (grade 3 pancreatitis and grade 3 fatigue) treated with 395 mg/m2. Common drug-related toxicities (grade 1 and 2) were fatigue, anorexia, diarrhea, nausea, and vomiting. Reversible elevations of liver enzymes occurred in 29.5% of patients. Hematologic toxicity was minimal. No objective responses were observed. 17AAG pharmacokinetics was linear. Peak plasma concentration and area under the curve of 17AG, the active major metabolite of 17AAG, increased with 17AAG dose, but the relationships were more variable than with 17AAG. 17AAG and 17AG in plasma were &gt;90% protein bound. There were no consistent changes in peripheral blood mononuclear cell HSP90 or HSP70 content.
Conclusions: 17AAG doses between 10 and 295 mg/m2 are well tolerated. 17AAG pharmacokinetics is linear. Peripheral blood mononuclear cell HSP90 and HSP70 are uninformative pharmacodynamic markers. The dose recommended for future studies is 295 mg/m2 weekly × 3, repeated every 4 weeks.
Resistance of Tumor Interstitial Pressure to the Penetration of Intraperitoneally Delivered Antibodies into Metastatic Ovarian Tumors
Authors: Flessner Michael F. , Choi Jaewah , Credit Kimberly , Deverkadra Ravi , Henderson Karla 
Published: September 2005

AbstractPurpose: Despite evidence that regional chemotherapy improves the treatment of metastatic peritoneal ovarian carcinoma, monoclonal antibodies have not shown significant success in i.p. delivery. The present study was designed to address the hypothesis that convective penetration of macromolecular antineoplastic agents depends on a positive pressure difference between the i.p. therapeutic solution and the tumor.Experimental Design: Nude rats with human ovarian xenografts implanted in the abdominal wall were used in experiments to facilitate in vivo measurement of tumor pressure and the treatment of the tumor with i.p. solutions at high pressures. Penetration of 125I-labeled trastuzumab was measured with quantitative autoradiography.Results: Tumor pressure profiles showed peak pressures of 32 mm Hg with mean pressures (± SD, mm Hg) in 12 SKOV3 tumors of 9.7 ± 8.3 and in 15 OVCAR3 tumors of 12.5 ± 7.0. I.p. therapeutic dwells at 6 to 8 mm Hg (maximum feasible pressure) showed significantly less penetration of trastuzumab than in adjacent normal muscle. To establish a driving force for convection into the tumor, various maneuvers were attempted to reduce tumor pressure, including treatment with taxanes or prostaglandin E1, elimination of tumor circulation, and removal of the tumor capsule. Tumor decapsulation decreased the pressure to zero but did not enhance the penetration of antibody. Binding to specific trastuzumab receptors on each tumor was shown to be not a significant barrier to antibody penetration.Conclusions: The results only partially support our hypothesis and imply that the microenvironment of the tumor is in itself a major barrier to delivery of charged macromolecules.
A Neutralizing Anti–Fibroblast Growth Factor 8 Monoclonal Antibody Shows Potent Antitumor Activity against Androgen-Dependent Mouse Mammary Tumors In vivo
Authors: Shimada Naoki , Ishii Toshihiko , Imada Teruyoshi , Takaba Katsumi , Sasaki Yuka , Maruyama-Takahashi Kumiko , Maekawa-Tokuda Yoshimi , Kusaka Hideaki , Akinaga Shiro , Tanaka Akira , Shitara Kenya 
Published: September 2005

