bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic Antitumor Effects of Combined Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor-2 Targeted Therapy
Authors: Tonra James R. , Deevi Dhanvanthri S. , Corcoran Erik , Li Huiling , Wang Su , Carrick Francine E. , Hicklin Daniel J. 
Published: April 2006

Abstract
Purpose: Combination therapies that target the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) pathways, are being actively tested for the treatment of cancer. In evaluating combination strategies, the ideal combination would be one in which the treatments interact in a way that is synergistic with regard to antitumor effects. Here, we have evaluated the interaction between anti-EGFR antibody Erbitux (cetuximab) and anti-VEGFR2 antibody, DC101, in preclinical models of pancreatic (BxPC-3) and colon (GEO) cancer.
Experimental Design: Analysis of the interaction between cetuximab and DC101 in vivo used a novel method for establishing the upper 95% confidence limits for the combination index (CI) of isobologram analyses, where CI &lt; 1 indicates synergy. Assessment of tumor cell proliferation, apoptosis, VEGF production, and hypoxia, as well as tumor vascularization, was performed to gain insights into the mechanistic basis for synergy between agents targeting different tumor compartments.
Results: Monotherapy ED50 values for tumor growth inhibition ranged from 1.8 to 2.3 mg/kg and 10.5 to 16.6 mg/kg for cetuximab and DC101, respectively. From the dose response of the combination treatment, it was determined that cetuximab and DC101 are synergistic in the BxPC-3 (CI = 0.1, P &lt; 0.01) and GEO (CI = 0.1, P &lt; 0.01) models. Overlapping effects on the tumor cell and vascular compartments form a basis for the interaction, with VEGF production and hypoxia-inducible factor 1α potentially acting as molecular links between EGFR and VEGFR2 inhibition.
Conclusions: Results show antitumor synergy for combined EGFR and VEGFR2 targeted therapy, supporting the significant therapeutic potential of this combination strategy.
Pediatric Cancers Are Infiltrated Predominantly by Macrophages and Contain a Paucity of Dendritic Cells: a Major Nosologic Difference with Adult Tumors
Authors: Vakkila Jukka , Jaffe Ronald , Michelow Marilyn , Lotze Michael T. 
Published: April 2006

AbstractPurpose: Adult cancer is frequently preceded by a period of prolonged chronic inflammation caused by infectious microbial agents or physical or chemical irritants. By contrast, an association between the classic pediatric neoplasias and inflammatory triggers is only rarely recognized. We hypothesized that the difference could be reflected in the inflammatory cell infiltrates of pediatric and adult cancer.Experimental Design: Three investigators retrospectively studied 27 pediatric and 13 adult cancers at first diagnosis by immunohistochemistry. Inflammatory cells were identified and counted, and their location in relation to tumor tissue was analyzed.Results: A majority of tumor-associated leukocytes (TAL) in adult tumors were located at the edges of tumor islands forming inflammatory foci between the supporting stroma and the malignant infiltrate. In contrast, TALs in pediatric tumors were scattered within the malignant tumor islands. In adult tumors, TALs were composed of diverse leukocyte types; but in pediatric tumors, the infiltrating cells were predominantly macrophages that accumulated in areas of necrosis within the tumors. The most striking feature in the pediatric tumors was the virtual absence of dendritic cells. The proportion of intratumoral dendritic cells in pediatric samples was 4.1%; whereas in adult tumors, they formed 36.9% of TALs within the tumor islands and 25.1% around the tumors.Conclusions: We conclude that TALs in pediatric cancers are composed mainly of macrophages and largely devoid of dendritic cell. The findings may provide a major nosologic difference reclassifying pediatric and adult tumors based on nominal inflammatory and noninflammatory etiologies.
Messenger RNA Expression of Leptin and Leptin Receptors and their Prognostic Value in 322 Human Primary Breast Cancers
Authors: Révillion Françoise , Charlier Madia , Lhotellier Valérie , Hornez Louis , Giard Sylvia , Baranzelli Marie-Christine , Djiane Jean , Peyrat Jean-Philippe 
Published: April 2006

