bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Drug Loading on the Antitumor Activity of a Monoclonal Antibody Drug Conjugate
Authors: Hamblett Kevin J. , Senter Peter D. , Chace Dana F. , Sun Michael M. C. , Lenox Joel , Cerveny Charles G. , Kissler Kim M. , Bernhardt Starr X. , Kopcha Anastasia K. , Zabinski Roger F. , Meyer Damon L. , Francisco Joseph A. 
Published: September 2005

Abstract
Purpose: An antibody-drug conjugate consisting of monomethyl auristatin E (MMAE) conjugated to the anti-CD30 monoclonal antibody (mAb) cAC10, with eight drug moieties per mAb, was previously shown to have potent cytotoxic activity against CD30+ malignant cells. To determine the effect of drug loading on antibody-drug conjugate therapeutic potential, we assessed cAC10 antibody-drug conjugates containing different drug-mAb ratios in vitro and in vivo.
Experimental Design: Coupling MMAE to the cysteines that comprise the interchain disulfides of cAC10 created an antibody-drug conjugate population, which was purified using hydrophobic interaction chromatography to yield antibody-drug conjugates with two, four, and eight drugs per antibody (E2, E4, and E8, respectively). Antibody-drug conjugate potency was tested in vitro against CD30+ lines followed by in vivo xenograft models. The maximum-tolerated dose and pharmacokinetic profiles of the antibody-drug conjugates were investigated in mice.
Results: Although antibody-drug conjugate potency in vitro was directly dependent on drug loading (IC50 values E8&lt;E4&lt;E2), the in vivo antitumor activity of E4 was comparable with E8 at equal mAb doses, although the E4 contained half the amount of MMAE per mAb. E2 was also an active antitumor agent but required higher doses. The maximum-tolerated dose of E2 in mice was at least double that of E4, which in turn was twice that of E8. MMAE loading affected plasma clearance, as E8 cleared 3-fold faster than E4 and 5-fold faster than E2.
Conclusions: By decreasing drug loading per antibody, the therapeutic index was increased demonstrating that drug loading is a key design parameter for antibody-drug conjugates.
HMMC-1
Authors: Nozawa Shiro , Aoki Daisuke , Tsukazaki Katsumi , Susumu Nobuyuki , Sakayori Motoko , Suzuki Nao , Suzuki Atsushi , Wakita Rie , Mukai Makio , Egami Yuko , Kojima-Aikawa Kyoko , Ishida Isao , Belot Frederic , Hindsgaul Ole , Fukuda Minoru , Fukuda Michiko N. 
Published: September 2005

Abstract
Purpose: The purpose of this research was to generate a human monoclonal antibody specific to gynecological cancers and to evaluate such an antibody as therapy for gynecological cancers.
Experimental Design: Transchromosomal KM mice were immunized with the human uterine endometrial cancer cell line SNG-S. Hybridomas were constructed between spleen cells from KM mice and mouse myeloma cells. Reactivity of the antibody was evaluated by immunohistochemistry of pathological specimens of gynecological cancers. Cytotoxicity of HMMC-1 against SNG-S cells was tested by in vitro cytotoxicity assays. The epitope of HMMC-1 was determined by transfection with a panel of glycosyltransferase cDNAs and by inhibition assays with chemically synthesized oligosaccharides.
Results: HMMC-1 is a human IgM monoclonal antibody that reacts positively with müllerian duct-related carcinomas with positive rates of 54.6% against uterine endometrial adenocarcinoma, 76.9% against uterine cervical adenocarcinoma, and 75.0% against epithelial ovarian cancer. HMMC-1 does not react with normal endometrium at proliferative or secretory phases, normal uterine cervix, or normal and malignant tissue from other organs, whereas it reacts weakly with the epithelium of the gall bladder and the collecting duct of the kidney. HMMC-1 exhibits antigen-dependent and complement-mediated cytotoxicity. Upon cotransfection with cDNAs encoding two glycosyltransferases required for fucosylated extended core 1 O-glycan, mammalian cells express HMMC-1 antigen. Finally, binding of HMMC-1 to SNG-S cells is inhibited by synthetic Fucα1→2Galβ1→4GlcNAcβ1→3Galβ1→3GalNAcα1-octyl.
Conclusions: These results indicate that HMMC-1 specifically recognizes a novel O-glycan structure. The unique specificity and cytotoxicity of HMMC-1 strongly suggest a therapeutic potential of this antibody.
Ran, a Small GTPase Gene, Encodes Cytotoxic T Lymphocyte (CTL) Epitopes Capable of Inducing HLA-A33–restricted and Tumor-Reactive CTLs in Cancer Patients
Authors: Azuma Koichi , Sasada Tetsuro , Takedatsu Hiroko , Shomura Hiroki , Koga Makoto , Maeda Yoshiaki , Yao Akihisa , Hirai Tatsuya , Takabayashi Arimichi , Shichijo Shigeki , Itoh Kyogo 
Published: September 2005