Abstract
Purpose: Fibroblast growth factor 8b (FGF8b) has been implicated in oncogenesis of sex hormone–related malignancies. A murine monoclonal anti-FGF8 antibody, KM1334, has been raised against a FGF8b-derived peptide and shown to neutralize FGF8b activity in an androgen-dependent mouse mammary cell line (SC-3) in vitro growth. The purpose of this study was to evaluate KM1334 as a therapeutic agent for FGF8-dependent cancer.
Experimental Design: Specificity and neutralizing activity of KM1334 were examined in vitro. In vivo therapeutic studies were done in nude mice bearing SC-3 tumors s.c.
Results: KM1334 recognized FGF8b and FGF8f specifically out of four human FGF8 isoforms and showed little binding to other members of FGF family. Neutralizing activity of KM1334 was confirmed by both blocking of FGF8b binding to its three receptors (FGFR2IIIc, FGFR3IIIc, and FGFR4) and FGF8b-induced phosphorylation of FGFR substrate 2α and extracellular signal-regulated kinase 1/2 in SC-3 cells. The in vitro inhibitory effect could be extended to in vivo tumor models, where KM1334 caused rapid regression of established SC-3 tumors in nude mice. This rapid regression of tumors after KM1334 treatment was explained by two independent mechanisms: (a) decreased DNA synthesis, as evidenced by a decrease in uptake of 5-bromo-2′-deoxyuridine, and (b) induction of apoptosis as shown by the terminal deoxynucleotidyl transferase–mediated nick end labeling assay.
Conclusions: KM1334 possesses strong blocking activity in vitro and antitumor activity in vivo and therefore may be an effective therapeutic candidate for the treatment of cancers that are dependent on FGF8b signaling for growth and survival.
In vitro Induction of Myeloid Leukemia–Specific CD4 and CD8 T Cells by CD40 Ligand – Activated B Cells Gene Modified to Express Primary Granule Proteins
Authors: Fujiwara Hiroshi , Melenhorst J. Joseph , El Ouriaghli Frank , Kajigaya Sachiko , Grube Matthias , Sconocchia Giuseppe , Rezvani Katayoun , Price David A. , Hensel Nancy F. , Douek Daniel C. , Barrett A. John 
Published: September 2005

Abstract
The primary granule proteins (PGP) of myeloid cells are a source of multiple antigens with immunotherapeutic potential for myeloid leukemias. Therefore, we developed a method to induce T-cell responses to PGP protein sequences. We found that gene-transfected antigen-presenting cells efficiently expand functionally competent PGP-specific CD4 and CD8 T cells. The system was optimized using T-cell responses to autologous CD40-activated B cells (CD40-B) transfected with a cytomegalovirus pp65-encoding expression vector. To generate leukemia-specific T cells, expression vectors encoding the PGP proteinase 3 (PR3), human neutrophil elastase, and cathepsin-G were transfected into CD40-B cells to stimulate postallogeneic stem cell transplantation T cells from five patients with myeloid and three with lymphoid leukemias. T-cell responses to PGP proteinase 3 and human neutrophil elastase were observed in CD8+ and CD4+ T cells only in patients with myeloid leukemias. T-cell responses against cathepsin-G occurred in both myeloid and lymphoblastic leukemias. T cells from a patient with chronic myelogenous leukemia (CML) and from a posttransplant CML patient, expanded against PGP, produced IFN-γ or were cytotoxic to the patient's CML cells, demonstrating specific antileukemic efficacy. This study emphasizes the clinical potential of PGP for expansion and adoptive transfer of polyclonal leukemia antigen-specific T cells to treat leukemia.
Farnesyltransferase Inhibitor, ABT-100, Is a Potent Liver Cancer Chemopreventive Agent
Authors: Carloni Vinicio , Vizzutti Francesco , Pantaleo Pietro 
Published: September 2005

Abstract
Purpose: Treatment of hepatocellular carcinoma raised on cirrhotic liver represents a major endeavor because surgery and chemotherapeutic management fail to improve the clinical course of the disease. Chemoprevention could represent an important means to inhibit the process of hepatocarcinogenesis. Farnesyltransferase inhibitors are a class of drugs blocking the growth of tumor cells with minimal toxicity towards normal cells.
Experimental Design: In the present study, we investigated the effects of a novel farnesyltransferase inhibitor, ABT-100, on human liver cancer cell lines, HepG2 and Huh7, and on an animal model of hepatocarcinogenesis.
Results: ABT-100 inhibited HepG2 and Huh7 cell growth as well as the invading ability of Huh7 on Matrigel. In HepG2 and Huh7 cells, ABT-100 inhibited growth factor–stimulated phosphoinositide 3-kinase and Akt/protein kinase B activity. Furthermore, ABT-100 inhibited Akt-dependent p27Kip1 phosphorylation and this event was associated with increased levels of p27Kip1 in the nucleus and reduced activity of the cyclin-dependent kinase 2. Moreover, ABT-100 treatment resulted in a significant reduction in tumor incidence and multiplicity.
Conclusions: Taken together, these findings identify a mechanism of ABT-100 function and show the efficacy of ABT-100 as a chemopreventive agent of hepatocellular carcinoma.
Neutral Endopeptidase 24.11/CD10 Suppresses Progressive Potential in Ovarian Carcinoma In vitro and In vivo
Authors: Kajiyama Hiroaki , Shibata Kiyosumi , Terauchi Mikio , Morita Takanori , Ino Kazuhiko , Mizutani Shigehiko , Kikkawa Fumitaka 
Published: September 2005

