bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I and Pharmacokinetic Study of Col-3 (Metastat), an Oral Tetracycline Derivative with Potent Matrix Metalloproteinase and Antitumor Properties
Authors: Syed Samira , Takimoto Chris , Hidalgo Manuel , Rizzo Jinee , Kuhn John G. , Hammond Lisa A. , Schwartz Garry , Tolcher Anthony , Patnaik Amita , Eckhardt S. Gail , Rowinsky Eric K. 
Published: September 2005

Abstract
Purpose: The purpose of this research was to assess the feasibility of administering Col-3, an oral chemically modified tetracycline derivative with potent inhibitory effects on matrix metalloproteinase activity and production, and recommend a dose on an uninterrupted once-daily schedule. The study also sought to characterize the pharmacokinetic behavior of Col-3 and seek evidence of anticancer activity.
Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of Col-3 with dose level assignment according to an accelerated titration scheme. Because photosensitivity skin reactions were being reported in concurrent trials of Col-3, patients were instructed to apply sunscreen rigorously throughout the trial. The maximum tolerated dose was defined as the highest dose at which &lt;2 of the first 6 new patients experienced dose-limiting toxicity. The pharmacokinetic behavior of Col-3 was characterized, and pharmacodynamic relationships were sought.
Results: Thirty-three patients were treated with 73 courses of Col-3 at four dose levels ranging from 36 to 98 mg/m2/day. Unacceptably high incidences of photosensitivity skin reactions and malaise were noted in the first 28-day courses of patients treated with Col-3 at doses exceeding 50 mg/m2/day. At 50 mg/m2/day, severe toxicity occurred in 2 of 12 new patients in first courses, and no additional dose-limiting toxicities were observed in subsequent courses. Other mild to modest adverse effects included nausea, vomiting, liver function tests abnormalities, diarrhea, mucositis, leukopenia, and thrombocytopenia. The pharmacokinetics of Col-3 were dose proportional, and mean trough concentrations at steady state were similar to biologically relevant concentrations in preclinical studies. Major responses did not occur, but durable disease stability was noted in 3 patients, one each with carcinosarcoma of the uterus, pancreas, and ovary, all of whom had experienced disease progression before Col-3 treatment.
Conclusions: The recommended dose for Phase II studies of Col-3 administered once daily on an uninterrupted schedule is 50 mg/m2/day accompanied by efforts that promote adherence to the use of sunscreen and other photoprotective measures. Pharmacokinetic results indicate that plasma concentrations above biologically relevant concentrations are readily maintained at this dose, and additional disease-directed studies, particularly in patients with soft tissue sarcoma, should be considered.
Effects of α1-Acid Glycoprotein on the Clinical Pharmacokinetics of 7-Hydroxystaurosporine
Authors: Sparreboom Alex , Chen Huachen , Acharya Milin R. , Senderowicz Adrian M. , Messmann Richard A. , Kuwabara Takashi , Venzon David J. , Murgo Anthony J. , Headlee Donna , Sausville Edward A. , Figg William D. 
Published: September 2005

Abstract
Objective: UCN-01 (7-hydroxystaurosporine) is a small molecule cyclin-dependent kinase modulator currently under clinical development as an anticancer agent. In vitro studies have demonstrated that UCN-01 is strongly bound to the acute-phase reactant α 1-acid glycoprotein (AAG). Here, we examined the role of protein binding as a determinant of the pharmacokinetic behavior of UCN-01 in patients.
Experimental Design: Pharmacokinetic data were obtained from a group of 41 patients with cancer receiving UCN-01 as a 72-hour i.v. infusion (dose, 3.6 to 53 mg/m2/day).
Results: Over the tested dose range, total drug clearance was distinctly nonlinear (P = 0.0076) and increased exponentially from 4.33 mL/hour (at 3.6 mg/m2/day) to 24.1 mL/hour (at 54 mg/m2/day). As individual values for AAG increased, values for clearance decreased in a linear fashion (R2 = 0.264; P = 0.0008), although the relationship was shallow, and the data showed considerable scatter. Interestingly, no nonlinearity in the unbound concentration (P = 0.083) or fraction at the peak plasma concentration of UCN-01 was apparent (P = 0.744).
Conclusion: The results suggest the following: (1) that extensive binding to AAG may explain, in part, the unique pharmacokinetic profile of UCN-01 described previously with a small volume of distribution and slow systemic clearance, and (2) that measurement of total UCN-01 concentrations in plasma is a poor surrogate for that of the pharmacologically active fraction unbound drug.
Cytoplasmic Phospholipase A2 Levels Correlate with Apoptosis in Human Colon Tumorigenesis
Authors: Dong Mei , Johnson Michael , Rezaie Anahita , Ilsley Jillian N.M. , Nakanishi Masako , Sanders Melinda M. , Forouhar Faripour , Levine Joel , Montrose David C. , Giardina Charles , Rosenberg Daniel W. 
Published: September 2005

