bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of α-Folate Receptor-Mediated Transport in the Antitumor Activity of Antifolate Drugs
Authors: Theti Davinder S. , Jackman Ann L. 
Published: September 2005

Abstract
Purpose: Raltitrexed, pemetrexed, lometrexol, and ZD9331 are antifolate drugs transported into cells via the ubiquitously expressed reduced-folate carrier. They display also high affinity for the α-folate receptor (α-FR), a low capacity folate transporter that is highly overexpressed in some epithelial tumors. The role of α-FR in the activity of the antifolates has been evaluated in two α-FR-overexpressing cell lines grown in a physiological concentration of folate (20 nm R,S-Leucovorin).
Experimental Design and Results: A431-FBP cells (transfected with the α-FR) were 3–5-fold more sensitive to the antifolates than A431 cells. KB cells (constitutive α-FR overexpression) were less sensitive to the drugs when coexposed to 1 μm folic acid to competitively inhibit binding to the α-FR. Raltitrexed, pemetrexed, and lometrexol are polyglutamated in cells leading to drug retention, e.g., the raltitrexed 4- and 24-h IC50s in A431 cells were ∼0.6 and 0.008 μm, respectively, compared with 0.003 μm for 72-h continuous exposure. A431-FBP cells were ∼3-fold more sensitive to raltitrexed and pemetrexed at all exposure times. ZD9331 is not polyglutamated, and the 4- and 24-h IC50s in A431 cells were &gt;100 and ∼100 μm, respectively, reducing to 2 and 0.1 μm, respectively, in A431-FBP cells. The ZD9331 4- and 24-h IC50s in KB cells were 20 and 1 μm, respectively, and reversible by coaddition of 1 μm folic acid. An in situ thymidylate synthase assay demonstrated continued thymidylate synthase inhibition after ZD9331-treated A431-FBP and KB, but not A431, cells were placed in drug-free medium for 16 h. A model is proposed in which the antifolates accumulate in the α-FR/endosomal apparatus, leading to slow release into the cytoplasm. In particular, this leads to cellular retention of the nonpolyglutamatable ZD9331.
Conclusions: Antifolate drugs, particularly ZD9331, have the potential for increased efficacy in tumors that highly overexpress the α-FR.
NADPH Alkenal/One Oxidoreductase Activity Determines Sensitivity of Cancer Cells to the Chemotherapeutic Alkylating Agent Irofulven
Authors: Dick Ryan A. , Yu Xiang , Kensler Thomas W. 
Published: September 2005

Abstract
Illudins S and M are extremely cytotoxic products of the fungus Omphalotus illudens. They were evaluated as possible anticancer chemotherapeutic agents but displayed unfavorable therapeutic indices. Irofulven (6-hydroxymethylacylfulvene), a less toxic, synthetic derivative of illudin S, has proven very effective in many preclinical and clinical studies. It has been postulated that metabolism via hydrogenation of the 8,9-double bonds of these molecules would unmask the electrophilic, and thus, the toxic nature of their cyclopropyl moieties. Illudins S and M were found to be rapidly metabolized by NADPH-dependent alkenal/one oxidoreductase (AOR) with maximal rates of 115.9 and 44.1 μmol min−1 mg−1, and Kms of 308 and 109 μm, respectively. Irofulven was reduced at a much slower rate: Vmax 275 nmol min−1 mg−1 and Km 145 μm. Human 293 cells transfected with an AOR overexpression vector were 100-fold more sensitive than control cells to irofulven, but displayed little differential sensitivity to illudin M. Addition of glutathione to the α,β-unsaturated ketone moiety of illudin M, but not irofulven, occurred readily at physiological concentrations. Electrophilic intermediates of irofulven and illudin M that were activated by AOR were trapped with glutathione and identified by high performance liquid chromatography with tandem mass spectrometry. Samples of the 60 human tumor cell line panel used by the National Cancer Institute to evaluate potential chemotherapeutic compounds were assayed for AOR activity, which correlated positively with previously determined growth inhibitory measures for irofulven, but not illudin M or S. Collectively, these data indicate that bioactivation of irofulven by AOR plays a predominant role in its chemotherapeutic activity.
Polymorphisms of the
CYP1B1
Gene as Risk Factors for Human Renal Cell Cancer
Authors: Sasaki Masahiro , Tanaka Yuichiro , Okino Steven T. , Nomoto Mitsuharu , Yonezawa Suguru , Nakagawa Masayuki , Fujimoto Seiichiro , Sakuragi Noriaki , Dahiya Rajvir 
Published: September 2005

