bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I and Pharmacokinetic Study of Tasidotin Hydrochloride (ILX651), a Third-Generation Dolastatin-15 Analogue, Administered Weekly for 3 Weeks Every 28 Days in Patients with Advanced Solid Tumors
Authors: Mita Alain C. , Hammond Lisa A. , Bonate Peter L. , Weiss Geoffrey , McCreery Heather , Syed Samira , Garrison Mitchell , Chu Quincy S.C. , DeBono Johann S. , Jones Christopher B. , Weitman Steve , Rowinsky Eric K. 
Published: September 2006

Abstract
Purpose: To determine the safety, tolerability, and pharmacokinetics and to seek preliminary evidence of anticancer activity of tasidotin (ILX651), a novel dolastatin analogue, when administered as a 30-minute i.v. infusion weekly for 3 weeks every 4 weeks.
Experimental Design: Thirty patients with advanced solid malignancies were treated with 82 courses at six dose levels ranging from 7.8 to 62.2 mg/m2 weekly, initially according to an accelerated dose-escalation scheme, which evolved into a Fibonacci scheme as a relevant degree of toxicity was observed. Plasma and urine were sampled to characterize the pharmacokinetic behavior of tasidotin.
Results: A high incidence of neutropenia complicated by fever (one patient), or precluding treatment on day 15 (three patients), was the principal toxicity of tasidotin, at doses above 46.8 mg/m2. At all dose levels, nonhematologic toxicities were generally mild to moderate and manageable. Grade 3 toxicities included diarrhea and vomiting (one patient each). Drug-induced neurosensory symptoms were mild and there was no evidence of cardiovascular toxicity, which has been previously associated with other dolastatins. Tasidotin pharmacokinetics were mildly nonlinear, whereas metabolite kinetics were linear. A patient with non–small cell lung carcinoma experienced a minor response, and a patient with hepatocellular carcinoma had stable disease lasting 11 months.
Conclusions: The recommended dose for phase II studies of tasidotin administered on this schedule is 46.8 mg/m2. The mild myelosuppression and manageable nonhematologic toxicities at the recommended dose, the evidence of antitumor activity, and the unique mechanistic aspects of tasidotin warrant further disease-directed evaluations on this and alternative schedules.
Aberrant Nuclear Accumulation of Glycogen Synthase Kinase-3β in Human Pancreatic Cancer: Association with Kinase Activity and Tumor Dedifferentiation
Authors: Ougolkov Andrei V. , Fernandez-Zapico Martin E. , Bilim Vladimir N. , Smyrk Thomas C. , Chari Suresh T. , Billadeau Daniel D. 
Published: September 2006

Abstract
Purpose: We have shown recently that glycogen synthase kinase-3 (GSK-3) β regulates nuclear factor-κB (NF-κB)–mediated pancreatic cancer cell survival and proliferation in vitro. Our objective was to determine the localization of GSK-3β in pancreatic cancer cells and assess the antitumor effect of GSK-3 inhibition in vivo to improve our understanding of the mechanism by which GSK-3β affects NF-κB activity in pancreatic cancer.
Experimental Design: Immunohistochemistry and cytosolic/nuclear fractionation were done to determine the localization of GSK-3β in human pancreatic tumors. We studied the effect of GSK-3 inhibition on tumor growth, cancer cell proliferation, and survival in established CAPAN2 tumor xenografts using a tumor regrowth delay assay, Western blotting, bromodeoxyuridine incorporation, and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling.
Results: We found nuclear accumulation of GSK-3β in pancreatic cancer cell lines and in 62 of 122 (51%) human pancreatic adenocarcinomas. GSK-3β nuclear accumulation is significantly correlated with human pancreatic cancer dedifferentiation. We have found that active GSK-3β can accumulate in the nucleus of pancreatic cancer cells and that inhibition of GSK-3 kinase activity represses its nuclear accumulation via proteasomal degradation within the nucleus. Lastly, we have found that inhibition of GSK-3 arrests pancreatic tumor growth in vivo and decreases NF-κB-mediated pancreatic cancer cell survival and proliferation in established tumor xenografts.
Conclusions: Our results show the antitumor effect of GSK-3 inhibition in vivo, identify GSK-3β nuclear accumulation as a hallmark of poorly differentiated pancreatic adenocarcinoma, and provide new insight into the mechanism by which GSK-3β regulates NF-κB activity in pancreatic cancer.
A Phase I Pharmacokinetic Study of HMN-214, a Novel Oral Stilbene Derivative with Polo-Like Kinase-1–Interacting Properties, in Patients with Advanced Solid Tumors
Authors: Garland Linda L. , Taylor Charles , Pilkington Deborah L. , Cohen Jan L. , Von Hoff Daniel D. 
Published: September 2006