Abstract
Purpose: Leptin and obesity are clearly related, and obesity is associated with an increased risk of breast cancer. We therefore measured the expression of leptin and its two main receptor isoforms, OBR-L and OBR-S, in 322 breast cancers. We analyzed their relations with the classical prognostic factors and with survival to establish their links with breast cancer.
Experimental Design: The expression of leptin and its receptors was quantified by real-time reverse transcription-PCR, using TaqMan fluorogenic probes and an ABI PRISM 7700 sequence detector system (Applied Biosystems, Courtaboeuf, France). TATA box binding protein was used to normalize expression. The human breast cancer cell, SK-BR-3, expressing the three targets, was chosen as the calibrator sample (i.e., target expression = 1).
Results: All the tumors expressed both receptors, and 318 of 322 expressed leptin. These three variables correlated positively with each other and with estradiol and progesterone receptors, whereas they correlated negatively with histoprognostic grading and tumor diameter. OBR-L/OBR-S expression was inversely correlated with progesterone receptors. Patients with elevated OBR-S expression had longer relapse-free survival (P = 0.008), whereas high OBR-L/OBR-S was associated with a shorter relapse-free survival (P = 0.05). In Cox multivariate analyses, OBR-S maintained its prognostic value (P = 0.02; relative risk, 0.51).
Conclusions: This study shows that (a) almost all of the breast cancers coexpress leptin and its two main isoforms of receptors, suggesting that the human epithelial breast cancer cells respond to leptin acting via an autocrine pathway; (b) high expression levels of leptin and leptin receptors are biological markers of a more differentiated phenotype; and that (c) OBR-S is an independent prognostic factor.
Carbon Beam Therapy Overcomes the Radiation Resistance of Uterine Cervical Cancer Originating from Hypoxia
Authors: Nakano Takashi , Suzuki Yoshiyuki , Ohno Tatsuya , Kato Shingo , Suzuki Michiya , Morita Shinroku , Sato Shinichiro , Oka Kuniyuki , Tsujii Hirohiko 
Published: April 2006

Abstract
Purpose: High linear energy transfer (LET) particles are believed to decrease tumor radiation resistance originating from hypoxia. However, no proof of this effect has been provided by clinical trials and related clinical research. Hence, we investigated the radiation biological aspects of high LET carbon beam therapy on cervical cancer.
Experimental Design: This study involved 49 patients with stage IIIb bulky and stage IVa cervical cancer treated with high LET carbon beams between October 1995 and June 2000. Oxygen partial pressure (pO2) was measured by using a needle-type polarographic oxygen electrode.
Results: The 4-year disease-free survival rates of patients with pO2 ≤ 20 mm Hg (hypoxic tumor) and pO2 &gt; 20 mm Hg (oxygenated tumor) before treatment were 37% and 21%, respectively. The local control rates of hypoxic and oxygenated tumors before treatment were 58% and 54%, respectively. The disease-free survival rates of hypoxic and oxygenated tumors assessed by oxygen status at the 5th day of irradiation were 33% and 32%, respectively. The local control rates of hypoxic and oxygenated tumors at the 5th day were 60% and 58%, respectively. There was no significant prognostic difference between hypoxic and oxygenated tumors.
Conclusion: The similar disease-free survival and local control rates between hypoxic and oxygenated tumors before and during treatment indicated that the role of the tumor oxygenation status was not so important in local control in carbon beam therapy. These results indicated that high LET carbon beam irradiation might reduce the radiation-resistant nature stemming from tumor hypoxia.
Phase II Trial of Celecoxib in Prostate-Specific Antigen Recurrent Prostate Cancer after Definitive Radiation Therapy or Radical Prostatectomy
Authors: Pruthi Raj S. , Derksen J. Eric , Moore Dominic , Carson Culley C. , Grigson Gayle , Watkins Cathy , Wallen Eric 
Published: April 2006

