bluuebunny/crossref_metadata_2025_split huggingface dataset:
Methionine Aminopeptidase 2 Inhibition Is an Effective Treatment Strategy for Neuroblastoma in Preclinical Models
Authors: Morowitz Michael J. , Barr Rosalind , Wang Qun , King Rebecca , Rhodin Nicholas , Pawel Bruce , Zhao Huaqing , Erickson Scott A. , Sheppard George S. , Wang Jieyi , Maris John M. , Shusterman Suzanne 
Published: September 2005

Abstract
Tumor vascularity is correlated with an aggressive disease phenotype in neuroblastoma, suggesting that angiogenesis inhibitors may be a useful addition to current therapeutic strategies. We previously showed that the antiangiogenic compound TNP-470, an irreversible methionine aminopeptidase 2 (MetAP2) inhibitor, suppressed local and disseminated human neuroblastoma growth rates in murine models but had significant associated toxicity at the effective dose. We have recently shown that a novel, reversible MetAP2 inhibitor, A-357300, significantly inhibits CHP-134–derived neuroblastoma s.c. xenograft growth rate with a treatment-to-control (T/C) ratio at day 24 of 0.19 (P &lt; 0.001) without toxicity. We now show that the combination of A-357300 with cyclophosphamide at the maximal tolerated dose sustained tumor regression with a T/C at day 48 of 0.16 (P &lt; 0.001) in the CHP-134 xenograft model. A-357300 also significantly inhibited establishment and growth rate of hematogenous metastatic deposits following tail vein inoculation of CHP-134 cells and increased overall survival (P = 0.021). Lastly, A-357300 caused regression of established tumors in a genetically engineered murine model with progression-free survival in five of eight mice (P &lt; 0.0001). There was no evidence of toxicity. These data show that MetAP2 may be an important molecular target for high-risk human neuroblastomas. We speculate that the growth inhibition may be through both tumor cell intrinsic and extrinsic (antiangiogenic) mechanisms. The potential for a wide therapeutic index may allow for treatment strategies that integrate MetAP2 inhibition with conventional cytotoxic compounds.
The Number of Lymph Node Metastases in Gastric Cancer Correlates with the Angiotensin I–Converting Enzyme Gene Insertion/Deletion Polymorphism
Authors: Röcken Christoph , Lendeckel Uwe , Dierkes Jutta , Westphal Sabine , Carl-McGrath Stacy , Peters Brigitte , Krüger Sabine , Malfertheiner Peter , Roessner Albert , Ebert Matthias P.A. 
Published: September 2005

Abstract
Purpose: In the present study, we aimed to substantiate the putative significance of angiotensin I–converting enzyme (ACE) on gastric cancer biology by investigating the influence of its gene polymorphism on gastric cancer progression.
Experimental Design: Genomic DNA was purified from peripheral blood mononuclear cells or tissue specimens. Amplified ACE gene fragments were separated on agarose gels. D or I alleles were identified by the presence of 190- or 490-bp fragments, respectively. Local expression of ACE was investigated by immunohistochemistry.
Results: Twenty-four of 113 (21%) gastric cancer patients had the II, 57 (51%) the ID, and 32 (28%) the DD genotype. The distribution of the ACE genotypes did not differ significantly from the control group of 189 patients without gastric cancer. However, the ACE genotypes correlated with the number of lymph node metastases and the Unio Internationale Contra Cancrum (UICC) tumor stage. Patients with the II genotype had a highly significantly smaller number of lymph node metastases (P &lt; 0.001) and a significantly lower UICC tumor stage (P = 0.01) than patients with the DD genotype. No correlation was found between tumor type, tumor location, local tumor growth, distant metastases, and the ACE genotype. The expression of ACE in gastric cancer was investigated by immunohistochemistry in 100 of 113 patients. ACE was expressed by endothelial cells in all (100%) specimens and by tumor cells in 56 (56%) specimens.
Conclusions: Our study shows that ACE is expressed locally in gastric cancer and that the gene polymorphism influences metastatic behavior.
Colocalization of the Tetraspanins, CO-029 and CD151, with Integrins in Human Pancreatic Adenocarcinoma: Impact on Cell Motility
Authors: Gesierich Sabine , Paret Claudia , Hildebrand Dagmar , Weitz Jürgen , Zgraggen Kaspar , Schmitz-Winnenthal Friedrich H. , Horejsi Vaclav , Yoshie Osamu , Herlyn Dorothee , Ashman Leonie K. , Zöller Margot 
Published: September 2005

