bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of the Novel Camptothecin Gimatecan against Orthotopic and Metastatic Human Tumor Xenograft Models
Authors: De Cesare Michelandrea , Pratesi Graziella , Veneroni Silvia , Bergottini Raffaella , Zunino Franco 
Published: September 2005

Abstract
Purpose: Gimatecan, a novel oral lipophilic camptothecin characterized by favorable features at molecular/cellular level and by a promising profile of preclinical activity, is currently in clinical phase I/II. The aim of the study was to additionally investigate the therapeutic potential of the drug in human tumor xenografts growing in different organs as models representative of tumor growth in the clinical setting.
Experimental Design: The models include two orthotopic central nervous system tumors, two melanomas growing intracranially, and an ovarian carcinoma growing i.p. In addition, gimatecan was tested against experimental lung metastases of two tumor types (lung and ovarian carcinomas). Gimatecan was delivered by oral gavage according to various schedules (daily or intermittent). The time (in days) mice required to show evident signs of disease was used as end point for drug efficacy.
Results: Gimatecan was highly effective in delaying disease manifestations in all tumor systems investigated. In the intracranially growing tumors, a significant time increase (versus control mice) was achieved by the drug administered according to all of the schedules. In addition, almost all treated mice were alive and tumor-free at the end of the experiment in the metastatic models and in the ascitic ovarian tumor. The daily prolonged treatment schedule was the best one.
Conclusions: In all tumor systems investigated, including orthotopic tumor growth models and lung metastases, the oral administration of gimatecan showed a therapeutic benefit in terms of survival increase. The good oral availability allowed a prolonged daily treatment regimen, which seems the most promising to exploit the therapeutic potential of the drug.
Genetic Analysis of the
RNASEL
Gene in Hereditary, Familial, and Sporadic Prostate Cancer
Authors: Wiklund Fredrik , Jonsson Björn-Anders , Brookes Anthony J. , Strömqvist Linda , Adolfsson Jan , Emanuelsson Monica , Adami Hans-Olov , Augustsson-Bälter Katarina , Grönberg Henrik 
Published: September 2005

Abstract
Purpose: The RNASEL gene has been proposed as a candidate gene for the HPC1 locus through a positional cloning and candidate gene approach. Cosegregation between the truncating mutation E265X and disease in a hereditary prostate cancer (HPC) family and association between prostate cancer risk and the common missense variant R462Q has been reported. To additionally evaluate the possible role of RNASEL in susceptibility to prostate cancer risk, we performed a comprehensive genetic analysis of sequence variants in RNASEL in the Swedish population.
Experimental Design: Using 1624 prostate cancer cases and 801 unaffected controls, the truncating mutation E265X and five common sequence variants, including the two missense mutations R462Q and D541E, were evaluated for association between genotypes/haplotypes and prostate cancer risk.
Results: The prevalence of E265X carriers among unaffected controls and prostate cancer patients was almost identical (1.9 and 1.8% in controls and cases, respectively), and evidence for segregation of E265X with disease was not observed within any HPC family. Overall, the analyses of common sequence variants provided limited evidence for association with prostate cancer risk. We found a marginally significant inverse association between the missense mutation D541E and sporadic prostate cancer risk (odds ratio, 0.77; 95% confidence interval, 0.59–1.00) and reduced risk of prostate cancer in carriers of two different haplotypes being completely discordant.
Conclusions: Considering the high quality in genotyping and the size of this study, these results provide solid evidence against a major role of RNASEL in prostate cancer etiology in Sweden.
The CC Chemokine Receptor 4 as a Novel Specific Molecular Target for Immunotherapy in Adult T-Cell Leukemia/Lymphoma
Authors: Ishida Takashi , Iida Shinsuke , Akatsuka Yoshiki , Ishii Toshihiko , Miyazaki Mikinori , Komatsu Hirokazu , Inagaki Hiroshi , Okada Noriko , Fujita Teizo , Shitara Kenya , Akinaga Shiro , Takahashi Toshitada , Utsunomiya Atae , Ueda Ryuzo 
Published: September 2005