Abstract
Objectives: Recent evidence has shown that cyclooxygenase-2 (COX-2) inhibitors have potent antitumor activity in prostate cancer both in vitro and in vivo. However, human trials are absent. This study evaluated the efficacy of the COX-2 inhibitor celecoxib in prostate-specific antigen (PSA) recurrent prostate cancer after radiation therapy (X-ray therapy or XRT) or radical prostatectomy.
Methods: Forty patients who had biochemical relapse after XRT or radical prostatectomy were treated with celecoxib 400 mg twice per day. Follow-up PSA levels were obtained at 3, 6, 12, and 18 months and subsequently every 6 months thereafter. Data were evaluated by calculating PSA doubling times and by calculating the slope of the curve of log(PSA) versus time to assess rate of PSA increase before and after celecoxib treatment for each patient.
Results: Thirty-six of 40 (90%) patients had a slowing effect on their rate of PSA after 3 months, including 11 of 40 with a decline and 8 of 40 with stabilization of PSA. Short-term responses at 3 months continued at 6, 12, 18 months. Comparison of rate of PSA increase before versus after celecoxib treatment showed significant flattening of slope of log(PSA) versus time from pretreatment for each of the time points. There was no significant change in testosterone levels, suggesting an androgen-independent mechanism.
Conclusions: COX-2 inhibitors may have an effect on serum PSA levels in patients with biochemical progression after XRT or radical prostatectomy. These results suggest that COX-2 inhibitors may help delay or prevent disease progression in these patients and thereby help extend the time until androgen deprivation therapy.
Preclinical Efficacy and Pharmacokinetics of AP5346, A Novel Diaminocyclohexane-Platinum Tumor-Targeting Drug Delivery System
Authors: Rice John R. , Gerberich Jennifer L. , Nowotnik David P. , Howell Stephen B. 
Published: April 2006

Abstract
Purpose: AP5346 is designed to target a diaminocyclohexane platinum (Pt) moiety to tumors through pH-sensitive linkage to a 25 kDa hydroxypropylmethacrylamide polymer. The goal of these studies was to determine the rate of release of Pt as a function of pH, the antitumor activity, and plasma and tumor pharmacokinetics of AP5346 in preclinical models.
Experimental Design: Antitumor activity was assessed in mice bearing B16F10 melanoma and M5076 and 2008 ovarian carcinomas. Pt levels in plasma, tumors, and tumor DNA were measured by atomic absorption and inductively coupled plasma mass spectrometry.
Results: AP5346 did not release Pt when suspended in 5% dextrose and released only 3.5% of its Pt in 24 hours in buffer at pH 7.4; the rate of release was 7-fold higher at pH 5.4. When given at their respective maximum tolerated doses, the antitumor activity of AP5346 was superior to that of oxaliplatin against both the B16 melanoma and 2008 human ovarian carcinoma. It was more effective than cisplatin in both cisplatin-sensitive and cisplatin-resistant variants of the M5076 tumor. When given at equitoxic doses, the peak plasma concentration was 25-fold higher, and AUC(0-∞) was 93 times higher, for AP5346 than for oxaliplatin. AP5346 delivered 16.3-fold more Pt to the tumor and 14.2-fold more Pt to tumor DNA than oxaliplatin based on AUC(1-168).
Conclusions: AP5346 has a substantially better therapeutic index than oxaliplatin. AP5346 produced a marked increase in the delivery of diaminocyclohexane Pt to the tumor and tumor DNA over and above that attainable with oxaliplatin.
Effects of Smoking on the Pharmacokinetics of Erlotinib
Authors: Hamilton Marta , Wolf Julie L. , Rusk Jason , Beard Shannon E. , Clark Gary M. , Witt Karsten , Cagnoni Pablo J. 
Published: April 2006

Abstract
Purpose: To compare the pharmacokinetic variables of erlotinib in current smokers with nonsmokers after receiving a single oral 150 or 300 mg dose of erlotinib.
Experimental Design: This was a single-center, open-label pharmacokinetic study in healthy male subjects. Subjects were enrolled into two treatment cohorts based on smoking status (current smokers and nonsmokers). The pharmacokinetic profile for erlotinib and its metabolite, OSI-420, was determined for each subject following each treatment.
Results: Current smokers achieved significantly less erlotinib exposure following a single 150 or 300 mg dose than nonsmokers. Following the 150 mg dose, the geometric mean erlotinib AUC0-∞ in smokers was 2.8-fold lower than in nonsmokers and similar to that of nonsmokers at the 300 mg dose. Cmax in smokers was two-thirds of that in nonsmokers, and C24h in smokers was 8.3-fold lower than in nonsmokers. The median C24h of smokers at the 300 mg dose was slightly less than the C24h of smokers at the 150 mg dose. The median Cmax was greater in smokers at the 300 mg dose than in nonsmokers at the 150 mg dose.
Conclusion: This study confirms that the pharmacokinetics of erlotinib is different in current smokers and nonsmokers. The observation that AUC0-∞ and C24h were significantly decreased in smokers compared with nonsmokers, and a smaller decrease in Cmax was observed, is consistent with increased metabolic clearance of erlotinib in current smokers.
Synergistic Interactions between DMAG and Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitors in Bcr/abl+ Leukemia Cells Sensitive and Resistant to Imatinib Mesylate
Authors: Nguyen Tri K. , Rahmani Mohamed , Gao Ning , Kramer Lora , Corbin Amie S. , Druker Brian J. , Dent Paul , Grant Steven 
Published: April 2006