AbstractColon cancers often display perturbations in arachidonic acid metabolism, with elevated levels of cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2) production frequently observed. Whereas COX-2 and PGE2 are associated with cancer cell survival and tumor angiogenesis, arachidonic acid itself is a strong apoptotic signal that may facilitate cancer cell death. To further explore how cancer cells exploit the progrowth actions of prostaglandins while suppressing the proapoptotic actions of intracellular arachidonic acid, we determined the cytoplasmic phospholipase A2 (cPLA2) and COX-2 expression levels in a panel of human colon tumors by immunohistochemistry. Although high levels of cPLA2 and COX-2 expression are predicted to facilitate maximal prostaglandin production, tumors frequently displayed a high-COX-2/low-cPLA2 phenotype. The least represented phenotype was the high expression of cPLA2, a characteristic predicted to generate the highest levels of intracellular arachidonic acid. The potential proapoptotic role of cPLA2 was supported by a higher frequency of terminal deoxynucleotidyl transferase–mediated nick end labeling staining in cPLA2-positive tumors. Moreover, analysis of preneoplastic aberrant crypt foci from high-risk patients suggests that acquisition of the high-COX-2/low-cPLA2 phenotype may arise at an early stage of colon carcinogenesis. We additionally inhibited cPLA2 in HT-29 cells using antisense oligonucleotides. Our results indicate that cPLA2 plays an important role in tumor necrosis factor α–induced apoptosis in human colon cancer cells. Our data further support the model in which colon cancer growth is favored when intracellular arachidonic acid levels are suppressed by inhibition of cPLA2 or by a high-COX-2/low-cPLA2 phenotype.
Messenger RNA Expression Levels of CXCR4 Correlate with Metastatic Behavior and Outcome in Patients with Osteosarcoma
Authors: Laverdiere Caroline , Hoang Bang H. , Yang Rui , Sowers Rebecca , Qin Jing , Meyers Paul A. , Huvos Andrew G. , Healey John H. , Gorlick Richard 
Published: September 2005

Abstract
Purpose: To determine if osteosarcoma cells express chemokine receptors and if their presence or absence relates to clinical features.
Experimental Design: Using fluorescent quantitative real-time PCR, the pattern of 17 chemokine receptors in 3 osteosarcoma cell lines and 68 osteosarcoma patient samples was analyzed.
Results: The expression of the chemokine receptors was generally low among the cell lines. In the high-grade osteosarcoma patient samples (n = 47), CXCR4 was the most commonly expressed (63%) and its expression level was inversely correlated to overall survival (P &lt; 0.0001), event-free survival (P &lt; 0.001), and metastasis-free survival (MFS; P = 0.002). There was also a correlation between the expression level of CXCR4 and the presence of metastasis at diagnosis (P = 0.002). CCR7 was expressed in 43% of the samples and its expression level was inversely correlated with overall survival (P = 0.03) and MFS (P = 0.007). CCR10 mRNA expression level was inversely correlated with MFS (P = 0.009). There was no association between the expression of CXCR4, CCR7, and CCR10. Of the 26 samples studied for stromal cell–derived factor-1 expression, 77% expressed it, but there was no correlation with the clinical variables or CXCR4 expression. Multivariate analysis revealed that mRNA expression level of CXCR4 was the only significant variable for overall survival (P = 0.0006), event-free survival (P = 0.004), and MFS (P = 0.025).
Conclusions: These data suggest that CXCR4 could be useful as a prognostic factor and as a predictor of potential metastatic development in osteosarcoma. If further studies confirm that it is relevant to metastases in this disease, it could represent a new therapeutic target.
Effect of Polyethylene Glycol Linker Chain Length of Folate-Linked Microemulsions Loading Aclacinomycin A on Targeting Ability and Antitumor Effect In vitro and In vivo
Authors: Shiokawa Tomonori , Hattori Yoshiyuki , Kawano Kumi , Ohguchi Yukino , Kawakami Hiroko , Toma Kazunori , Maitani Yoshie 
Published: September 2005