Abstract
Purpose: Patients with pancreatic adenocarcinoma have a poor prognosis due to the extraordinary high invasive capacity of this tumor. Altered integrin and tetraspanin expression is suggested to be an important factor. We recently reported that after protein kinase C activation, colocalization of α6β4 with the tetraspanin CO-029 strongly supports migration of a rat pancreatic adenocarcinoma. The finding led us to explore whether and which integrin-tetraspanin complexes influence the motility of human pancreatic tumors.
Experimental Design: Integrin and tetraspanin expression of pancreatic and colorectal adenocarcinoma was evaluated with emphasis on colocalization and the impact of integrin-tetraspanin associations on tumor cell motility.
Results: The majority of pancreatic and colorectal tumors expressed the α2, α3, α6, β1, and β4 integrins and the tetraspanins CD9, CD63, CD81, CD151, and CO-029. Expression of α6β4 and CO-029 was restricted to tumor cells, whereas α1, α2, α3, α6, β1, and CD9, CD81, CD151 were also expressed by the surrounding stroma. CD63, CD81, and β1 expression was observed at comparably high levels in healthy pancreatic tissue. α3β1 frequently colocalized and coimmunoprecipitated with CD9, CD81, and CD151, whereas α6β4 colocalized and coimmunoprecipitated mostly with CD151 and CO-029. Notably, protein kinase C activation strengthened only the colocalization of CD151 and CO-029 with β4 and was accompanied by internalization of the integrin-tetraspanin complex, decreased laminin 5 adhesion, and increased cell migration.
Conclusion: α6β4 is selectively up-regulated in pancreatic and colorectal cancer. The association of α6β4 with CD151 and CO-029 correlates with increased tumor cell motility.
A Phase I Clinical, Pharmacologic, and Biologic Study of Thrombopoietin and Granulocyte Colony-Stimulating Factor in Children Receiving Ifosfamide, Carboplatin, and Etoposide Chemotherapy for Recurrent or Refractory Solid Tumors: A Children's Oncology Group Experience
Authors: Angiolillo Anne L. , Davenport Virginia , Bonilla Mary Ann , van de Ven Carmella , Ayello Janet , Militano Olga , Miller Langdon L. , Krailo Mark , Reaman Gregory , Cairo Mitchell S. 
Published: September 2005

Abstract
Purpose: Ifosfamide, carboplatin, and etoposide (ICE) are associated with grade III/IV dose-limiting thrombocytopenia. The Children's Oncology Group conducted a phase I dose escalation, pharmacokinetic, and biological study of recombinant human thrombopoietin (rhTPO) after ICE in children with recurrent/refractory solid tumors (CCG-09717) to assess the toxicity and maximum tolerated dose of rhTPO administered at 1.2, 2.4, or 3.6 μg/kg per dose.
Experimental Design: Children received ifosfamide 1,800 mg/m2 on days 0 to 4, carboplatin 400 mg/m2 on days 0 to 1, and etoposide 100 mg/m2 on days 0 to 4. rhTPO was administered i.v. on days +4, +6, +8, +10, and +12 at 1.2, 2.4, or 3.6 μg/kg per dose.
Results: rhTPO was well tolerated and maximum tolerated dose was not reached. Median time to platelet recovery ≥100,000/μL of rhTPO at 1.2, 2.4, and 3.6 μg/kg/d was 24 days (22-24d), 25 days (23-29d), and 22 days (16-37d), respectively. Patients required a median of 2 days of platelet transfusions (0-7 days). Mean (± SD) rhTPO maximum serum concentrations were 63.3 ± 9.7 and 89.3 ± 15.7 ng/mL and terminal half-lives were 47 ± 13 and 64 ± 42 hours after 2.4 and 3.6 μg/kg/d, respectively. There was a significant increase in colony-forming unit megakaryocyte upon WBC count recovery.
Conclusions: rhTPO was well tolerated. Time to hematologic recovery and median number of platelet transfusions seem to be improved compared with historical controls receiving ICE + granulocyte colony-stimulating factor (CCG-0894).
Intraprostatic Chemotherapy: Distribution and Transport Mechanisms
Authors: Wientjes M. Guillaume , Zheng Jenny H. , Hu Leijun , Gan Yuebo , Au Jessie L-S. 
Published: September 2005