Abstract
Recently, numerous studies have shown that endothelin-1 (ET-1) is expressed in ovarian carcinoma and that ET-1 selectively acts as an autocrine or paracrine growth factor through the endothelin A receptor (ETAR), and is involved in cell proliferation, invasiveness, neovascularization, and prevention of apoptosis. Neutral endopeptidase 24.11 (NEP) is a cell surface aminopeptidase with a ubiquitous expression and is capable of degrading a number of bioactive peptides including ET-1. Our previous report showed that stromal NEP expression in ovarian carcinoma was down-regulated as the histologic grade advanced. Here, we confirmed that NEP was expressed in tumor cells as well as stromal tissues in ovarian carcinoma, and investigated the functions of NEP in this carcinoma. We showed that there was a significant decrease in cell proliferation and invasiveness with a reduction in the concentration of ET-1 in the conditioned medium on the NEP overexpression of NEP in ovarian carcinoma cells. In addition, the overexpression of NEP enhanced susceptibility to paclitaxel, resulting in an increased occurrence of apoptotic morphologic change. Furthermore, tumorigenesis was reduced in vivo with the overexpression of NEP, down-regulation of both matrix metalloproteinase-2, and vascular endothelial growth factor expression. This evidence suggests that NEP functionally suppresses the progression of ovarian carcinoma and further study of this enzyme may reveal an effective way to target ET-1 for the treatment of this carcinoma.
Plasma Pharmacokinetics, Oral Bioavailability, and Interspecies Scaling of the DNA Methyltransferase Inhibitor, Zebularine
Authors: Holleran Julianne L. , Parise Robert A. , Joseph Erin , Eiseman Julie L. , Covey Joseph M. , Glaze Elizabeth R. , Lyubimov Alexander V. , Chen Ya-Fei , D'Argenio David Z. , Egorin Merrill J. 
Published: September 2005

Abstract
Purpose: Zebularine is a DNA methyltransferase inhibitor proposed for clinical evaluation.
Experimental Design: We developed a liquid chromatography/mass spectrometry assay and did i.v. and oral studies in mice, rats, and rhesus monkeys.
Results: In mice, plasma zebularine concentrations declined with terminal half-lives (t1/2) of 40 and 91 minutes after 100 mg/kg i.v. and 1,000 mg/kg given orally, respectively. Zebularine plasma concentration versus time curves (area under the curve) after 100 mg/kg i.v. and 1,000 mg/kg given orally were 7,323 and 4,935 μg/mL min, respectively, corresponding to a total body clearance (CLtb) of 13.65 mL/min/kg, apparent total body clearance (CLapp) of 203 mL/min/kg, and oral bioavailability of 6.7%. In rats, plasma zebularine concentrations declined with t1/2 of 363, 110, and 126 minutes after 50 mg/kg i.v., 250 mg/kg given orally, and 500 mg/kg given orally, respectively. Zebularine areas under the curve after 50 mg/kg i.v., 250 mg/kg given orally, and 500 mg/kg given orally were 12,526, 1,969, and 7,612 μg/mL min, respectively, corresponding to a CLtb of 3.99 mL/min/kg for 50 mg/kg i.v. and CLapp of 127 and 66 mL/min/kg for 250 and 500 mg/kg given orally, respectively. Bioavailabilities of 3.1% and 6.1% were calculated for the 250 and 500 mg/kg oral doses, respectively. In monkeys, zebularine t1/2 was 70 and 150 minutes, CLtb was 3.55 and 10.85 mL/min/kg after i.v. administration, and CLapp was 886 and 39,572 mL/min/kg after oral administration of 500 and 1,000 mg/kg, respectively. Zebularine oral bioavailability was &lt;1% in monkeys. Interspecies scaling produced the following relationship: CLtb = 6.46(weight0.9).
Conclusions: Zebularine has limited oral bioavailability. Interspecies scaling projects a CLtb of 296 mL/min in humans.
Drg1 Expression in 131 Colorectal Liver Metastases: Correlation with Clinical Variables and Patient Outcomes
Authors: Shah Manish A. , Kemeny Nancy , Hummer Amanda , Drobnjak Marija , Motwani Monica , Cordon-Cardo Carlos , Gonen Mithat , Schwartz Gary K. 
Published: September 2005

