bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor Vascular Response to Photodynamic Therapy and the Antivascular Agent 5,6-Dimethylxanthenone-4-Acetic Acid: Implications for Combination Therapy
Authors: Seshadri Mukund , Spernyak Joseph A. , Mazurchuk Richard , Camacho Susan H. , Oseroff Allan R. , Cheney Richard T. , Bellnier David A. 
Published: September 2005

Abstract
Purpose: Photodynamic therapy (PDT) is a clinically approved treatment for a variety of solid malignancies. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a potent vascular targeting agent that has been shown to be effective against a variety of experimental rodent tumors and xenografts and is currently undergoing clinical evaluation. We have previously reported that the activity of PDT against transplanted mouse tumors is selectively enhanced by DMXAA. In the present study, we investigated the in vivo tumor vascular responses to the two treatments given alone and in combination.
Experimental Design: Vascular responses to (i) four different PDT regimens using the photosensitizer 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) at two different fluences (128 and 48 J/cm2) and fluence rates (112 and 14 mW/cm2), (ii) 5-aminolevulinic acid (ALA)–sensitized PDT (135 J/cm2 at 75 mW/cm2), (iii) DMXAA at a high (30 mg/kg) and low dose (25 mg/kg), and (iv) the combination of HPPH-PDT (48 J/cm2 at 112 mW/cm2) and low-dose DMXAA were studied in BALB/c mice bearing Colon-26 tumors.
Results: PDT-induced changes in vascular permeability, determined using noninvasive magnetic resonance imaging with a macromolecular contrast agent, were regimen dependent and did not predict tumor curability. However, a pattern of increasing (4 hours after treatment) and then decreasing (24 hours after) contrast agent concentrations in tumors, seen after high-dose DMXAA or the combination of PDT and low-dose DMXAA, was associated with long-term cure rates of &gt;70%. This pattern was attributed to an initial increase in vessel permeability followed by substantial endothelial cell damage (CD31 immunohistochemistry) and loss of blood flow (fluorescein exclusion assay). Low dose–rate PDT, regardless of the delivered dose, increased the level of magnetic resonance contrast agent in peritumoral tissue, whereas treatment with either DMXAA alone, or PDT and DMXAA in combination resulted in a more selective tumor vascular response.
Conclusions: The observed temporal and spatial differences in the response of tumor vessels to PDT and DMXAA treatments could provide valuable assistance in the optimization of scheduling when combining these therapies. The combination of PDT and DMXAA provides therapeutically synergistic and selective antitumor activity. Clinical evaluation of this combination is warranted.
The Role of Gefitinib in Lung Cancer Treatment
Authors: Giaccone Giuseppe 
Published: September 2005

Abstract
Gefitinib (Iressa) is a novel targeted therapy that inhibits the tyrosine kinase activity of the epidermal growth factor receptor by competitively blocking the ATP binding site. In preclinical studies gefitinib has shown potent activity in a number of tumor models, including several lung cancer cell lines and xenografts. Two large randomized Phase II studies (IDEAL 1 and IDEAL 2) in pretreated non-small cell lung cancer reported a response rate approaching 20% in second-line patients and ∼10% in those pretreated with two or more chemotherapy regimens. The median survival in these two studies approached 6–8 months. As a first-line therapy, gefitinib has been assessed in combination with two different chemotherapy regimens in two large randomized studies (INTACT 1 and INTACT 2). Both studies failed to show an improvement in survival on a total patient accrual of &gt;1000 patients in each study. Other end points (e.g., time to progression and response rate) were also not improved by the addition of gefitinib. Additional studies are indicated to assess the possible role of gefitinib in the maintenance of patients who received chemotherapy or chemoradiotherapy. Studies investigating gefitinib as first-line monotherapy are also required.
The Biology of Epidermal Growth Factor Receptor in Lung Cancer
Authors: Scagliotti Giorgio V. , Selvaggi Giovanni , Novello Silvia , Hirsch Fred R. 
Published: September 2005

Abstract
The prognostic significance of epidermal growth factor receptor (EGFR) expression in lung cancer and, more importantly, its ability to predict response to anti-EGFR therapies, are currently subjects of active research. In a meta-analysis, EGFR overexpression confirmed a worse prognosis (HR 1.13) in eight studies using immunohistochemistry, although cutoff values were generally selected arbitrarily by investigators. Most applied clinical research on the EGFR has been focused on the overexpression of the receptor, whereas less research has addressed the potential role of other mechanisms of increased signaling or of nonmembrane-bound events. The emerging concept of EGFR signaling reveals a multilayered network that allows for horizontal interactions and permits multiple combinatorial responses that may explain the specificity of cellular outcomes to receptor activation. New technologies such as nucleotide arrays and proteomics will help to elucidate the issue by providing information on how EGFR signaling may affect the expression of genes and proteins in cancer cells.
Pemetrexed (ALIMTA), A Novel Multitargeted Antineoplastic Agent
Authors: Adjei Alex A. 
Published: September 2005