AbstractPurpose: The purpose is to identify a gene coding for tumor-associated antigen and peptide capable of inducing CTLs reactive to tumor cells with a HLA-A33–restricted fashion to provide scientific basis for specific immunotherapy to HLA-A33+ cancer patients.Experimental Design: An expression gene-cloning method was used to identify the tumor-associated antigen gene. Northern blot analysis and immunohistochemistry were used to examine the mRNA and protein expression levels in various cells and tissues, respectively. Synthetic peptides were examined for their ability to induce HLA-A33+ tumor-reactive CTLs in peripheral blood mononuclear cells from cancer patients.Result: A gene of small GTPase, Ran, which controls the cell cycle through the regulation of nucleocytoplasmic transport, mitotic spindle organization, and nuclear envelope formation, was found to encode epitopes recognized by the HLA-A33–restricted CTLs established from T cells infiltrating into gastric adenocarcinoma. The expression of the Ran gene was increased in most cancer cell lines and cancer tissues at both the mRNA and protein levels. However, it was not enhanced in the surrounding normal cells or tissues. It was also undetectable in normal tissues as far as tested. Ran-derived peptides at positions 48–56 and 87–95 could induce CD8+ peptide-specific CTLs reactive to tumor cells from HLA-A33+ epithelial cancer patients in a HLA class I-restricted manner.Conclusions: Because of its increased expression in cancer cells and involvement in malignant transformation and/or the enhanced proliferation of cancer cells, the two Ran-directed peptides could be potent candidates in use for specific immunotherapy against HLA-A33+ epithelial cancers.
Overexpression of 5-Lipoxygenase in Rat and Human Esophageal Adenocarcinoma and Inhibitory Effects of Zileuton and Celecoxib on Carcinogenesis
Authors: Chen Xiaoxin , Wang Su , Wu Nan , Sood Sandeep , Wang Peng , Jin Zhe , Beer David G. , Giordano Thomas J. , Lin Yong , Shih Wei-chung J. , Lubet Ronald A. , Yang Chung S. 
Published: September 2005