Abstract
Purpose: The differentiation-related gene-1 (Drg1) is a recently identified gene down-regulated in malignancy and a putative suppressor of colorectal cancer metastases. Its expression is associated with improved survival in patients with prostate or breast cancer. Drg1 expression is also associated with resistance to irinotecan therapy in preclinical colorectal cancer models. The clinical evaluation of Drg1 in colorectal cancer has been limited. We performed this study to evaluate the role of Drg1 in a large cohort of patients with metastatic colorectal cancer who were irinotecan naïve.
Experimental Design: We examined Drg1 expression by immunohistochemistry in 131 patients with metastatic colorectal cancer enrolled in a clinical trial of adjuvant fluorouracil-based therapy from 1991 to 1995. We correlated expression of Drg1 to numerous clinical and tumor related variables and to patient outcomes, including a subset of patients who recurred and received irinotecan-based therapy.
Results: Drg1 expression was identified in all metastatic tissue samples. There was a trend for unilobar metastases with high Drg1 expression (P = 0.07) and a suggestion of improved 2-year survival (82.4% versus 69.6%, P = 0.148). High Drg1 expression suggested irinotecan resistance (P = 0.07).
Conclusions: In colorectal cancer, Drg1 expression may be associated with a less aggressive, indolent colorectal cancer. High Drg1 may also be associated with relative resistance to irinotecan. The role of Drg1 in malignancy continues to be defined.
Promoter Hypermethylation Profile of Ovarian Epithelial Neoplasms
Authors: Makarla Prakash B. , Saboorian M. Hossein , Ashfaq Raheela , Toyooka Kiyomi O. , Toyooka Shinichi , Minna John D. , Gazdar Adi F. , Schorge John O. 
Published: September 2005

Abstract
Purpose: Ovarian carcinomas are believed to arise de novo from surface epithelium, but the actual molecular pathogenesis is unknown. The aim of this study was to compare the promoter hypermethylation profiles of ovarian epithelial neoplasms to better understand the role of epigenetic silencing in carcinogenesis.
Experimental Design: We analyzed the DNA promoter methylation status of eight tumor suppressor and cancer-related genes (p16, RARβ, E-cadherin,H-cadherin, APC, GSTP1, MGMT, RASSF1A) in 23 benign cystadenomas, 23 low malignant potential (LMP) tumors, and 23 invasive carcinomas by methylation-specific PCR.
Results: Benign cystadenomas exhibited promoter hypermethylation in only two genes, p16 (13%) and E-cadherin (13%). LMP tumors also showed p16 (22%) and E-cadherin (17%) methylation, in addition to RARβ (9%) and H-cadherin (4%). All eight genes were hypermethylated in invasive cancers at a frequency of 9% to 30%. The mean methylation index was highest in invasive tumors [0.20 versus 0.065 (LMP) and 0.033 (cystadenomas); P = 0.001]. Promoter methylation of at least one gene was most commonly observed among invasive cancers [78% versus 44% (LMP; P = 0.03) and 26% (cystadenomas; P = 0.0009)]. Three genes exhibited higher methylation frequencies in invasive tumors: RASSF1A (30% versus 0%; P = 0.0002), H-cadherin (22% versus 2%; P = 0.013), and APC (22% versus 0%; P = 0.003).
Conclusions: Promoter hypermethylation is a frequent epigenetic event that occurs most commonly in invasive epithelial ovarian carcinomas. The profile of aberrant methylation suggests that an accumulation of events at specific genes may trigger malignant transformation of some benign cystadenomas and LMP tumors.
Distinct Methylation Patterns of Benign and Malignant Liver Tumors Revealed by Quantitative Methylation Profiling
Authors: Lehmann Ulrich , Berg-Ribbe Ina , Wingen Luzie U. , Brakensiek Kai , Becker Thomas , Klempnauer Jürgen , Schlegelberger Brigitte , Kreipe Hans , Flemming Peer 
Published: September 2005