Abstract
Purpose: The present study evaluated the tissue distribution and targeting advantage of intraprostatic chemotherapy.
Experimental Design: We studied the delivery and spatial distribution of a fluorescent drug, doxorubicin, in the prostate of beagle dogs, after intraprostatic or i.v. administration. Drug concentrations were measured using high-performance liquid chromatography and confocal fluorescence microscopy.
Results: I.v. and intraprostatic injections yielded qualitatively and quantitatively different doxorubicin distribution in the prostate. A relatively homogeneous distribution was found after i.v. administration, whereas intraprostatic injection yielded a highly heterogeneous distribution with &gt;10-fold higher concentrations localized in a cone-shaped glandular lobule bound by fibromuscular stroma, compared with other parts of the prostate. Compared with i.v. injection, intraprostatic injection yielded, on average, ∼100-fold higher tissue-to-plasma concentration ratio, ranging from 963-fold near the injection site to 19-fold in the contralateral half of the prostate. The drug distribution within the prostate further suggests an important role for acinar flow in intraprostatic drug transport.
Conclusions: Intraprostatic administration represents a viable option to deliver high drug concentrations within the prostate. The results further suggest the fibromuscular stroma separating the prostatic lobules as a major barrier to drug transport and convective flow as an important drug transport mechanism in the prostate.
Growth Factor Regulation of a 26S Proteasomal Subunit in Breast Cancer
Authors: Barnes Christopher J. , Li Feng , Talukder Amjad H. , Kumar Rakesh 
Published: September 2005

Abstract
Purpose: We sought to gain insight into the mechanisms of heregulin-β1 (HRG) action on breast epithelial cells by identifying and characterizing HRG-regulated proteins.
Experimental Design: Differential display mRNA screening of human breast cancer cells grown in the presence or absence of HRG was used to identify HRG-regulated genes. Biochemical and functional studies were undertaken to examine the impact of HRG and the therapeutic antibody herceptin on protein expression, localization, and function.
Results: We identified the ATPase subunit 4 (S4) of the 26S proteasome as a HRG-regulated target. Both S4 mRNA and protein levels were increased by HRG; however, this HRG-stimulated increase was blocked by the therapeutic antibody herceptin. S4 expression was significantly increased in primary human breast tumors and in estrogen receptor–negative tumors. Coimmunoprecipitation, immunofluorescence, and ATPase activity assays suggested that HRG also induced S4 activity and formation of a functional proteasome complex.
Conclusions: This is the first demonstration of growth factor–regulated expression, localization, and activity of the S4 subunit of the 26S proteasome in human breast cancer cells. These findings now provide a potential mechanistic rationale for the use of proteasome inhibitors in breast cancers with active HRG signaling.
Functionality of Androgen Receptor–Based Gene Expression Imaging in Hormone Refractory Prostate Cancer
Authors: Sato Makoto , Johnson Mai , Zhang Liqun , Gambhir Sanjiv S. , Carey Michael , Wu Lily 
Published: September 2005

Abstract
Purpose: A highly augmented, prostate-specific two-step transcriptional amplification (TSTA) method was developed with the ultimate goal of delivering an effective and safe gene-based treatment to prostate cancer patients. Because very limited treatment options are available for recurrent hormone refractory prostate cancer (HRPC), it is imperative to assess whether the prostate-specific antigen (PSA) promoter-based TSTA gene therapy will be functional in HRPC.
Experimental Design: We tested the TSTA-driven adenovirus vector on three androgen-dependent and six HRPC models. Real-time gene expression was monitored by both optical imaging and the combined modality of positron emission tomography (PET) and computed tomography.
Results: The TSTA-driven firefly luciferase expressing adenoviral vector was active in all androgen receptor (AR)–expressing HRPC models, but inactive in AR- and PSA-negative lines. Interestingly, the TSTA-mediated gene expression was induced by hydrocortisone in MDA PCa 2b, a cell line with mutated AR that possesses altered ligand specificity. In animal models, the TSTA-mediated optical signal was more robust in the HRPC than androgen-dependent tumors. In a parallel trend, a TSTA vector that expresses the herpes simplex virus thymidine kinase PET reporter gene also displayed more robust PET signal in the HRPC tumor.
Conclusions: The activity of TSTA system is AR dependent and it recapitulates the functional status of endogenous AR. These data support the conclusion that AR function is activated in HRPC despite castrated levels of androgen. Together with the fact that majority of recurrent prostate cancers express AR and PSA, we foresee that the TSTA approach can be a promising gene therapy strategy for the advanced stages of prostate cancer.
Overexpression of Osteopontin Is Associated with More Aggressive Phenotypes in Human Non–Small Cell Lung Cancer
Authors: Hu Zhi , Lin Dongmei , Yuan Jingsong , Xiao Ting , Zhang Husheng , Sun Wenyue , Han Naijun , Ma Ying , Di Xuebing , Gao Meixia , Ma Jinfang , Zhang Junhang , Cheng Shujun , Gao Yanning 
Published: September 2005