AbstractAdult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm with dismal prognosis, and no optimal therapy has been developed. We tested the defucosylated chimeric anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, KM2760, to develop a novel immunotherapy for this refractory tumor. In the presence of peripheral blood mononuclear cells (PBMCs) from healthy adult donors, KM2760 induced CCR4-specific antibody-dependent cellular cytotoxicity (ADCC) against CCR4-positive ATLL cell lines and primary tumor cells obtained from ATLL patients. We next examined the KM2760-induced ADCC against primary ATLL cells in an autologous setting. Antibody-dependent cellular cytotoxicity mediated by autologous effector cells was generally lower than that mediated by allogeneic control effector cells. However, a robust ADCC activity was induced in some cases, which was comparable with that mediated by allogeneic effector cells. It suggests that the ATLL patients’ PBMCs retain substantial ADCC-effector function, although the optimal conditions for maximal effect have not yet been determined. In addition, we also found a high expression of FoxP3 mRNA and protein, a hallmark of regulatory T cells, in ATLL cells, indicating the possibility that ATLL cells originated from regulatory T cells. KM2760 reduced FoxP3 mRNA expression in normal PBMCs along with CCR4 mRNA by lysis of CCR4+ T cells in vitro. Our data suggest not only that the CCR4 molecule could be a suitable target for the novel antibody-based therapy for patients with ATLL but also that KM2760 may induce effective tumor immunity by reducing the number of regulatory T cells.
pRb2/p130 Decreases Sensitivity to Apoptosis Induced by Camptothecin and Doxorubicin but not by Taxol
Authors: Tonini Tiziana , Gabellini Chiara , Bagella Luigi , D’Andrilli Giuseppina , Masciullo Valeria , Romano Gaetano , Scambia Giovanni , Zupi Gabriella , Giordano Antonio 
Published: September 2005

Abstract
Purpose: In addition to their original function as cell cycle regulators, retinoblastoma (Rb) family members were recently reported to modulate the sensitivity of cancer cells to chemotherapeutic agents. The purpose of this study is to investigate the possible role of pRb2/p130 in the sensitivity of ovarian cancer to camptothecin, doxorubicin, and taxol.
Experimental Design: pRb2/p130 was overexpressed in the CAOV-3 ovarian cancer cell line, and the effect of pRb2/p130 overexpression on sensitivity to apoptosis trigged by IC50 doses of different drugs was evaluated by various methods, including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, and Western blot analyses.
Results: The results reported in this study support the conclusion that overexpression of pRb2/p130 in the CAOV-3 ovarian cancer cell line lacking wild-type p53 is able to inhibit apoptosis triggered by camptothecin and doxorubicin through the c-Jun NH2-terminal kinase signaling transduction pathway. Conversely, taxol-induced cell death is not influenced by the pRb2/p130 protein level.
Conclusions: A careful analysis of pRb2/p130 expression in tumor specimens could help to identify the best clinical protocol to be used for each patient, improving efficacy and tolerance and therefore offering additional progress in the treatment of advanced ovarian cancer.
Proteomic Analysis to Identify Breast Cancer Biomarkers in Nipple Aspirate Fluid
Authors: Alexander Hannah , Stegner Andrew L. , Wagner-Mann Colette , Du Bois Garrett C. , Alexander Stephen , Sauter Edward R. 
Published: September 2005

Abstract
Purpose: Proteomic analysis of breast nipple aspirate fluid (NAF) holds promise as a noninvasive method to identify markers of breast cancer. The objectives of the study were to: (a) describe the NAF proteome, (b) identify candidate markers of breast cancer in NAF by using proteomic analysis, and (c) validate the markers identified by using a quantitative, high-throughput ELISA analysis.
Experimental Design: For proteome analysis, NAF proteins from a single subject without breast cancer were separated by two-dimensional PAGE and were subjected to matrix-assisted laser desorption ionization time-of-flight mass spectometry identification. A total of 41 different proteins were identified, 25 of which were known to be secreted. To identify breast cancer markers, we separated 20 NAF samples (10 normal, 10 cancer) by two-dimensional PAGE. Three protein spots were detected that were up-regulated in three or more cancer samples. These spots were identified to be gross cystic disease fluid protein (GCDFP)-15, apolipoprotein D (apoD), and α1-acid glycoprotein (AAG). To validate these three potential biomarkers, 105 samples (53 from benign breasts and 52 from breasts with cancer) were analyzed using ELISA.
Results: Among all of the subjects, GCDFP-15 levels were lower (P &lt; 0.001) and AAG levels were higher (P = 0.001) in breasts with cancer. This was also true in premenopausal (GCDFP-15, P = 0.011; AAG, P = 0.002) but not in postmenopausal women. GCDFP-15 levels were lowest (P = 0.003) and AAG levels highest (P &lt; 0.001) in women with ductal carcinoma in situ (DCIS). Menopausal status influenced GCDFP-15 and AAG more in women without breast cancer than in women with breast cancer. apoD levels did not correlate significantly with breast cancer.
Conclusions: Our study revealed that the NAF proteome, as defined by two-dimensional PAGE, consists of a limited number of proteins, and that the expression of AAG and GCDFP-15 correlates with disease presence and stage.
Efficient Elimination of B-Lineage Lymphomas by Anti-CD20–Auristatin Conjugates
Authors: Law Che-Leung , Cerveny Charles G. , Gordon Kristine A. , Klussman Kerry , Mixan Bruce J. , Chace Dana F. , Meyer Damon L. , Doronina Svetlana O. , Siegall Clay B. , Francisco Joseph A. , Senter Peter D. , Wahl Alan F. 
Published: September 2005