Abstract
Purpose: HMN-214 is an oral prodrug of HMN-176, a stilbene derivative that interferes with the subcellular spatial location of polo-like kinase-1, a serine/threonine kinase that regulates critical mitotic events. We conducted a dose escalation study of HMN-214 in patients with advanced cancer to assess the safety profile and pharmacokinetics of HMN-214 and to establish the maximum tolerated dose.
Experimental Design: Thirty-three patients were enrolled onto four dosing cohorts of HMN-214 from 3 to 9.9 mg/m2/d using a continuous 21-day dosing schedule every 28 days, with pharmacokinetic sampling during cycle 1.
Results: A severe myalgia/bone pain syndrome and hyperglycemia were dose-limiting toxicities at 9.9 mg/m2/d. A dose reduction and separate enrollment by pretreatment status (lightly versus heavily pretreated) was undertaken, with one dose-limiting toxicity (grade 3 bone pain) at 8 mg/m2/d. The maximum tolerated dose was defined as 8 mg/m2/d for both treatment cohorts. Dose-proportional increases were observed in AUC but not Cmax. There was no accumulation of HMN-176, the metabolite of HMN-214, with repeated dosing. Seven of 29 patients had stable disease as best tumor response, including 6-month stable disease in a heavily pretreated breast cancer patient. A transient decline in carcinoembryonic antigen in a patient with colorectal cancer was noted.
Conclusions: The maximum tolerated dose and recommended phase II dose of HMN-214 when administered on this schedule was 8 mg/m2/d regardless of pretreatment status. Further development of HMN-214 will focus on patient populations for which high expression of polo-like kinase-1 is seen (i.e., prostate and pancreatic cancer patients).
Eliminating Established Tumor in nu/nu Nude Mice by a Tumor Necrosis Factor-α-Related Apoptosis-Inducing Ligand–Armed Oncolytic Adenovirus
Authors: Dong Fengqin , Wang Li , Davis John J. , Hu Wenxian , Zhang Lidong , Guo Wei , Teraishi Fuminori , Ji Lin , Fang Bingliang 
Published: September 2006

Abstract
Purpose: The tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) and oncolytic viruses have recently been investigated extensively for cancer therapy. However, preclinical and clinical studies have revealed that their clinical application is hampered by either weak anticancer activity or systemic toxicity. We examined whether the weaknesses of the two strategies can be overcome by integrating the TRAIL gene into an oncolytic vector.
Experimental Design: We constructed a TRAIL-expressing oncolytic adenovector designated as Ad/TRAIL-E1. The expression of both the TRAIL and viral E1A genes is under the control of a synthetic promoter consisting of sequences from the human telomerase reverse transcriptase promoter and a minimal cytomegalovirus early promoter. The transgene expression, apoptosis induction, viral replication, antitumor activity, and toxicity of Ad/TRAIL-E1 were determined in vitro and in vivo in comparison with control vectors.
Results: Ad/TRAIL-E1 elicited enhanced viral replication and/or stronger oncolytic effect in vitro in various human cancer cell lines than a TRAIL-expressing, replication-defective adenovector or an oncolytic adenovector–expressing green fluorescent protein. Intralesional administration of Ad/TRAIL-E1 eliminated all s.c. xenograft tumors established from a human non–small cell lung cancer cell line, H1299, on nu/nu nude mice, resulting in long-term, tumor-free survival. Furthermore, we found no treatment-related toxicity.
Conclusions: Viral replication and antitumor activity of oncolytic adenovirus can be enhanced by the TRAIL gene and Ad/TRAIL-E1 could become a potent therapeutic agent for cancer therapy.
Selective Profiling of Proteins in Lung Cancer Cells from Fine-Needle Aspirates by Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry
Authors: Amann Joseph M. , Chaurand Pierre , Gonzalez Adriana , Mobley James A. , Massion Pierre P. , Carbone David P. , Caprioli Richard M. 
Published: September 2006