Abstract
Purpose: To characterize interactions between the heat shock protein 90 antagonist 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG) and the mitogen-activated protein kinase/extracellular signal–regulated kinase (ERK) kinase 1/2 inhibitor PD184352 in Bcr/abl+ leukemia cells sensitive and resistant to imatinib mesylate.
Experimental Design: K562 and LAMA 84 cells were exposed to varying concentrations of DMAG and PD184352 for 48 hours; after which, mitochondrial integrity, caspase activation, and apoptosis were monitored. Parallel studies were done in imatinib mesylate–resistant cells, including BaF3 cells transfected with plasmids encoding clinically relevant Bcr/abl mutations conferring imatinib mesylate resistance (e.g., E255K, M351T, and T315I) and primary CD34+ bone marrow cells from patients refractory to imatinib mesylate.
Results: Cotreatment of Bcr/abl+ cells with minimally toxic concentrations of DMAG and PD184352 resulted in synergistic induction of mitochondrial injury (cytochrome c release and Bax conformational change), events associated with the pronounced and sustained inactivation of ERK1/2 accompanied by down-regulation of Bcl-xL. Conversely, cells ectopically expressing Bcl-xL displayed significant protection against PD184352/DMAG–mediated lethality. This regimen effectively induced apoptosis in K562 cells overexpressing Bcr/abl, in BaF3 cells expressing various clinically relevant Bcr/abl mutations, and in primary CD34+ cells from patients resistant to imatinib mesylate, but was relatively sparing of normal CD34+ bone marrow cells.
Conclusions: A regimen combining the heat shock protein 90 antagonist DMAG and the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor potently induces apoptosis in Bcr/abl+ cells, including those resistant to imatinib mesylate through various mechanisms including Bcr/abl kinase mutations, through a process that may involve sustained ERK1/2 inactivation and Bcl-xL down-regulation. This strategy warrants further attention in Bcr/abl+ hematopoietic malignancies, particularly those resistant to Bcr/abl kinase inhibitors.
Erythropoietin Fails to Interfere with the Antiproliferative and Cytotoxic Effects of Antitumor Drugs
Authors: Gewirtz David A. , Di Xu , Walker Teneille D. , Sawyer Stephen T. 
Published: April 2006

Abstract
Purpose: Erythropoietin (EPO) therapy is widely used for the prevention and treatment of anemia resulting from cancer chemotherapy. Native EPO regulates erythropoiesis, at least in part, by protecting erythroid progenitor cells from apoptotic cell death. The recent discovery of the EPO receptor (EPOR) on cancer cells raises the concern that EPO therapy might stimulate tumor growth and/or protect cancer cells from drug-induced apoptosis. Therefore, the capacity of EPO to interfere with the effects of conventional chemotherapeutic drugs on proliferation, apoptosis, and the induction of senescence was investigated in MCF-7 and MDA-MB231 breast tumor cells, which express the EPOR as well as in F-MEL erythroleukemia cells.
Experimental Design: Breast cancer cells and F-MEL leukemic cells were cultured in the presence or absence of EPO and then exposed to antitumor drugs. Cell proliferation was assessed by a standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye reduction assay 72 hours after drug exposure. Cytotoxicity was monitored by clonogenic survival. Apoptosis was evaluated either by the terminal deoxyribonucleotide transferase–mediated nick-end labeling assay or fluorescence-activated cell sorting analysis, and senescence was monitored by β-galactosidase staining. EPO signaling was assessed by monitoring the phosphorylation/activation of specific signaling proteins.
Results: EPO failed to stimulate the proliferation of MCF-7 or MDA-MB231 breast tumor cells or F-MEL leukemic cells. EPO treatment also failed to interfere with the antiproliferative and/or cytotoxic effects of Adriamycin, Taxol, and tamoxifen in breast tumor cells (or of cytarabine and daunorubicin in F-MEL cells). EPO failed to prevent apoptosis induced by Taxol or senescence induced by Adriamycin in MCF-7 cells. EPO stimulated the activation of extracellular signal-regulated kinase, p38, and c-Jun-NH2-kinase in MCF-7 cells but did not activate Akt or signal transducers and activators of transcription 5 (STAT5). EPO failed to activate any of these signaling pathways in MDA-MB231 cells. Cytarabine and daunorubicin interfered with EPO signaling in F-MEL cells.
Conclusions: These findings suggest that EPO is unlikely to directly counteract the effectiveness of cancer chemotherapeutic drugs. This may be a consequence of either ineffective signaling through the EPOR or drug-mediated suppression of EPO signaling.
Analysis of c-ErbB1/Epidermal Growth Factor Receptor and c-ErbB2/HER-2 Expression in Bronchial Dysplasia: Evaluation of Potential Targets for Chemoprevention of Lung Cancer
Authors: Merrick Daniel T. , Kittelson John , Winterhalder Ralph , Kotantoulas Georgia , Ingeberg Steen , Keith Robert L. , Kennedy Timothy C. , Miller York E. , Franklin Wilbur A. , Hirsch Fred R. 
Published: April 2006