Abstract
The anti-CD20 antibody rituximab is useful in the treatment of certain B-cell malignancies, most notably non-Hodgkin’s lymphoma. Its efficacy has been increased when used in combination with chemotherapy, yet anti-CD20 monoclonal antibodies (mAbs) directly conjugated with drugs such as doxorubicin (Dox) have failed to deliver drug or to demonstrate antitumor activity. We have produced anti-CD20 antibody-drug conjugates that possess potent antitumor activity by using the anti-mitotic agent, monomethyl auristatin E (MMAE), linked via the lysosomally cleavable dipeptide, valine-citrulline (vc). Two anti-CD20 conjugates, rituximab-vcMMAE and 1F5-vcMMAE, were selectively cytotoxic against CD20+ B-lymphoma cell lines, with IC50 values ranging from 50 ng/mL to 1 μg/mL. Unlike rituximab, which showed diffuse surface localization, rituximab-vcMMAE capped and was internalized within 4 hours after binding to CD20+ B cells. Internalization of rituximab-vcMMAE was followed by rapid G2-M phase arrest and onset of apoptosis. Anti-CD20 antibody-drug conjugates prepared with Dox were internalized and localized as with rituximab-vcMMAE, yet these were not effective for drug delivery (IC50 &gt; 50 μg/mL). Consistent with in vitro activity, rituximab-vcMMAE showed antitumor efficacy in xenograft models of CD20-positive lymphoma at doses where rituximab or rituximab-Dox conjugates were ineffective. These data indicate that anti-CD20–based antibody-drug conjugates are effective antitumor agents when prepared with a stable, enzyme-cleavable peptide linkage to highly potent cytotoxic agents such as MMAE.
c-
erb
B-2 Related Aggressiveness in Breast Cancer Is Hypoxia Inducible Factor-1α Dependent
Authors: Giatromanolaki Alexandra , Koukourakis Michael I. , Simopoulos Costantinos , Polychronidis Alexandros , Gatter Kevin C. , Harris Adrian L. , Sivridis Efthimios 
Published: September 2005

Abstract
c-erbB-2–positive breast carcinomas are highly aggressive tumors. In vitro data on breast cell lines showed that c-erbB-2 enhanced translational efficiency of hypoxia inducible factor-1α (HIF1α) production (Laughner et al., Mol Cell Biol 2001;21:3995–4005). We investigated the clinical correlate of this observation to assess whether c-erbB-2 expression was related to HIF1α expression, angiogenesis, and prognosis. A series of 180 breast carcinomas of known c-erbB-2 status (90 c-erbB-2–positive and 90 c-erbB-2–negative carcinomas) were stained immunohistochemically for HIF1α and CD31 endothelial cell antigen. c-erbB-2 positivity was clearly related to HIF1α protein expression and high angiogenesis. However, prognosis was decreased only in cases with simultaneous c-erbB-2 and HIF1α expression. If activation of c-erbB-2 in humans results in overexpression of HIF1α independently of conditions of hypoxia, as occur in experimental studies, this interaction may represent a main pathway conferring clinical aggressiveness to c-erbB-2–positive breast tumors.
Human Autologous Tumor-Specific T-Cell Responses Induced by Liposomal Delivery of a Lymphoma Antigen
Authors: Neelapu Sattva S. , Baskar Sivasubramanian , Gause Barry L. , Kobrin Carol B. , Watson Thelma M. , Frye Andrea Robin , Pennington Robin , Harvey Linda , Jaffe Elaine S. , Robb Richard J. , Popescu Mircea C. , Kwak Larry W. 
Published: September 2005