Abstract
Purpose: Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been used to analyze tumor sections and can determine tumor type, nodal involvement, and survival, and shows promise in predicting therapeutic response. Our purpose was to develop a method compatible with MALDI-TOF MS that allows selective analysis of cancer cells in mixed clinical samples such as fine-needle aspirates.
Experimental Design: Lung cancer cell lines were cytocentrifuged onto metal-coated, transparent glass slides and used for optimization of fixation, staining, and RBC lysis protocols. Fine-needle aspirates from human tumors and mouse model tumors were used to provide fresh tissue samples for determining the feasibility of this method.
Results: The MALDI-TOF MS compatible fixation and staining techniques provided high-resolution cellular morphology, which allowed identification and selective spotting of tumor cells. The RBC lysis step efficiently removed contaminating RBC yielding spectra nearly free from hemoglobin peaks. Protein profiles of fine-needle aspirates were found highly reproducible and similar to the profiles of the tissue from which they were obtained. Using this method, we were able to differentiate between xenograft tumors derived from two different human cell lines, A549 and H460.
Conclusion: This procedure results in the production of high-quality, cancer cell–specific protein profiles. This highly reproducible technique could be applied to many other types of mixed clinical samples and has the potential to be very useful in the clinical diagnosis, classification, and, potentially, the individualized treatment of cancer patients.
Identification of Cripto-1 as a Novel Serologic Marker for Breast and Colon Cancer
Authors: Bianco Caterina , Strizzi Luigi , Mancino Mario , Rehman Aasia , Hamada Shin , Watanabe Kazuhide , De Luca Antonella , Jones Brenda , Balogh Gabriela , Russo Jose , Mailo Daniel , Palaia Raffaele , D'Aiuto Giuseppe , Botti Gerardo , Perrone Francesco , Salomon David S. , Normanno Nicola 
Published: September 2006

Abstract
Purpose: Human Cripto-1 (CR-1), a cell membrane glycosylphosphatidylinositol-anchored glycoprotein that can also be cleaved from the membrane, is expressed at high levels in several different types of human tumors. We evaluated whether CR-1 is present in the plasma of patients with breast and colon cancer, and if it can represent a new biomarker for these malignancies.
Experimental Design: We determined CR-1 plasma levels using a sandwich-type ELISA in 21 healthy volunteers, 54 patients with breast cancer, 33 patients with colon carcinoma, and 21 patients with benign breast lesions. Immunohistochemical analysis was also used to assess CR-1 expression in cancerous tissues.
Results: Very low levels of CR-1 (mean ± SD) were detected in the plasma of healthy volunteers (0.32 ± 0.19 ng/mL). A statistically significant increase in the levels of plasma CR-1 was found in patients with colon carcinoma (4.68 ± 3.5 ng/mL) and in patients with breast carcinoma (2.97 ± 1.48 ng/mL; P &lt; 0.001). Although moderate levels of plasma CR-1 were found in women with benign lesions of the breast (1.7 ± 0.99 ng/mL), these levels were significantly lower than in patients with breast cancer (P &lt; 0.001). Finally, immunohistochemical analysis and real-time reverse transcription-PCR confirmed strong positivity for CR-1 in colon and/or breast tumor tissues.
Conclusion: This study suggests that plasma CR-1 might represent a novel biomarker for the detection of breast and colon carcinomas.
Validity of Messenger RNA Expression Analyses of Human Saliva
Authors: Kumar Shalini V. , Hurteau Gregory J. , Spivack Simon D. 
Published: September 2006

Abstract
Purpose: The origins of expression microarray and reverse transcription-PCR (RT-PCR) signals in human saliva were evaluated.
Experimental Design: The “RNA” extracts from human saliva samples were treated with vehicle, DNase, or RNase. Two-step amplification and hybridization to Affymetrix 133A cDNA microarrays were then done. Confirmatory RT-PCR experiments used conventionally designed PCR primer pairs for the reference housekeeper transcripts encoding 36B4, β-actin, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA sequences, which are known to be homologous to genomic DNA pseudogene sequences. Negative controls included the omission of reverse transcriptase (“no-RT”) to detect any DNA-derived signal. Finally, an RNA-specific RT-PCR strategy eliminated confounding signals from contaminating genomic DNA.
Results: Microarray experiments revealed that untreated, DNase-treated, and RNase-treated “RNA” extracts from saliva all yielded negligible overall signals. Specific microarray signals for 36B4, β-actin, and GAPDH were low, and were unaffected by RNase. Real-time quantitative RT-PCR reactions using conventional, non–RNA-specific primers on saliva samples yielded PCR products for 36B4, β-actin, and GAPDH; DNase-treated saliva samples did not yield a PCR product, and the “no-RT” and “+RT” conditions yielded similar amounts of PCR product. The RNA-specific RT-PCR strategy, across all conditions, yielded no PCR product from saliva.
Conclusions: The combination of (a) a minimal microarray signal, which was unaffected by RNase treatment, (b) the presence of a conventional RT-PCR housekeeper product in both RNase-treated and no-RT saliva samples, (c) the absence of a conventional RT-PCR housekeeper product in DNase-treated conditions, and (d) the absence of a RNA-specific RT-PCR product shows that any microarray or RT-PCR signal in the saliva must arise from genomic DNA, not RNA. Thus, saliva extracts do not support mRNA expression studies.
Liver Intestine-Cadherin (CDH17) Haplotype Is Associated with Increased Risk of Hepatocellular Carcinoma
Authors: Wang Xiao Qi , Luk John M. , Garcia-Barcelo Mercè , Miao Xiaoping , Leung Pauline P. , Ho David W. , Cheung Siu Tim , Lam Brian Y. , Cheung Cindy K. , Wong Ashley S. , Lau Silvana S. , So Man Ting , Yu Wan Ching , Cai Qi , Liu Karen S. , Hui Chee Kin , Lau George K. , Poon Ronnie T.P. , Wong John , Fan Sheung Tat 
Published: September 2006