Abstract
Purpose: To establish a novel formulation tumor-targeted drug carrier of lipophilic antitumor antibiotics, aclacinomycin A (ACM), folate-linked microemulsions were prepared and investigated both in vitro and in vivo.
Experimental Design: Three kinds of folate-linked microemulsions with different polyethylene glycol (PEG) chain lengths loading ACM were formulated with 0.24 mol% folate-PEG2000-distearoylphosphatidylethanolamine (DSPE), folate-PEG5000-DSPE, and folate-lipid (without PEG linker) in microemulsions. In vitro studies were done in a human nasopharyngeal cell line, KB, which overexpresses the folate receptor (FR), and a human hepatoblastoma cell line, [FR(−)] HepG2. In vivo experiments were done in a KB xenograft by systemic administration of folate-linked microemulsions loading ACM.
Results: The association of folate-linked microemulsions to KB cells could be blocked by 2 mmol/L free folic acid. Selective FR-mediated cytotoxicity of folate-linked microemulsions loading ACM was obtained in KB but not in HepG2 cells. The association of the folate-PEG5000-linked microemulsion and folate-PEG2000-linked microemulsion with the cells was 200- and 4-fold higher, whereas their cytotoxicity was 90- and 3.5-fold higher than those of nonfolate microemulsion, respectively. The folate-PEG5000-linked microemulsions showed 2.6-fold higher accumulation in solid tumors 24 hours after i.v. injection and greater tumor growth inhibition than free ACM.
Conclusion: These findings suggest that a folate-linked microemulsion is feasible for tumor-targeted ACM delivery. This study shows that folate modification with a sufficiently long PEG chain on emulsions is an effective way of targeting emulsion to tumor cells.
Associations and Interactions between Ets-1 and Ets-2 and Coregulatory Proteins, SRC-1, AIB1, and NCoR in Breast Cancer
Authors: Myers Eddie , Hill Arnold D.K. , Kelly Gabrielle , McDermott Enda W. , O'Higgins Niall J. , Buggy Yvonne , Young Leonie S. 
Published: September 2005

Abstract
Purpose: Associations between p160 coactivator proteins and the development of resistance to endocrine treatment have been described. We hypothesized that nuclear receptor coregulatory proteins may interact with nonsteroid receptors. We investigated the mitogen-activated protein kinase–activated transcription factors, Ets, as possible interaction proteins for the coactivators SRC-1 and AIB1 and the corepressor NCoR in human breast cancer.
Experimental Design: Expression and coexpression of Ets and the coregulatory proteins was investigated using immunohistochemistry and immunofluorescence in a cohort of breast tumor patients (N = 134). Protein expression, protein-DNA interactions and protein-protein interactions were assessed using Western blot, electromobility shift, and coimmunoprecipitation analysis, respectively.
Results: Ets-1 and Ets-2 associated with reduced disease-free survival (P &lt; 0.0292, P &lt; 0.0001, respectively), whereas NCoR was a positive prognostic indicator (P &lt; 0.0297). Up-regulation of Ets-1 protein expression in cell cultures derived from patient tumors in the presence of growth factors associated with tumor grade (P &lt; 0.0013; n = 28). In primary breast tumor cell cultures and in the SKBR3 breast cell line, growth factors induced interaction between Ets and their DNA response element, induced recruitment of coactivators to the transcription factor-DNA complex, and up-regulated protein expression of HER2. Ets-1 and Ets-2 interacted with the coregulators under basal conditions, and growth factors up-regulated Ets-2 interaction with SRC-1 and AIB1. Coexpression of Ets-2 and SRC-1 significantly associated with the rate of recurrence and HER expression, compared with patients who expressed Ets-2 but not SRC-1 (P &lt; 0.0001 and P &lt; 0.0001, respectively).
Conclusions: These data describe associations and interactions between nonsteroid transcription factors and coregulatory proteins in human breast cancer.
A Small Interfering RNA Targeting Vascular Endothelial Growth Factor Inhibits Ewing's Sarcoma Growth in a Xenograft Mouse Model
Authors: Guan Hui , Zhou Zhichao , Wang Hua , Jia Shu-Fang , Liu Wenbiao , Kleinerman Eugenie S. 
Published: September 2005