Abstract
Purpose: CYP1B1 activates various environmental carcinogens in human tissues, including renal tissues. We hypothesize that certain polymorphisms of the CYP1B1 gene are risk factors for renal cell cancer. The rationale for this hypothesis is that chemical procarcinogenic compounds require metabolic activation by oxidative enzymes such as CYP1B1 to be transformed into potentially carcinogenic forms. To test this hypothesis, we investigated the genotypic distributions of six different loci on the CYP1B1 gene and their association with renal cell cancer.
Experimental Design: DNA from 211 cases of human renal cell cancer and 200 healthy controls was analyzed by sequence-specific PCR and direct DNA sequencing to determine the genotypic frequencies of six different polymorphic loci on the CYP1B1 gene.
Results: The results of this study demonstrate that the frequencies of genotype 119T/T and genotype 432G/G were significantly higher in renal cell cancer patients compared with healthy normal controls. The relative risks were calculated as 3.01 and 2.17 for genotypes 119T/T and 432G/G, respectively, in renal cell carcinoma patients. These genotypic distributions were also significantly different between male and female patients. The relative risks of genotype 119T/T were calculated as 3.95 in males and 1.92 in females, and the relative risks of genotype 432G/G were calculated as 2.81 in males and 1.35 in females.
Conclusions: The present study demonstrates for the first time that the polymorphisms at codons 119 and 432 may be risk factors for renal cancer, especially in the male population.
Pretargeted α Emitting Radioimmunotherapy Using 213Bi 1,4,7,10-Tetraazacyclododecane-N,N′,N″,N‴-Tetraacetic Acid-Biotin
Authors: Yao Zhengsheng , Zhang Meili , Garmestani Kayhan , Axworthy Donald B. , Mallett Robert W. , Fritzberg Alan R. , Theodore Lou J. , Plascjak Paul S. , Eckelman William C. , Waldmann Thomas A. , Pastan Ira , Paik Chang H. , Brechbiel Martin W. , Carrasquillo Jorge A. 
Published: September 2005

AbstractPurpose: The use of an α emitter for radioimmunotherapy has potential advantages compared with β emitters. When administered systemically optimal targeting of intact antibodies requires &gt;24 h, therefore limiting the use of short-lived α emitters. This study investigated the biodistribution of bismuth-labeled biotin in A431 tumor-bearing mice pretargeted with antibody B3-streptavidin (B3-SA) and examined the therapeutic efficacy of the α emitter, 213Bi-labeled biotin.Experimental Design: Biotinidase-resistant 7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA)-biotin was radiolabeled with 205,206Bi or 213Bi. Treatment of tumor-bearing mice began by administration of B3-SA (400 μg) to target the tumor sites for 24 h. Then, an agent containing biotin and galactose groups was used to clear the conjugate from the circulation. Four h later, bismuth-radiolabeled DOTA-biotin was given, and biodistribution or therapy was evaluated. Dose escalation treatment from 3.7–74 MBq was performed, and the effects on tumors of different sizes were investigated. Tumor growth, complete blood cell counts, toxicity, and survival were monitored.Results: Radiolabeled biotin cleared rapidly. Rapid tumor uptake resulted in much higher tumor:nontumor targeting ratios than achieved with the directly labeled monoclonal antibody. Dose escalation revealed that 74 MBq caused acute death of mice, whereas 0.37–37 MBq doses inhibited tumor growth and prolonged survival significantly. Evidence of mild hematological toxicity was noted. At therapeutically effective doses renal toxicity was observed.Conclusions: 213Bi-DOTA-biotin, directed by the Pretarget method to tumor-targeted B3-SA, showed a therapeutic effect, although the therapeutic index was low. The source of the toxicity was most likely related to the renal toxicity.
Cyclooxygenase-2 Activation Mediates the Proangiogenic Effect of Nitric Oxide in Colorectal Cancer
Authors: Cianchi Fabio , Cortesini Camillo , Fantappiè Ornella , Messerini Luca , Sardi Iacopo , Lasagna Nadia , Perna Federico , Fabbroni Valentina , Di Felice Annamaria , Perigli Giuliano , Mazzanti Roberto , Masini Emanuela 
Published: September 2005