Abstract
Purpose: Aberrant arachidonic acid (AA) metabolism, especially through the cyclooxygenase (Cox) and 5-lipoxygenase (5-Lox) pathways, has been suggested to play an important role in the development of esophageal adenocarcinoma (EAC). The purpose of this study was to investigate the expression of 5-Lox in EAC of a rat model and in human samples as well as the chemopreventive effects of zileuton (a specific 5-Lox inhibitor) and celecoxib (a specific Cox2 inhibitor) in the rat EAC model.
Experimental Design: 5-Lox expression in EAC of a rat esophagogastroduodenal anastomosis model and of humans was examined with immunohistochemistry. A chemoprevention study was designed to test whether zileuton and celecoxib could suppress aberrant AA metabolism and esophageal adenocarcinogenesis.
Results: With immunohistochemistry, we found that 5-Lox was overexpressed during esophageal adenocarcinogenesis in our rat model and in humans. In the chemoprevention study, EAC incidence was reduced in a dose-dependent manner from 68.8% (11 of 16) to 44.4% (8 of 18; P &gt; 0.05) and 31.3% (5 of 16; P &lt; 0.05) by 500 and 1,000 ppm zileuton, respectively, and to 33.3% (7 of 21; P &lt; 0.05) and 20% (3 of 15; P &lt; 0.05) by 500 and 1,000 ppm celecoxib, respectively. With isobolographic analysis, zileuton and celecoxib, both at a dose of 500 ppm, had an additive effect by reducing the tumor incidence to 16.7% (3 of 18, P &lt; 0.01). Leukotriene B4 and prostaglandin E2 levels in the esophageal tissues were also significantly reduced by zileuton and celecoxib.
Conclusions: This study clearly demonstrated that 5-Lox and Cox2 play important roles in the development of EAC. Both zileuton and celecoxib had inhibitory effects on esophageal adenocarcinogenesis through inhibition on their respective enzymes of AA metabolism.
Treatment of Neuroblastoma Meningeal Carcinomatosis with Intrathecal Application of α-Emitting Atomic Nanogenerators Targeting Disialo-Ganglioside GD2
Authors: Miederer Matthias , McDevitt Michael R. , Borchardt Paul , Bergman Ira , Kramer Kim , Cheung Nai-Kong V. , Scheinberg David A. 
Published: September 2005

Abstract
Labeling of specific antibodies with bifunctional chelated Actinium-225 (225Ac; an α generator) allows the formation of new, highly potent and selective α-emitting anticancer drugs. We synthesized and evaluated a radioimmunoconjugate based on 3F8, an IgG3 antibody that specifically binds to ganglioside GD2, which is overexpressed by many neuroectodermal tumors including neuroblastoma. The 225Ac-1,4,7,10-tetra-azacylododecane (DOTA)-3F8 construct was evaluated for radiochemical purity and sterility, immunoreactivity, cytotoxicity in vitro, induction of apoptosis on GD2-positive cells, as well as for pharmacological biodistribution and metabolism of the 225Ac generator and its daughters in a nude mouse xenograft model of neuroblastoma. The 225Ac-3F8 showed an IC50 of 3 Bq/ml (80 pCi/ml) on the neuroblastoma cell line, NMB7, in vitro. Apoptosis of these cells was not observed. Biodistribution in mice showed specific targeting of a subcutaneous tumor; there was redistribution of the 225Ac daughter nuclides mainly from blood to kidneys and to small intestine. Toxicity was examined in cynomolgus monkeys. Monkeys injected with 1 to 3 doses of intrathecal 225Ac-3F8 radioimmunoconjugate (80 to 150 kBq/kg total dose) did not show signs of toxicity based on blood chemistry, complete blood counts, or by clinical evaluations. Therapeutic efficacy of intrathecal 225Ac-3F8 was studied in a nude rat xenograft model of meningeal carcinomatosis. The 225Ac-3F8 treatment improved survival 2-fold from 16 to 34 days (P = 0.01). In conclusion, in vivo α generators targeted by 3F8 warrant additional study as a possible new approach to the treatment of carcinomatous meningitis.
A Selective c-Met Inhibitor Blocks an Autocrine Hepatocyte Growth Factor Growth Loop in ANBL-6 Cells and Prevents Migration and Adhesion of Myeloma Cells
Authors: Hov Håkon , Holt Randi Utne , Rø Torstein Baade , Fagerli Unn-Merete , Hjorth-Hansen Henrik , Baykov Vadim , Christensen James G. , Waage Anders , Sundan Anders , Børset Magne 
Published: September 2005