Abstract
Angiogenesis plays an essential role in tumor growth and metastasis and is a promising therapeutic target for cancer. Vascular endothelial growth factor (VEGF) is a key regulator in vasculogenesis as well as in angiogenesis. TC71 human Ewing's sarcoma cells overexpress VEGF, with a shift in isoform production from membrane-bound VEGF189 to the more soluble VEGF165. Transfection of TC71 cells with a vector-based VEGF targeted small interfering RNA expression system (VEGFsi) inhibited VEGF165 expression by 80% and VEGF165 protein production by 98%, with no alteration in VEGF189 expression. Human microvascular endothelial cell proliferation and migration induced by conditioned medium from VEGFsi-transfected TC71 cells was significantly less than that induced by conditioned medium from TC71 cells and control vector-transfected TC71 cells. Furthermore, after s.c. injection into athymic nu/nu mice, the tumor growth of VEGFsi-expressing TC71 cells was significantly less than that of parental or control vector-transfected cells. Vessel density as assessed by CD31 immunohistochemical analysis and VEGF165 expression as assessed by Northern blotting were also decreased. Intratumor gene therapy with polyethylenimine/VEGFsi also resulted in tumor growth suppression. When inoculated into the tibias of nude mice, VEGFsi-expressing TC71 cells induced osteolytic bone lesions that were less severe than those induced by control groups. These data suggest that targeting VEGF165 may provide a therapeutic option for Ewing's sarcoma.
Gene Expression Profiling of the Irinotecan Pathway in Colorectal Cancer
Authors: Yu Jinsheng , Shannon William D. , Watson Mark A. , McLeod Howard L. 
Published: September 2005

Abstract
The exact mechanism responsible for large variation of response to chemotherapy remains unclear. This study profiled the gene expression for the entire irinotecan pathway to provide insights into individualized cancer therapy. The RNA expressions of 24 irinotecan pathway genes were measured in paired tumor and normal tissues from 52 patients with Dukes' C colorectal cancer using a real-time quantitative reverse transcription-PCR assay. The relative expression levels across the 24 pathway genes varied considerably, with a 441-fold range from highest to lowest expression levels for the tumor tissues and a 934-fold range for the normal tissues. Interpatient variability was also quite large, with a 33.6 median fold change in the tumor tissue genes and a 30.1 median fold change in the normal tissue genes. Six of the 24 irinotecan pathway genes had dramatically lower expression levels in the tumor samples than did the genes in the normal tissues (median range, 1.28-4.39 folds; P = 0.001-0.029). Eight genes had significantly higher levels (median range, 1.35-2.42 folds; P = 0.001-0.011). Using hierarchical clustering, three gene clusters and three patient groups were observed with high similarity indices by the RNA expressions in colorectal tumors. The three patient groups had no unique clinical pathologic features but could be differentiated by the statistically significant differences in RNA expression level of seven genes. Our study indicates that gene expression profiling could be valuable for predicting tumor response to chemotherapy and for tailoring therapy to individual cancer patients.
Variance in the Expression of 5-Fluorouracil Pathway Genes in Colorectal Cancer
Authors: Kidd Elizabeth A. , Yu Jinsheng , Li Xia , Shannon William D. , Watson Mark A. , McLeod Howard L. 
Published: September 2005

Abstract
Although colorectal cancer has the third highest cancer mortality rate, the treatment remains far from optimized with patients showing variable responses to standard treatment. Molecular differences in pharmacologically relevant genes may contribute to the variability in response. This study used Taqman PCR to investigate the expression of 24 5-fluorouracil (5-FU) pathway genes in colorectal cancer using paired nontumor and tumor sample from 52 patients with Dukes' C colon cancer. In comparing tumor versus nonmalignant tissue, 14 of the 24 genes showed significant variation in gene expression. For 11 of these same genes (FPGS, DHFR, GGH, NME1, NME2, RRM2, UMPH2, UNG, UMPS, TP53, and TK1), a significant proportion of the patients showed an over expression of the particular gene in tumor tissue with a tumor-to-nonmalignant (T/N) ratio &gt;1.2, whereas one gene (DPYD) showed the converse with a large number of patients showing a lower expression in the tumor tissue (T/N &lt; 0.8). Multiple gene correlations for the genes of the 5-FU pathway were found with the Spearman rank correlation of &gt;0.6 (all P &gt; 0.001), suggesting possible coregulation mechanisms. Hierarchical clustering analysis created at least three groups of genes, which were consistent with groupings by the other statistical methods. Additionally, the hierarchical clustering showed two distinct groups of patients based on their gene expression. These variations in gene expression could provide valuable insights for optimizing treatment selection for patients with colorectal cancer.
Phase I Trial of Combretastatin A-4 Phosphate with Carboplatin
Authors: Bilenker Joshua H. , Flaherty Keith T. , Rosen Mark , Davis Lisa , Gallagher Maryann , Stevenson James P. , Sun Weijing , Vaughn David , Giantonio Bruce , Zimmer Ross , Schnall Mitchell , O'Dwyer Peter J. 
Published: September 2005