AbstractPurpose: Hepatocellular carcinoma (HCC), the most common form of liver cancer, is a leading cause of cancer death worldwide. We previously showed that aberrant mRNA splicing of the liver intestine-cadherin gene CDH17 in liver tissues was triggered by the specific constellation of two CDH17 single nucleotide polymorphisms (651T and IVS6+35G). CDH17 aberrant splicing was highly associated with tumor dissemination and shorter survival of HCC patients. Consequently, it is highly relevant to assess whether the presence of these single nucleotide polymorphisms in the general population represents a risk to the development of HCC.Experimental Design: We conducted a case-control study including 164 HCC and 99 cirrhosis patients and 293 healthy controls. Genotyping was done by PCR and direct sequencing. Odds ratio (OR) and χ2 analysis were used to analyze genotypes and haplotypes.Results: Genotypes 651TT [OR, 2.62; 95% confidence interval (95% CI), 1.34-5.03] and IVS6+35 GG (OR, 1.95; 95% CI, 1.04-3.62) were highly associated with HCC disease. The 651T (C&gt;T) and IVS6+35G (A&gt;G) alleles were also overrepresented in HCC patients and, in particular, the T-G haplotype was the most prevalent in HCC patients when compared with healthy controls (OR, 1.57; 95% CI, 1.167-2.109; P = 0.004), which was in agreement with the aberrant splicing observed in tumor tissues. There was no significant difference in genotype and allele frequencies between cirrhosis patients and controls.Conclusion: The functional T-G haplotype of CDH17 (651 C&gt;T and IVS6+35A&gt;G) is a genetic susceptibility factor for the development of HCC in a Chinese population.
Preclinical Characterization of AEG35156/GEM 640, a Second-Generation Antisense Oligonucleotide Targeting X-Linked Inhibitor of Apoptosis
Authors: LaCasse Eric C. , Cherton-Horvat Gabriele G. , Hewitt Kimberley E. , Jerome Lori J. , Morris Stephen J. , Kandimalla Ekambar R. , Yu Dong , Wang Hui , Wang Wei , Zhang Ruiwen , Agrawal Sudhir , Gillard John W. , Durkin Jon P. 
Published: September 2006

Abstract
Purpose: Cancer cells can use X-linked inhibitor of apoptosis (XIAP) to evade apoptotic cues, including chemotherapy. The antitumor potential of AEG35156, a novel second-generation antisense oligonucleotide directed toward XIAP, was assessed in human cancer models when given as a single agent and in combination with clinically relevant chemotherapeutics.
Experimental Design: AEG35156 was characterized for its ability to cause dose-dependent reductions of XIAP mRNA and protein in vitro and in vivo, to sensitize cancer cell lines to death stimuli, and to exhibit antitumor activity in multiple human cancer xenograft models as a single agent or in combination with chemotherapy.
Results: AEG35156 reduced XIAP mRNA levels with an EC50 of 8 to 32 nmol/L and decreased XIAP protein levels by &gt;80%. Loss of XIAP protein correlated with increased sensitization to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–mediated apoptosis in Panc-1 pancreatic carcinoma cells. AEG35156 exhibited potent antitumor activity relative to control oligonucleotides in three human cancer xenograft models (prostate, colon, and lung) and was capable of inducing complete tumor regression when combined with taxanes. Antitumor effects of AEG35156 correlated with suppression of tumor XIAP levels.
Conclusions: AEG35156 reduces XIAP levels and sensitizes tumors to chemotherapy. AEG35156 is presently under clinical assessment in multiple phase I trials in cancer patients as a single agent and in combination with docetaxel in solid tumors or cytarabine/idarubicin in leukemia.
Adenovirus-Mediated Calponin h1 Gene Therapy Directed against Peritoneal Dissemination of Ovarian Cancer: Bifunctional Therapeutic Effects on Peritoneal Cell Layer and Cancer Cells
Authors: Ogura Tomonori , Kobayashi Hiroaki , Ueoka Yousuke , Okugawa Kaoru , Kato Kiyoko , Hirakawa Toshio , Hashimoto Shigenari , Taniguchi Shun'ichiro , Wake Norio , Nakano Hitoo 
Published: September 2006