Abstract
Purpose: We wanted to examine the role of the hepatocyte growth factor (HGF) receptor c-Met in multiple myeloma by applying a novel selective small molecule tyrosine kinase inhibitor, PHA-665752, directed against the receptor.
Experimental Design: Four biological sequels of HGF related to multiple myeloma were studied: (1) proliferation of myeloma cells, (2) secretion of interleukin-11 from osteogenic cells, (3) migration of myeloma cells, and (4) adhesion of myeloma cells to fibronectin. We also examined effects of the c-Met inhibitor on intracellular signaling pathways in myeloma cells.
Results: PHA-665752 effectively blocked the biological responses to HGF in all assays, with 50% inhibition at 5 to 15 nmol/L concentration and complete inhibition at around 100 nmol/L. PHA-665752 inhibited phosphorylation of several tyrosine residues in c-Met (Tyr1003, Tyr1230/1234/1235, and Tyr1349), blocked HGF-mediated activation of Akt and p44/42 mitogen-activated protein kinase, and prevented the adaptor molecule Gab1 from complexing with c-Met. In the HGF-producing myeloma cell line ANBL-6, PHA-665752 revealed an autocrine HGF–c-Met–mediated growth loop. The inhibitor also blocked proliferation of purified primary myeloma cells, suggesting that autocrine HGF–c-Met–driven growth loops are important for progression of multiple myeloma.
Conclusions: Collectively, these findings support the role of c-Met and HGF in the proliferation, migration, and adhesion of myeloma cells and identify c-Met kinase as a therapeutic target for treatment of patients with multiple myeloma.
The Spermatozoa Protein, SLLP1, Is a Novel Cancer–Testis Antigen in Hematologic Malignancies
Authors: Wang Zhiqing , Zhang Yana , Mandal Arabinda , Zhang Jian , Giles Francis J. , Herr John C. , Lim Seah H. 
Published: September 2005

Abstract
Purpose: Neoplastic cells often aberrantly express normal testicular proteins. Because these proteins have a very restricted normal tissue expression, they may be suitable targets for immunotherapy. SLLP1 is an intra-acrosomal, nonbacteriolytic, c lysozyme–like protein recently isolated from human spermatozoa. In this study, we determined whether SLLP1 is a novel cancer–testis antigen in hematologic malignancies
Experimental Design: SLLP1 expression in hematologic tumor cells and normal tissues was determined using a combination of reverse transcription-PCR, real-time PCR, and Western blot analysis. The presence of antibodies against SLLP1 was determined by ELISA analysis.
Results: SLLP1 was aberrantly expressed in the tumor cells from 2 of 9 acute myeloid leukemia, 3 of 11 chronic lymphocytic leukemia, 4 of 14 chronic myeloid leukemia, and 6 of 17 multiple myeloma. In contrast, they were not detected in corresponding specimens from any healthy donors. SLLP1 exhibited a very restricted normal tissue expression, being found only in testis/spermatozoa. SLLP1 was expressed in some tumor cells at a level of &gt;25%. High titer IgG antibodies against SLLP1 were also detected in the sera of some of these patients.
Conclusions: SLLP1 is a novel cancer–testis antigen in hematologic malignancies and is capable of eliciting B-cell immune responses in vivo in cancer-bearing individuals. Our results, therefore, support SLLP1 as a protein target appropriate for additional in vitro study to define its suitability for immunotherapy.
Flavopiridol Blocks Integrin-Mediated Survival in Dormant Breast Cancer Cells
Authors: Najmi Saltanat , Korah Reju , Chandra Rachna , Abdellatif Maha , Wieder Robert 
Published: September 2005