Abstract
Purpose: Preclinical evidence of synergy led to a phase I trial employing combretastatin A-4 phosphate (CA4P), a novel tubulin-binding antivascular drug, in combination with carboplatin.
Experimental Design: Based on preclinical scheduling studies, patients were treated on day 1 of a 21-day cycle. Carboplatin was given as a 30-minute i.v. infusion and CA4P was given 60 minutes later as a 10-minute infusion.
Results: Sixteen patients with solid tumors received 40 cycles of therapy at CA4P doses of 27 and 36 mg/m2 together with carboplatin at area under the concentration-time curve (AUC) values of 4 and 5 mg min/mL. The dose-limiting toxicity of thrombocytopenia halted the dose escalation phase of the study. Four patients were treated at an amended dose level of CA4P of 36 mg/m2 and carboplatin AUC of 4 mg min/mL although grade 3 neutropenia and thrombocytopenia were still observed. Three lines of evidence are adduced to suggest that a pharmacokinetic interaction between the drugs results in greater thrombocytopenia than anticipated: the carboplatin exposure (as AUC) was greater than predicted; the platelet nadirs were lower than predicted; and the deviation of the carboplatin exposure from predicted was proportional to the AUC of CA4, the active metabolite of CA4P. Patient benefit included six patients with stable disease lasting at least four cycles.
Conclusion: This study of CA4P and carboplatin given in combination showed dose-limiting thrombocytopenia. Pharmacokinetic/pharmacodynamic modeling permitted the inference that altered carboplatin pharmacokinetics caused the increment in platelet toxicity.
Prognostic Value of Tumor-Infiltrating Dendritic Cells in Colorectal Cancer: Role of Maturation Status and Intratumoral Localization
Authors: Sandel Maro H. , Dadabayev Alisher R. , Menon Anand G. , Morreau Hans , Melief Cornelis J.M. , Offringa Rienk , van der Burg Sjoerd H. , Janssen-van Rhijn Connie M. , Ensink N. Geeske , Tollenaar Rob A.E.M. , van de Velde Cornelis J.H. , Kuppen Peter J.K. 
Published: September 2005

Abstract
The clinical significance of tumor-infiltrating dendritic cells has been reported in a variety of human solid tumors as shown by the correlations found between the presence of tumor-infiltrating dendritic cells and clinical prognosis. In this study, we evaluated whether there is an association between the presence and maturation status of tumor-infiltrating dendritic cells, T lymphocytes, and clinical course in 104 primary tumor samples of patients with colorectal cancer. Dendritic cells were identified with four different markers (S-100, HLA class II, CD208, and CD1a) in double immunohistochemistry, with laminin as second marker to support the exact localization. Tumor-infiltrating dendritic cells showed a distinct infiltration pattern based on their maturation status. CD1a-positive dendritic cells resided in the advancing tumor margins in relatively high numbers, whereas mature CD208-positive dendritic cells were sparsely present in the tumor epithelium but mainly distributed in the tumor stroma and advancing tumor margin. Furthermore, high infiltration of CD1a-positive dendritic cells in the tumor epithelium was significantly correlated to the infiltration of CD4 lymphocytes (P = 0.006). Patients with relatively high numbers of mature CD208-positive infiltrating dendritic cells in the tumor epithelium had a shorter overall survival (P = 0.004). In addition, patients with relatively high numbers of CD1a-positive dendritic cells in the advancing margin of the tumor had a shorter disease-free survival (P = 0.03). We found that tumor-infiltrating dendritic cells had preferential infiltration sites within a tumor, affected local tumor cell-immune cell interactions, and correlated to the clinical prognosis of colorectal cancer patients.