Abstract
Purpose: Up-regulation of both inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) enzymes has been reported in colorectal cancer. We aimed at evaluating the possible interaction between the nitric oxide and COX-2 pathways, and its effect on promoting tumor angiogenesis.
Experimental Design: Expression of iNOS, COX-2, vascular endothelial growth factor (VEGF), and CD31 was analyzed in tumor samples and corresponding normal mucosa obtained from 46 surgical specimens. We also evaluated iNOS activity, prostaglandin E2 (PGE2), cyclic GMP and cyclic AMP production in the same specimens. Nitrite/nitrate levels, and PGE2 and VEGF production were assessed in HCT116 and HT29 colon cancer cell lines after induction and selective inhibition of the two enzyme pathways.
Results: A significant correlation was found between iNOS and COX-2 immunohistochemical expression. PGE2 production significantly correlated with iNOS activity and cGMP levels. A significant correlation was also found among PGE2 production, microvessel density, and VEGF expression. Coinduction of both iNOS and COX-2 activities occurred after lipopolysaccharide (LPS) and epidermal growth factor (EGF) treatment in HCT116 and HT29 cells. Inhibition of iNOS by 1400W significantly reduced both LPS- and EGF-induced PGE2 production. Treatment with LPS, EGF, and arachidonic acid significantly increased VEGF production in the iNOS-negative/COX-2-positive HT29 cells. This effect was completely reversed by treatment with the selective COX-2 inhibitor celecoxib.
Conclusions: Our data showed a prominent role of nitric oxide in stimulating COX-2 activity in colorectal cancer. This interaction is likely to produce a cooperative effect in promoting angiogenesis through PGE2-mediated increase in VEGF production.
Treatment of HER-2/
neu
Overexpressing Breast Cancer Xenograft Models with Trastuzumab (Herceptin) and Gefitinib (ZD1839): Drug Combination Effects on Tumor Growth, HER-2/
neu
and Epidermal Growth Factor Receptor Expression, and Viable Hypoxic Cell Fraction
Authors: Warburton Corinna , Dragowska Wieslawa H. , Gelmon Karen , Chia Stephen , Yan Hong , Masin Dana , Denyssevych Tetyana , Wallis Anne E. , Bally Marcel B. 
Published: September 2005

Abstract
Purpose: The purpose of this research was to assess the effects of single agent and combination treatment with trastuzumab and gefitinib on tumor growth and tumor microenvironment in two HER-2/neu overexpressing breast xenograft models, MDA-MB-435/LCC6HER-2 (LCC6HER-2; estrogen receptor negative) and MCF-7HER-2 (estrogen receptor positive).
Experimental Design: LCC6HER-2 and MCF-7HER-2 cells, both in tissue culture and xenografts grown in SCID-Rag 2M mice, were treated with trastuzumab and gefitinib, alone or in combination. The rate of tumor growth was determined. In addition, tumor HER-2/neu and epidermal growth factor receptor expression, cell viability, cell cycle distribution, and proportion of viable hypoxic cells were determined by flow cytometric analyses of single tumor cell suspensions.
Results: Both tumor models were very sensitive to trastuzumab and moderately sensitive to gefitinib in vivo. The combination resulted in therapeutic effects, as judged by inhibition of tumor growth, which was greater (albeit not statistically significant) than that observed with trastuzumab administered as a single agent. Trastuzumab was effective in down-regulating HER-2/neu, and gefitinib mediated a reduction in epidermal growth factor receptor expression on tumor cells. In LCC6HER-2 tumors, trastuzumab significantly reduced tumor cell viability, which was not improved by the addition of gefitinib. Gefitinib dramatically reduced the proportion of viable hypoxic cells in LCC6HER-2 and MCF-7HER-2 tumors. This effect was abrogated by the addition of trastuzumab.
Conclusions: Although in vivo efficacy studies in two HER-2/neu overexpressing breast xenograft models showed that the combination of trastuzumab and gefitinib was effective, analyses of various cellular parameters failed to reveal beneficial effects and argue that this drug combination may not be favorable.
HER2 Expression in Salivary Gland Carcinomas
Authors: Glisson Bonnie , Colevas A. Dimitrios , Haddad Robert , Krane Jeoffrey , El-Naggar Adel , Kies Merrill , Costello Rosemary , Summey Carmen , Arquette Matthew , Langer Corey , Amrein Philip C. , Posner Marshall 
Published: September 2005