AbstractPurpose: The idiotype (Id) of the immunoglobulin on a given B-cell malignancy is a clonal marker that can serve as a tumor-specific antigen. We developed a novel vaccine formulation by incorporating Id protein with liposomal lymphokine that was more potent than a prototype, carrier-conjugated Id protein vaccine in preclinical studies. In the present study, we evaluated the safety and immunogenicity of this vaccine in follicular lymphoma patients.Experimental Design: Ten patients with advanced-stage follicular lymphoma were treated with five doses of this second generation vaccine after chemotherapy-induced clinical remission. All patients were evaluated for cellular and humoral immune responses.Results: Autologous tumor and Id-specific type I cytokine responses were induced by vaccination in 10 and 9 patients, respectively. Antitumor immune responses were mediated by both CD4+ and CD8+ T cells, were human lymphocyte antigen class I and II associated, and persisted 18 months beyond the completion of vaccination. Specific anti-Id antibody responses were detected in four patients. After a median follow-up of 50 months, 6 of the 10 patients remain in continuous first complete remission.Conclusions: This first clinical report of a liposomal cancer vaccine demonstrates that liposomal delivery is safe, induces sustained tumor-specific CD4+ and CD8+ T-cell responses in lymphoma patients, and may serve as a model for vaccine development against other human cancers and infectious pathogens.
Genetic Polymorphisms of Human
Flavin Monooxygenase 3
in Sulindac-Mediated Primary Chemoprevention of Familial Adenomatous Polyposis
Authors: Hisamuddin Irfan M. , Wehbi Mohammad A. , Chao Ann , Wyre Hadley W. , Hylind Linda M. , Giardiello Francis M. , Yang Vincent W. 
Published: September 2005

Abstract
Purpose: Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) effective in regressing adenomas in patients with familial adenomatous polyposis (FAP). However, a recent randomized trial showed that sulindac, when compared with placebo, failed to prevent the development of adenomatous polyps in genotypically positive but phenotypically negative FAP patients. The present study determined whether polymorphisms in the gene encoding flavin monooxygenase 3 (FMO3), a hepatic microsomal enzyme that inactivates sulindac, played a role in determining the efficacy of sulindac in preventing polyposis in this cohort of FAP patients.
Experimental Design: Genotyping was performed on seven established FMO3 polymorphisms previously shown to have functional relevance—M66I, P153L, E158K, V257M, E305X, E308G, and R492W—in 21 and 20 FAP patients, who received sulindac and placebo, respectively.
Results: None of the 41 patients exhibited heterozygous or homozygous M66I and R492W variant alleles, or homozygous P153L, V257M, and E305X variant alleles. Among sulindac-treated patients who did not develop adenomas (“responders”), 4 (33%) were homozygous for E158K and 2 (17%) were homozygous for E308G variant alleles. In contrast, none of the patients on sulindac who developed adenomas (“nonresponders”) exhibited homozygosity for either of the two variant alleles. In addition, polymorphisms in the E158K or E308G allele were associated with a significant reduction in mucosal prostanoid levels in patients treated with sulindac.
Conclusions: Polymorphisms in FMO3, particularly at the E158K and E308G loci, may reduce activity in catabolizing sulindac and result in an increased efficacy to prevent polyposis in FAP.
Evaluation of Combination Chemotherapy
Authors: Zhao Liang , Wientjes M. Guillaume , Au Jessie L-S. 
Published: September 2005

AbstractIsobologram and combination index (CI) analyses are the two most popular methods for evaluating drug interactions in combination cancer chemotherapy. As the commonly used CI-based software program uses linear regression, our first objective was to evaluate the effects of logarithmic data transformation on data analysis and conclusions. Monte-Carlo simulations were conducted with experimentally relevant parameter values to generate error-containing effect or concentration-effect data of single agents and combinations. The simulated data were then analyzed with linear and nonlinear regression. The results showed that data transformation reduced the accuracy and precision of the regression-derived IC50, curve shape parameter and CI values. Furthermore, as neither isobologram nor CI analyses provide output of concentration-effect curves for investigator evaluation, our second objective was to develop a method and the associated computer program/algorithm to (a) normalize drug concentrations in IC50 equivalents and thereby enable simultaneous presentation of the curves for single agents and combinations in a single plot for visual inspection of potential curve shifts, (b) analyze concentration-effect data with nonlinear regression, and (c) use the curve shift analysis simultaneously with isobologram and CI analyses. The applicability of this method was shown with experimentally obtained data for single agent doxorubicin and suramin and their combinations in cultured tumor cells. In summary, this method, by incorporating nonlinear regression and curve shift analysis, although retaining the attractive features of isobologram and CI analyses, reduced the potential errors introduced by logarithmic data transformation, enabled visual inspection of data variability and goodness of fit of regression analysis, and simultaneously provided information on the extent of drug interaction at different combination ratios/concentrations and at different effect levels.
Phase I/II Randomized Trial Evaluating the Safety and Clinical Effects of Repifermin Administered to Reduce Mucositis in Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation
Authors: Freytes Cesar O. , Ratanatharathorn Voravit , Taylor Charles , Abboud Camille , Chesser Nancy , Restrepo Alejandro , Arango Jorge , Odenheimer Daniel 
Published: September 2005