Abstract
Purpose: Lung cancer is preceded by a premalignant phase during which intervention could decrease associated morbidity and mortality. Molecular characterization of factors involved in controlling progression of bronchial dysplasias will provide markers of premalignant change and identify targets for chemoprevention.
Experimental Design: Immunohistochemical analysis of epidermal growth factor receptor (EGFR; c-ErbB1/EGFR), HER-2/neu (c-ErbB2/HER-2), Ki-67, and minichromosome maintenance protein 2 (MCM2) expression in bronchial dysplasia was undertaken to characterize molecular alterations associated with the progression of these lesions in 268 bronchoscopically obtained biopsies from 134 subjects.
Results: Analysis of biopsies with the most severe diagnosis from each subject showed a linear relationship between increasing marker expression and severity of dysplastic change for EGFR (P &lt; 0.001), Ki-67 (P &lt; 0.001), and MCM2 (P = 0.001) but not HER-2 (P = 0.102). Increased expression of either EGFR or HER-2 was associated with increased levels of Ki-67 and MCM2 expression, and combined overexpression of these receptors was associated with the highest levels of proliferation, suggesting a synergistic effect. Finally, the lack of an associated trend toward increased EGFR expression when comparing the worst and best biopsies within each subject indicated a potential field effect in the induction of EGFR expression.
Conclusions: The results suggest a prominent role for EGFR overexpression in the development and progression of bronchial dysplasia and provide rationale for exploring inhibition of EGFR signaling in lung cancer chemoprevention.
Antisense Suppression of Pygopus2 Results in Growth Arrest of Epithelial Ovarian Cancer
Authors: Popadiuk Cathy M. , Xiong Jieying , Wells Malcolm G. , Andrews Phillip G. , Dankwa Kweku , Hirasawa Kensuke , Lake Blue B. , Kao Kenneth R. 
Published: April 2006

Abstract
Purpose: The Pygopus proteins are critical elements of the canonical Wnt/β-catenin transcriptional complex. In epithelial ovarian cancer, constitutively active Wnt signaling is restricted to one (endometrioid) tumor subtype. The purpose of this study was to determine the level of expression and growth requirements of human Pygopus2 (hPygo2) protein in epithelial ovarian cancer.
Experimental Design: Expression and subcellular localization of hPygo2 was determined in epithelial ovarian cancer cell lines and tumors using Northern blot, immunoblot, and immunofluorescence. Immunohistochemistry was done on 125 archived patient epithelial ovarian cancer tumors representing all epithelial ovarian cancer subtypes. T-cell factor–dependent transcription levels were determined in epithelial ovarian cancer cells using TOPflash/FOPflash in vivo assays. Phosphorothioated antisense oligonucleotides were transfected into cell lines and growth assayed by cell counting, anchorage-independent colony formation on soft agar, and xenografting into severe combined immunodeficient mice.
Results: All six epithelial ovarian cancer cell lines and 82% of the patient samples overexpressed nuclear hPygo2 compared with control cells and benign disease. Depletion of hPygo2 by antisense oligonucleotides in both Wnt-active (TOV-112D) and Wnt-inactive serous (OVCAR-3, SKOV-3) and clear cell (TOV-21G) carcinoma cell lines halted growth, assessed using tissue culture, anchorage-independent, and xenograft assays.
Conclusions: hPygo2 is unexpectedly widely expressed in, and required in the absence of, Wnt signaling for malignant growth of epithelial ovarian cancer, the deadliest gynecologic malignancy. These findings strongly suggest that inhibition of hPygo2 may be of therapeutic benefit for treating this disease.