Abstract
Purpose: Previous evaluation of HER2 overexpression in salivary gland cancers indicated an incidence varying between 7 and 56%, with no clear difference among three histologically different subtypes. As part of a Phase II trial of trastuzumab for treatment of incurable salivary gland cancer, we screened 137 tumors for HER2 expression.
Experimental Design: Unstained sections of paraffin-embedded tumor samples were stained with p185/HER2 receptor antibody. Tumors with moderate (2+) to strong (3+) complete membrane staining in at least 10% of the tumor cells were scored as positive for overexpression.
Results: The overall frequency of overexpression for HER2 was 17% (23 of 137), whereas it was only 8% in the three most common histological subtypes screened. Overexpression was distinctly rare in the most common subtype screened, adenoid cystic carcinoma (4%, 3 of 70). Overexpression was very common in salivary duct cancers; 10 (83%) of 12 were positive for HER2. This observation is consistent with the typical high-grade histological features and aggressive behavior of this subtype as well as with its histogenetic similarity to breast cancer. Analysis based on histogenesis (intercalated duct versus excretory duct) indicated a higher frequency of overexpression in the latter (55%) than in the former (7%).
Conclusions: Our overall results suggest that trastuzumab will not have a major role in treatment of salivary gland cancers of intercalated duct origin. Further systematic evaluation of trastuzumab in subtypes of excretory duct origin could be supported.
N-Cadherin Is Regulated by Activin A and Associated with Tumor Aggressiveness in Esophageal Carcinoma
Authors: Yoshinaga Keiji , Inoue Hiroshi , Utsunomiya Tohru , Sonoda Hideto , Masuda Takaaki , Mimori Koshi , Tanaka Yoichi , Mori Masaki 
Published: September 2005

Abstract
Purpose: Activin A is a member of the transforming growth factor β superfamily and plays an important role in the differentiation of embryonic stem cells. We have reported previously that the expression of activin A is associated with lymph node metastasis in esophageal cancer, and our purpose in the current work is to clarify the molecular mechanism of the aggressive behavior of tumors that have high activin A expression.
Experimental Design: We have compared the gene expression profiles of human esophageal carcinoma cell lines that were stably transfected with activin βA, which is a subunit of activin A, with those of control human esophageal carcinoma cell lines, using a cDNA microarray.
Results: We found that the expression level of neuronal cadherin (N-cadherin) was higher in the transfectants than in the control cells. N-cadherin was located on the cell surface of the transfectants, irrespective of the expression of epithelial cadherin (E-cadherin), and the expression of N-cadherin mRNA was significantly associated with that of activin βA mRNA in clinical samples of esophageal carcinoma (n = 51; r = 0.855). A clinicopathologic analysis suggested that expression of N-cadherin mRNA was associated with the depth of tumor wall invasion, and a group of patients with high expression of N-cadherin mRNA showed a significantly poorer prognosis than a group of patients with low N-cadherin expression (P = 0.046).
Conclusions: These results indicate that activin A might mediate the expression of N-cadherin and that this may be associated with depth of invasion and poor prognosis.
A Novel Human Cancer Vaccine Elicits Cellular Responses to the Tumor-Associated Antigen, Human Chorionic Gonadotropin β
Authors: He Li-Zhen , Ramakrishna Venky , Connolly John E. , Wang Xi-Tao , Smith Patricia A. , Jones Charles L. , Valkova-Valchanova Maria , Arunakumari Alahari , Treml John F. , Goldstein Joel , Wallace Paul K. , Keler Tibor , Endres Michael J. 
Published: September 2005

AbstractPurpose: The oncofetal antigen, human chorionic gonadotropin β subunit (hCGβ), is expressed by a number of carcinomas and is a prognostic indicator in renal, colorectal, bladder, and pancreatic cancers. We describe the development of a novel antibody-based dendritic cell (DC)-targeted cancer vaccine capable of eliciting cellular immune responses directed against hCGβ.Experimental Design: The tumor-associated antigen hCGβ was coupled genetically to a human anti-DC antibody (B11). The resulting fusion protein (B11-hCGβ) was evaluated for its ability to promote tumor antigen-specific cellular immune responses in a human in vitro model. Monocyte-derived human DCs from normal donors were exposed to purified B11-hCGβ, activated with CD40 ligand, mixed with autologous lymphocytes, and tested for their ability to promote hCGβ-specific proliferative and cytotoxic T-lymphocyte responses.Results: B11-hCGβ was found to be a soluble, well-defined, and readily purified product that specifically recognized the human mannose receptor via the B11 antibody portion of the fusion protein. B11-hCGβ functionally promoted the uptake and processing of tumor antigen by DCs, which led to the generation of tumor-specific HLA class I and class II-restricted T-cell responses, including CTLs capable of killing human cancer cell lines expressing hCGβ.Conclusions: Although other hCG vaccines have been shown to be capable of eliciting antibody responses to hCGβ, this is the first time that cellular immune responses to hCGβ have been induced by a vaccine in a human system. This DC-targeted hCGβ vaccine holds promise for the management of a number of cancers and merits additional clinical development.
A Cox-2 Promoter-Based Replication-Selective Adenoviral Vector to Target the Cox-2-Expressing Human Bladder Cancer Cells
Authors: Shirakawa Toshiro , Hamada Katsuyuki , Zhang Zhujun , Okada Hiroshi , Tagawa Masatoshi , Kamidono Sadao , Kawabata Masato , Gotoh Akinobu 
Published: September 2005