Abstract
Purpose: Calponin h1 (CNh1), one of the family of actin-binding proteins, stabilizes the filaments of actin and modulates various cellular biological phenotypes. Recent studies revealed the close correlation between the invasive tumor spread and the reduced expression of CNh1 and α-smooth muscle actin in the surrounding stromal cells. The purpose of this study is to evaluate the efficacy of i.p. CNh1 gene therapy against peritoneal dissemination of ovarian cancer.
Experimental Design: We used an adenoviral vector to induce the CNh1 gene into peritoneal cells and ovarian cancer cells as a means of enhancing or inducing the expression of α-smooth muscle actin as well as CNh1. The efficacy of gene transfer was examined by in vitro cell culture and in vivo animal experiments.
Results: The formation of longer and thicker actin fibers was observed in each transfected cell line, and the localization of these fibers coincided with that of externally transducted CNh1. With respect to changes in cell behavior, the CNh1-transfected peritoneal cells acquired an ability to resist ovarian cancer-induced shrinkage in cell shape; thus, cancer cell invasion through the monolayer of peritoneal cells was inhibited. In addition, CNh1-transfected ovarian cancer cells showed suppressed anchorage-independent growth and invasiveness, the latter of which accompanied impaired cell motility. The concomitant CNh1 transfection into both peritoneal cells and ovarian cancer cells produced an additive inhibitory effect with respect to cancer cell invasion through the peritoneal cell monolayer. By in vivo experiments designed to treat nude mice that had been i.p. inoculated with ovarian cancer cells, we found that the i.p. injected CNh1 adenovirus successfully blocked cancer-induced morphologic changes in peritoneal cell surface and significantly prolonged the survival time of tumor-bearing mice. Moreover, CNh1 adenovirus could successfully enhance the therapeutic effect of an anticancer drug without increase in side effects.
Conclusions: Thus, CNh1 gene therapy against peritoneal dissemination of ovarian cancer is bifunctionally effective (i.e., through inhibitory effects on the infected peritoneal cell layers that suppress cancer invasion and through direct antitumor effects against invasion and growth properties of cancer cells).
Effect of Raloxifene on the Incidence of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis Categorized by Breast Cancer Risk
Authors: Lippman Marc E. , Cummings Steven R. , Disch Damon P. , Mershon John L. , Dowsett Sherie A. , Cauley Jane A. , Martino Silvana 
Published: September 2006

Abstract
Purpose: To assess the effect of raloxifene, indicated for osteoporosis treatment and prevention, on invasive breast cancer in subgroups of postmenopausal women defined by risk factors for breast cancer.
Experimental Design: Data from the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) trial (N = 7,705) and a follow-up study, the 4-year Continuing Outcomes Relevant to Evista (CORE) trial (N = 4,011), were analyzed. Prespecified subgroups were defined by age (≥65 versus &lt;65 years), age at menopause (≥49 versus &lt;49 years), body mass index (≥25 versus &lt;25 kg/m2), family history of breast cancer (yes/no), serum estradiol level (5-10 versus &lt;5, &gt;10 versus &lt;5 pmol/L), prior estrogen therapy (yes/no), and bone mass at MORE baseline, and 5-year predicted risk, assessed using the modified Gail model (≥1.67 versus &lt;1.67%), at CORE baseline. Time-to-first invasive breast cancer was analyzed using Cox proportional hazards models.
Results: In the placebo group, older age, higher estradiol level, and a family history of breast cancer were associated with an increased breast cancer risk (P &lt; 0.05). Raloxifene therapy was associated with a reduced breast cancer risk in both women at lower and those at higher breast cancer risk. Hazard ratio point estimates were 0.11 to 0.67, corresponding to a 33% to 89% reduction in breast cancer risk with raloxifene versus placebo. The therapy by family history interaction was significant (P = 0.04).
Conclusions: Raloxifene therapy was associated with a reduced risk of invasive breast cancer in postmenopausal women irrespective of the presence/absence of risk factors; its effect was greater in women with a family history of breast cancer.