Abstract
Purpose: The extracellular matrix (ECM) molecule osteopontin is implicated in many pathologic processes, including inflammation, cell proliferation, ECM invasion, tumor progression, and metastasis. The present study evaluated the clinical and biological importance of osteopontin in human lung cancer.
Experimental Design and Results: Tissue microarrays derived from non–small cell lung cancer (NSCLC) patients were analyzed immunohistochemically. Osteopontin protein expression was observed in 64.5% (205 of 318) of primary tumors and 75.5% (108 of 143) of lymph node metastases, but in only 27.9% (12 of 43) of normal-appearing bronchial epithelial and pulmonary tissues. Osteopontin expression was associated with tumor growth, tumor staging, and lymph node invasion. In vitro osteopontin enhanced ECM invasion of NSCLC cells, and an osteopontin antibody abolished this effect. We further analyzed osteopontin levels in circulating plasma derived from 158 patients with NSCLC, 54 patients of benign pulmonary disease, and 25 healthy donors, and found that the median osteopontin levels for the three groups were 319.1, 161.6, and 17.9 ng/mL, respectively.
Conclusions: Overexpression of osteopontin is common in primary NSCLC and may be important in the development and progression of the cancer. Osteopontin levels in the plasma may serve as a biomarker for diagnosing or monitoring patients with NSCLC.
Antimetastatic Effect of Salvicine on Human Breast Cancer MDA-MB-435 Orthotopic Xenograft Is Closely Related to Rho-Dependent Pathway
Authors: Lang Jing-Yu , Chen Hua , Zhou Jin , Zhang Yi-Xiang , Zhang Xiong-Wen , Li Mei-Hong , Lin Li-Ping , Zhang Jin-Sheng , Waalkes Michael P. , Ding Jian 
Published: September 2005

Abstract
Purpose: Salvicine is a novel DNA topoisomerase II inhibitor with potent anticancer activity. In present study, the effect of salvicine against metastasis is evaluated using human breast carcinoma orthotopic metastasis model and its mechanism is further investigated both in animal and cellular levels.
Experimental Design: The MDA-MB-435 orthotopic xenograft model was applied to detect the antimetastatic effect of salvicine. Potential target candidates were detected and analyzed by microarray technology. Candidates were verified and explored by reverse transcription-PCR and Western blot. Salvicine activities on stress fiber formation, invasion, and membrane translocation were further investigated by immunofluorescence, invasion, and ultracentrifugal assays.
Results: Salvicine significantly reduced the lung metastatic foci of MDA-MB-435 orthotopic xenograft, without affecting primary tumor growth obviously. A comparison of gene expression profiles of primary tumors and lung metastatic focus between salvicine-treated and untreated groups using the CLOTECH Atlas human Cancer 1.2 cDNA microarray revealed that genes involved in tumor metastasis, particularly those closely related to cell adhesion and motility, were obviously down-regulated, including fibronectin, integrin α3, integrin β3, integrin β5, FAK, paxillin, and RhoC. Furthermore, salvicine significantly down-regulated RhoC at both mRNA and protein levels, greatly inhibited stress fiber formation and invasiveness of MDA-MB-435 cells, and markedly blocked translocation of both RhoA and RhoC from cytosol to membrane.
Conclusion: The unique antimetastatic action of salvicine, particularly its specific modulation of cell motility in vivo and in vitro, is closely related to Rho-dependent signaling pathway.
Antisense Inhibition of Methylenetetrahydrofolate Reductase Reduces Cancer Cell Survival In vitro and Tumor Growth In vivo
Authors: Stankova Jitka , Shang Jijun , Rozen Rima 
Published: September 2005

Abstract
Purpose: Many cancer lines are methionine dependent and decrease proliferation when methionine supply is limited. Methylenetetrahydrofolate reductase (MTHFR) generates the folate derivative for homocysteine remethylation to methionine. We investigated the effect of antisense-mediated inhibition of MTHFR on survival of human cancer cells.
Experimental Design: We examined the in vitro and in vivo anticancer effects of a combination of MTHFR antisense and standard cytotoxic drugs.
Results: Specific antisense against MTHFR (EX5) showed significant inhibitory effects on growth of human colon, lung, breast, prostate, and neuroblastoma tumor cells in vitro compared with that of the control oligonucleotide. Cytotoxic drugs (5-fluorouracil, cisplatin, or paclitaxel) potentiated the effect of EX5. In vivo, antisense alone or in combination with cytotoxic drugs inhibited the growth of human colon and lung carcinoma xenografts. In comparison with control oligonucleotide, treatment with EX5 inhibited growth of colon tumors and lung tumors by 60% and 45%, respectively. EX5 with 5-fluorouracil decreased growth of colon tumors by an additional 30% compared with EX5 alone, and EX5 with cisplatin decreased growth of lung tumors by an additional 40% compared with cisplatin alone. Growth inhibition by EX5 was associated with decreased amounts of MTHFR protein and with increased amounts of an apoptosis marker.
Conclusions: Our results confirm that MTHFR inhibition decreases tumor growth and suggest that inhibition of MTHFR by antisense or small molecules may be a novel anticancer approach.
Elevated Physiologic Tumor Pressure Promotes Proliferation and Chemosensitivity in Human Osteosarcoma
Authors: Nathan Saminathan S. , DiResta Gene R. , Casas-Ganem Jorge E. , Hoang Bang H. , Sowers Rebecca , Yang Rui , Huvos Andrew G. , Gorlick Richard , Healey John H. 
Published: September 2005