Abstract
Purpose: Cyclooxygenase-2 (Cox-2), an enzyme that catalyzes the synthesis of prostaglandins, is overexpressed in a variety of premalignant and malignant conditions, including urinary bladder cancer. In the present study, we examined the feasibility of using Cox-2 promoter-based replication-selective adenovirus for targeting bladder cancer cells that express Cox-2 transcriptional activity.
Experimental Design: A series of human cancer cell lines, including three bladder cancer cell lines (KK47, T24, and 5637), were evaluated for their Cox-2 and CAR (the Coxsackievirus and adenovirus receptor) mRNA expression levels by quantitative real-time PCR. AdE3-cox2–327, a replication-selective adenovirus in which the expression of E1a is controlled by the Cox-2 promoter, was generated, and its tissue-specific activity was tested in vitro and in vivo.
Results: Three bladder cancer cell lines express higher levels of Cox-2 mRNA than does the human prostate cancer cell line PC3, the primary cultured human benign prostatic fibroblast, PF cells, and the human colon cancer cell line Colo320. Relatively higher expression of CAR mRNA was detected in the KK47, 5637, respectively, and Colo320 than in the T24, PC-3, and PF cells. In vitro assays revealed significant growth suppression of both Cox-2- and CAR-expressing bladder cancer cells KK47 and 5637 in comparison with the other cells that lack Cox-2 expression and/or CAR expression.
Conclusions: The present study demonstrated both specificity and efficacy of AdE3-cox2–327, a selectively replicated adenovirus, toward the Cox-2-expressing bladder cancer cells in vitro and in vivo. We also found that CAR expression in the target cancer cells is an important factor for the efficacy of selectively replicated adenovirus-based gene therapy.
Mutational Analysis of
BRAF
in Fine Needle Aspiration Biopsies of the Thyroid: A Potential Application for the Preoperative Assessment of Thyroid Nodules
Authors: Cohen Yoram , Rosenbaum Eli , Clark Douglas P. , Zeiger Martha A. , Umbricht Christopher B. , Tufano Ralph P. , Sidransky David , Westra William H. 
Published: September 2005

Abstract
Background: Fine needle aspiration (FNA) is routinely used in the preoperative evaluation of thyroid nodules, but subsequent patient management is often complicated by the inability to decisively recognize malignancy on cytologic grounds alone. Activating mutations of the BRAF oncogene commonly occur in papillary thyroid carcinomas (PTCs) but not in other types of benign and malignant thyroid lesions. Mutational analysis of FNAs could enhance selection of thyroid nodules for surgical removal.
Methods: Ninety-five excised PTCs along with 49 corresponding FNAs were evaluated for BRAF mutations by a newly developed assay that uses a novel primer extension method (MutectorR assay) and by direct sequencing. An additional 42 FNAs from thyroid nodules that were excised based on a suspicion of malignancy were also evaluated.
Results: BRAF mutations were identified in 36 of the 95 (38%) excised PTCs. By histological subtype, BRAF mutations were more common in conventional PTCs than in the follicular variant (67% versus 12%; P &lt; 0.0001; χ2). Analysis of the preoperative FNAs accurately reflected BRAF status of the resected PTC in 46 of the 49 paired samples (94% concordance). In FNA samples grouped according to the preoperative cytologic findings (malignant, n = 25; benign, n = 11; and indeterminate, n = 55), a BRAF mutation confirmed the diagnosis of PTC in 72% of carcinomas within the malignant group, and it established the diagnosis of PTC in 16% of carcinomas within the indeterminate group. BRAF mutations were not detected in FNAs from 32 benign thyroid lesions. Direct sequencing and the MutectorR assay yielded completely concordant results.
Conclusions: BRAF mutations are common in conventional PTCs, and they are specific for PTC. A BRAF mutation can be reliably detected in cells aspirated from a thyroid nodule suggesting a role for this marker in the preoperative evaluation of thyroid nodules.