Abstract
Purpose: A comparative quantitative methylation profiling of hepatocellular carcinoma and the most frequent benign liver tumor, hepatocellular adenoma, was set up for the identification of tumor-specific methylation patterns.
Experimental Design: The quantitative methylation levels of nine genes (RASSF1A, cyclinD2, p16INK4a, DAP-K, APC, RIZ-1, HIN-1, GSTπ1, SOCS-1) were analyzed in hepatocellular carcinoma and adjacent normal tissue (n = 41), hepatocellular adenoma and adjacent normal tissue (n = 26), focal nodular hyperplasia (n = 10), and unrelated normal liver tissue (n = 28). Accumulated methylation data were analyzed using various statistical algorithms, including hierarchical clustering, to detect tumor-specific methylation patterns.
Results: Cluster analysis revealed that hepatocellular adenoma displays a methylation profile much more similar to that found in normal liver tissue and focal nodular hyperplasia than to that found in hepatocellular carcinoma. Many characteristic differences were not detected when using mere qualitative methylation assays. The cyclinD2 gene was identified as a new and frequent target for aberrant hypermethylation in hepatocellular carcinoma (68%). In the control group of 28 liver specimens from healthy donors, a clear correlation between age of patient and frequency and level of aberrant methylation was seen, which could not be detected in the group of hepatocellular carcinoma specimens.
Conclusions: Methylation profiling can clearly contribute to the unequivocal classification of suspicious lesions, but only if done in a quantitative manner applying cell type and gene-specific thresholds. In hepatocellular carcinoma, the altered methylation patterns accompanying malignant transformation override the age-dependent increase in gene methylation.
Circulating Tumor Cells in Breast Cancer: Correlation to Bone Marrow Micrometastases, Heterogeneous Response to Systemic Therapy and Low Proliferative Activity
Authors: Müller Volkmar , Stahmann Nicole , Riethdorf Sabine , Rau Thomas , Zabel Tanja , Goetz Alexander , Jänicke Fritz , Pantel Klaus 
Published: September 2005

AbstractPurpose: The incidence and biological characteristics of circulating tumor cells in the blood of patients with breast cancer were examined and subgroups were evaluated in the context of systemic treatment and the presence of disseminated tumor cells in bone marrow.Experimental Design: Circulating tumor cells were isolated from the peripheral blood of patients with breast cancer using a gradient system designed for the enrichment of circulating tumor cells (OncoQuick). Circulating tumor cells were identified with the anti-cytokeratin antibody, A45-B/B3. In subsets of patients, expression of the proliferation-associated Ki-67 antigen in circulating tumor cells and the concomitant presence of micrometastases in bone marrow were examined.Results: In patients with primary breast cancer (stage M0), circulating tumor cells were detected in 5 of 60 patients (8.3%) after surgery and before initiation of adjuvant chemotherapy; a positive correlation to the presence of disseminated tumor cells in bone marrow was observed (P = 0.030, n = 53). During the course of adjuvant chemotherapy, repeated analysis of 20 M0 patients revealed the occurrence of circulating tumor cells in 7 of 16 patients that were initially negative. Patients with metastatic disease (stage M1) showed circulating tumor cells in 25 of 63 cases (39.7%, P &lt; 0.0001 as compared with M0 patients), and a positive finding was correlated with elevated concentrations of the serum tumor marker CA15.3 (P = 0.0093). Performing repeated analysis in a subgroup of 25 M1 patients, circulating tumor cells were found more frequently in patients with progressive disease than in patients with stable disease or remission (87.5% versus 43.8% of patients with circulating tumor cells, respectively; P = 0.047). Independent of the disease-stage, none of the 47 patients examined for the proliferative status of their circulating tumor cells showed coexpression of Ki-67.Conclusions: Circulating tumor cells seem to be nonproliferating cells that persist during chemotherapy. Circulating tumor cell detection is linked to disease progression and elevated tumor marker concentrations in patients with metastatic breast cancer.
Detection and Staging of Preinvasive Lesions and Occult Lung Cancer in the Central Airways with 18F-Fluorodeoxyglucose Positron Emission Tomography: A Pilot Study
Authors: Pasic Arifa , Brokx Hes A. , Comans Emile F. , Herder Gerarda J. , Risse Elle K. , Hoekstra Otto S. , Postmus Pieter E. , Sutedja Tom G. 
Published: September 2005

AbstractPurpose: To evaluate the role of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in radiologically occult preinvasive lesions and lung cancer in the central airways.Experimental Design: Twenty-two patients with 24 preinvasive lesions and early squamous cell cancer (SCC) being occult on high-resolution computed tomography were studied. All lesions were diagnosed based on histology sampled using autofluorescence bronchoscopy. FDG-PET findings were correlated with WHO histologic classification. FDG-PET was considered true-positive when the final diagnosis was SCC and true-negative when the lesions were classified as severe dysplasia or less.Results: FDG-PET was true-positive in 8 of 11 and true-negative in 11 of 13 cases corresponding with a sensitivity of 73% [95% confidence interval (CI), 0.43-0.91] and specificity of 85% (95% CI, 0.57-0.97). Positive and negative predictive values were 80% (95% CI, 0.48-0.96) and 79% (95% CI, 0.52-0.93), respectively.Conclusions: Our very preliminary data suggest that FDG-PET might be useful for the evaluation of early central airway lesions, being positive in most SCC and negative in cases of severe dysplasia. Validation in a larger multicenter study is needed.