Abstract
Purpose: This study investigates the effect of constitutively raised interstitial fluid pressure on osteosarcoma physiology and chemosensitivity.
Experimental Design: We did pressure and blood flow assessments at the time of open biopsy in patients with the diagnosis of high-grade osteosarcoma and correlated this to survival and chemotherapy-associated tumor necrosis. Osteosarcoma cell lines were then evaluated for proliferative and therapeutic indices in a replicated high-pressure environment.
Results: Sixteen osteosarcomas in vivo were assessed and exhibited elevated interstitial fluid pressures (mean 35.2 ± SD, 18.6 mmHg). This was not associated with significantly impeded blood flow as measured by a Doppler probe at a single site (P &lt; 0.12). Nonetheless, greater chemotherapy-associated necrosis and associated longer survival were seen in tumors with higher interstitial fluid pressures (P &lt; 0.05).
In vitro, cells undergo significant physiologic changes under pressure. Osteosarcoma cell lines grown in a novel hydrostatically pressurized system had variable cell line–specific growth proportional to the level of pressure. They were more proliferative as indicated by cell cycle analysis with more cells in S phase after 48 hours of pressurization (P &lt; 0.01). There was a significant elevation in the cell cycle–related transcription factors E2F-1 (P &lt; 0.03) and E2F-4 (P &lt; 0.002). These changes were associated with increased chemosensitivity. Cells tested under pressure showed an increased sensitivity to cisplatin (P &lt; 0.00006) and doxorubicin (P &lt; 0.03) reminiscent of the increased chemotherapy-associated necrosis seen in tumors with higher interstitial fluid pressure in the clinical study.
Conclusions: The results of this study suggest that cells in the in vivo pressurized environment are at a higher state of regenerative activity than is demonstrable in conventional cell culture systems. Variations in tumor interstitial fluid pressure have the potential to alter chemotherapeutic effects.
Combined Liposome-Mediated Cytosine Deaminase Gene Therapy with Radiation in Killing Rectal Cancer Cells and Xenografts in Athymic Mice
Authors: Li Shiyong , Yu Bo , An Ping , Chen Gang , Lu Wenping , Cai Huiyun , Guo Wenhua , Zuo Fuyi 
Published: September 2005

Abstract
Purpose: The aim of this study was to assess the antitumor efficacy of combination of cytosine deaminase (CD) suicide gene therapy with radiation and to grope for new therapeutic strategy for local recurrent rectal cancer.
Experimental Design: HR-8348 cell line of human rectal cancer was used to assess efficiency of transfection with plasmid pEGFP-N1 and PXJ41-CD. The cells were exposed to radiation followed by liposome-mediated transfection. Cell inhibition assay was done with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Antitumor efficacy of combined liposome-mediated CD suicide gene therapy with radiation was determined by treatment of nude mice bearing HR-8348 cancer cell xenograft.
Results: The efficiency of liposome-mediated CD gene transfection can be improved by radiation. With radiation at 2, 4, 6, and 8 Gy, the efficiency of liposome-mediated transfection increased from 21.3% to 62.2%, 78.0%, 83.2%, and 87.8%, respectively. CD expression was enhanced as well. Cancer cell inhibition experiment showed that combined liposome-mediated CD gene therapy with radiation had much stronger antitumor effect. With HR-8348 tumor xenograft model, suppression of tumor xenograft was observed. Compared with control group, tumor volume was inhibited by 81.5%, 48.5%, and 37.4%, respectively, in the combined CD/5-fluorocytosine with radiation group, CD/5-fluorocytosine group, and radiation group and the wet weight of tumor was decreased by 80%, 41.7%, and 37.7%, respectively.
Conclusion: These findings suggested that combination of liposome-mediated CD gene therapy with radiation is a safer and efficient anticancer method. Its therapeutic efficacy may meet clinical treatment on local recurrent rectal cancer.