Abstract
Purpose: To evaluate the safety of repifermin (keratinocyte growth factor-2) administered before and after autologous hematopoietic stem cell transplantation (auto-HSCT). A preliminary analysis of the ability of keratinocyte growth factor-2 to prevent mucositis was also done.
Experimental Design: Forty-two patients received intravenous repifermin (25 μg/kg or 50 μg/kg) or placebo for 3 days before their auto-HSCT conditioning regimen and for up to 10 days after auto-HSCT. Within each dose level, 14 patients were randomized to repifermin and 7 patients to placebo. Clinical evaluations of mucositis were scheduled before auto-HSCT conditioning regimen, on the day of transplant, and three times per week until mucositis resolved.
Results: In general, the incidence of adverse events was similar for patients treated with repifermin and placebo. No clinically meaningful differences were noted among treatment groups for clinical laboratory variables. Treatment groups experienced similar time to engraftment. The frequency of Grade 2 to 4 mucositis was 100% for patients in the placebo group, 64% for patients in the 25 μg/kg group (P = 0.041 versus placebo), and 50% for patients in the 50 μg/kg group (P = 0.006 versus placebo). Results of other endpoints, including pain on swallowing and use of pain medication specifically for mucositis, suggested a better outcome for patients in the 50 μg/kg group compared with the placebo and 25 μg/kg groups.
Conclusions: Repifermin was well tolerated. Repifermin given before and after auto-HSCT seems to be active in reducing mucositis, but a larger trial will be necessary to determine the efficacy of repifermin with this dose schedule.
A Novel
Ex vivo
Model System for Evaluation of Conditionally Replicative Adenoviruses Therapeutic Efficacy and Toxicity
Authors: Kirby Tyler O. , Rivera Angel , Rein Daniel , Wang Minghui , Ulasov Ilya , Breidenbach Martina , Kataram Manjula , Contreras Juan L. , Krumdieck Carlos , Yamamoto Masato , Rots Marianne G. , Haisma Hidde J. , Alvarez Ronald D. , Mahasreshti Parameshwar J. , Curiel David T. 
Published: September 2005

Abstract
Purpose: Current animal tumor models are inadequate for the evaluation of toxicity and efficacy of conditionally replicative adenoviruses. A novel model system is needed that will provide insight into the anticipated therapeutic index of conditionally replicative adenoviruses preclinically. We endeavored to show a novel model system, which involves ex vivo evaluation of conditionally replicative adenovirus toxicity and therapeutic efficacy in thin, precision-cut slices of human primary tumor and liver.
Experimental Design: The Krumdieck thin-slice tissue culture system was used to obtain and culture slices of tumor xenografts of ovarian cancer cell lines, human primary ovarian tumors, and human liver. We determined the viability of slices in culture over a period of 36 to 48 hours by ([3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxphenyl-2-(4-sulfophenyl)-2H-tetrazolium, inner salt)]) (MTS) assay. In vitro Hey cells, slices of Hey xenografts, and human ovarian tumor or human liver slices were infected with 500vp/cell of either replication competent wild-type adenovirus (Ad5/3wt), conditionally replicative adenovirus (Ad5/3cox-2), or the replication deficient adenovirus (Ad5/3luc1). At 12-, 24-, and 36-hour intervals, the replication of adenoviruses in these slices was determined by quantitative reverse transcription-PCR of adenoviral E4 copy number.
Results: Primary tumor slices were able to maintain viability for up to 48 hours after infection with nonreplicative virus (Ad5luc1). Infection of Hey xenografts with Ad5/3cox-2 showed replication consistent with that seen in Hey cells infected in an in vitro setting. Primary tumor slices showed replication of both Ad5/3wt and Ad5/3cox over a 36-hour time period. Human liver slices showed replication of Ad5/3wt but a relative reduction in replication of Ad5/3cox-2 indicative of conditional replication “liver off” phenotype, thus predicting lower toxicity.
Conclusions: The thin-slice model system represents a stringent method of ex vivo evaluation of novel replicative adenoviral vectors and allows assessment of human liver replication relative to human tumor replication. This is the first study to incorporate this system for evaluation of therapeutic efficacy and replicative specificity of conditionally replicative adenoviruses. Also, the study is the first to provide a valid means for preclinical assay of potential conditionally replicative adenovirus-based hepatotoxicities, thus providing a powerful tool to determine therapeutic index for clinical translation of conditionally replicative adenoviruses.