Abstract
Purpose: Breast cancer micrometastases in the bone marrow are resistant to chemotherapy. They can remain dormant for years before some begin to proliferate. We seek to understand survival mechanisms and develop targeted approaches to eliminating these cells.
Experimental Design: In an in vitro model of dormancy, basic fibroblast growth factor 2 (FGF-2), abundant in the bone marrow, inhibits the growth of well-differentiated cells in the 2- to 10-cell stage and up-regulates integrin α5β1. Through this integrin, cells bind fibronectin, spread out, and acquire a survival advantage, partly through activation of the phosphatidylinositol 3-kinase/Akt pathway. We investigated the effects of Taxotere, flavopiridol, and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase and p38 inhibitors on survival of dormant clones and that of flavopiridol on expression of integrins, adhesion strength, and phosphorylation of Akt, ERK 1/2, and p38.
Results: Dormant MCF-7 and T-47D cell clones were resistant to Taxotere concentrations 10-fold higher than needed to eliminate growing clones but were almost completely eradicated by 200 nmol/L flavopiridol. Flavopiridol caused a decrease in FGF-2–induced expression of integrins, including α5 and β1, and decreased FGF-2–induced specific adhesion to fibronectin. It diminished Akt phosphorylation, but reexpression of active Akt was not sufficient to reverse dormant clone inhibition. Flavopiridol did not affect phosphorylation of ERK 1/2 and p38 but diminished total protein levels. Chemical inhibition of these pathways partially abrogated dormant clone survival.
Conclusions: Flavopiridol has pleiotropic effects on key targets involved with survival of dormant breast cancer cells and may represent a useful approach to eliminating cells dependent on multiple signal pathways for survival.
Accurate Discrimination of Barrett's Esophagus and Esophageal Adenocarcinoma Using a Quantitative Three-Tiered Algorithm and Multimarker Real-time Reverse Transcription-PCR
Authors: Mitas Michael , Almeida Jonas S. , Mikhitarian Kaidi , Gillanders William E. , Lewin David N. , Spyropoulos Demetri D. , Hoover Loretta , Graham Amanda , Glenn Tammy , King Peter , Cole David J. , Hawes Robert , Reed Carolyn E. , Hoffman Brenda J. 
Published: September 2005

Abstract
Esophageal adenocarcinoma (EA) is increasing faster than any other cancer in the U.S. In this report, we first show that EA can be distinguished from normal esophagus (NE) and esophageal squamous cell carcinoma by plotting expression values for EpCam, TFF1, and SBEM in three-dimensional Euclidean space. For monitoring progression of Barrett's esophagus (BE) to EA, we developed a highly sensitive assay for limited quantities of tissue whereby 50 ng of RNA are first converted to cDNA using 16 gene-specific primers. Using a set of training tissues, we developed a novel quantitative three-tiered algorithm that allows for accurate (overall accuracy = 61/63, 97%) discrimination of BE versus EA tissues using only three genes. The gene used in the first tier of the algorithm is TSPAN: samples not diagnosed as BE or EA by TSPAN in the first tier are then subjected to a second-tier analysis using ECGF1, followed by a third-tier analysis using SPARC. Addition of TFF1 and SBEM to the first tier (i.e., a five-gene marker panel) increases the overall accuracy of the assay to 98% (62/63) and results in mean molecular diagnostic scores (± SD) that are significantly different between EA and BE samples (3.19 ± 1.07 versus −2.74 ± 1.73, respectively). Our results suggest that relatively few genes can be used to monitor progression of BE to EA.
Overexpression of the Aldo-Keto Reductase Family Protein AKR1B10 Is Highly Correlated with Smokers' Non–Small Cell Lung Carcinomas
Authors: Fukumoto Shin-ichi , Yamauchi Naoko , Moriguchi Hisashi , Hippo Yoshitaka , Watanabe Akira , Shibahara Junji , Taniguchi Hirokazu , Ishikawa Shumpei , Ito Hirotaka , Yamamoto Shogo , Iwanari Hiroko , Hironaka Mitsugu , Ishikawa Yuichi , Niki Toshiro , Sohara Yasunori , Kodama Tatsuhiko , Nishimura Masaharu , Fukayama Masashi , Dosaka-Akita Hirotoshi , Aburatani Hiroyuki 
Published: September 2005

AbstractPurpose: Squamous cell carcinoma (SCC) and adenocarcinoma of the lung are currently subject to similar treatment regimens despite distinct differences in histology and epidemiology. The aim of this study is to identify a molecular target with diagnostic and therapeutic values for SCC.Experimental Design: Genes specifically up-regulated in SCC were explored through microarray analysis of 5 SCCs, 5 adenocarcinomas, 10 small cell lung carcinomas, 27 normal tissues, and 40 cancer cell lines. Clinical usefulness of these genes was subsequently examined mainly by immunohistochemical analysis.Results: Seven genes, including aldo-keto reductase family 1, member B10 (AKR1B10), were identified as SCC-specific genes. AKR1B10 was further examined by immunohistochemical analysis of 101 non–small cell lung carcinomas (NSCLC) and its overexpression was observed in 27 of 32 (84.4%) SCCs and 19 of 65 (29.2%) adenocarcinomas. Multiple regression analysis showed that smoking was an independent variable responsible for AKR1B10 overexpression in NSCLCs (P &lt; 0.01) and adenocarcinomas (P &lt; 0.01). AKR1B10 staining was occasionally observed even in squamous metaplasia, a precancerous lesion of SCC.Conclusion: AKR1B10 was overexpressed in most cases with SCC, which is closely associated with smoking, and many adenocarcinoma cases of smokers. These results suggest that AKR1B10 is a potential diagnostic marker specific to smokers' NSCLCs and might be involved in tobacco-related carcinogenesis.
Lack of Telomerase Activity in Lung Carcinoids Is Dependent on Human Telomerase Reverse Transcriptase Transcription and Alternative Splicing and Is Associated with Long Telomeres
Authors: Zaffaroni Nadia , Villa Raffaella , Pastorino Ugo , Cirincione Rosalia , Incarbone Matteo , Alloisio Marco , Curto Maria , Pilotti Silvana , Daidone Maria Grazia 
Published: September 2005

Abstract
Purpose: Preliminary evidence indicates that telomerase activity is significantly less expressed in typical carcinoids than in large cell neuroendocrine carcinomas or in small cell lung cancers. Knowledge of the mechanisms by which telomerase is differentially regulated in neuroendocrine lung tumors is important for a better understanding of the pathogenesis of these malignancies.
Experimental Design: We investigated telomerase activity in 86 neuroendocrine lung tumors and correlated the enzyme activity with the expression of the enzyme subunits [human RNA component (hTR), human telomerase reverse transcriptase (hTERT), and alternatively spliced hTERT variants], with the telomere-associated protein human protection of telomere-1, and with the telomere length pattern.
Results: A significantly (P = 0.0001) lower frequency of telomerase-positive cases was found in typical carcinoids (14%) than in large cell neuroendocrine carcinomas (87%) and small cell lung cancers (92%). hTR was constitutively expressed in all carcinoids. Telomerase-negative carcinoids were characterized by the absence of any hTERT transcript, only displayed the β− alternatively spliced variant, or concomitantly expressed the α+β+ full-length message with different combinations of alternatively spliced variants. However, in these tumors, a more abundant level of alternatively spliced transcripts than that of the α+β+ full-length transcript was generally found. No significant difference was observed in human protection of telomere-1 expression between telomerase-negative and telomerase-positive carcinoids. Telomeres were significantly (P &lt; 0.05) longer in telomerase-negative carcinoids than in telomerase-positive carcinoids (median value, 9.15 versus 4.47 kb). However, alternative lengthening of telomeres, as shown by associated promyelocytic leukemia bodies, was not observed in these tumors.
Conclusions: Our results indicate that telomerase is repressed in most lung carcinoids and that hTERT transcription and alternative splicing play a role in such a negative regulation. Moreover, the absence of any telomerase maintenance mechanism may contribute to the favorable prognosis of this malignancy.