Abstract
Pemetrexed (ALIMTA, LY231514, MTA) is a novel antimetabolite that inhibits at least three enzymes involved in the folate pathway. These enzymes are thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated clinical activity in non-small cell lung cancer as well as in a broad array of other solid tumors, including mesothelioma, breast, colorectal, bladder, cervical, gastric and pancreatic cancer. In non-small cell lung cancer, single-agent activity has been documented in the first- and second-line settings in Phase II and Phase III trials. Promising activity has also been demonstrated when pemetrexed is combined with platinum compounds (cisplatin, carboplatin, and oxaliplatin), vinorelbine, and gemcitabine. Low level dietary supplement of folic acid and vitamin B12 has significantly decreased the mucosal and bone marrow toxicity of pemetrexed without compromising its antitumor effect.
Bronchioloalveolar Carcinoma
Authors: Gandara David R. , West Howard , Chansky Kari , Davies Angela M. , Lau Derick H. M. , Crowley John , Gumerlock Paul H. , Hirsch Fred R. , Franklin Wilbur A. 
Published: September 2005

Abstract
Bronchioloalveolar carcinoma (BAC) is a previously uncommon subset of non-small cell lung cancer (NSCLC) with unique epidemiology, pathology, clinical features, radiographic presentation, and natural history compared with other NSCLC subtypes. Recent data suggest that the incidence of BAC is increasing, notably in younger nonsmoking women. Despite reports of prolonged survival after repeated surgical resection of multifocal lesions and slow growth kinetics, advanced bilateral or recurrent diffuse BAC remains incurable, with the vast majority of patients dying of respiratory failure or intercurrent pneumonia within 5 years. Limited data suggest that chemotherapy may yield poor results in BAC. However, anecdotal reports of prolonged complete response to tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR), a member of the human epidermal growth factor receptor (erbB) family, have raised considerable interest in studying this NSCLC subset. Here we present clinical data and preliminary results of correlative science studies analyzing human epidermal growth factor receptor pathways from the following two prospective Southwest Oncology Group clinical trials performed in advanced stage BAC: S9714 testing a 96-h continuous infusion of paclitaxel (Taxol) and S0126 evaluating the small molecule EGFR inhibitor gefitinib (ZD1839 or Iressa). These studies provide a biological rationale for investigating BAC as a model of predictive markers of EGFR inhibition.
The Role of Erlotinib (Tarceva, OSI 774) in the Treatment of Non-Small Cell Lung Cancer
Authors: Perez-Soler Roman 
Published: September 2005

Abstract
Erlotinib (Tarceva) is a reversible and highly specific inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase. Phase I studies established a fixed daily oral dose of 150 mg as the recommended dose for Phase II studies. Using this dose and schedule, the response rate in a group of 57 patients with EGFR-positive non-small cell lung cancer after failure of platinum-containing chemotherapy was 12%. The median survival was 8.4 months, and the 1-year survival was 40%. Occurrence and severity of rash were correlated with an improved survival independently of performance status. Another ongoing Phase II study in 50 patients with bronchoalveolar carcinoma has shown a response rate of 26%. Results from two Phase III front-line studies in combination with chemotherapy, TALENT and TRIBUTE, have been recently reported. The addition of erlotinib did not improve response rate, time to progression, or survival. Efforts in the continued development of erlotinib should be focused on the following: (a) investigating the reasons for the lack of relationship between EGFR expression and clinical outcome; (b) the reasons for the failure of the front-line combination trials; and (c) confirming the rash/clinical outcome relationship. Progress in these tasks will allow a better selection of patients who can benefit from this therapy, permit the development of more effective combination schedules with cytotoxics, and define whether this agent should be used at the optimal biological dose or at the maximum-tolerated dose.
Molecularly Targeted Approaches to the Chemoprevention of Lung Cancer
Authors: Khuri Fadlo R. , Cohen Victor 
Published: September 2005

Abstract
Large, randomized trials have been conducted in the primary prevention of lung cancer using micronutrients or derivative agents for which epidemiological data suggested a potential role in lung cancer prevention. The disappointing primary prevention trials of β-carotene, α-tocopherol, and retinyl palmitate have led to the development of a more compact, biomarker-driven series of translational trials of lung cancer prevention that target reversal of premalignancy as the primary end point. Serial trials of 13-cis-retinoic acid (isotretinoin) and other retinoids have failed to show a difference in reversal of premalignancy in active smokers or in second primary tumor prevention. However, a trial of 9-cis-retinoic acid, a pan retinoid/rexinoid agonist, showed up-regulation of retinoic acid receptor β (RAR-β), a potentially important intermediate marker of response in lung cancer premalignancy. Other planned or ongoing trials currently target important molecular markers of lung carcinogenesis and progression including cyclooxygenase-2, the ras-signaling pathway through farnesyl transferase inhibitors, and the tyrosine kinase/epidermal growth factor receptor pathway (gefitinib, erlotinib). Early results of bioadjuvant trials in head and neck cancer suggest that combination chemoprevention will ultimately be an important option.
Long-Term Exposure to Tamoxifen Induces Hypersensitivity to Estradiol
Authors: Berstein Lev M. , Wang Ji-Ping , Zheng Hong , Yue Wei , Conaway Mark , Santen Richard J. 
Published: September 2005

Abstract
In women with hormone-dependent breast cancer, tamoxifen (TAM) frequently induces tumor regression, but regrowth occurs with continuation of antiestrogen therapy. Studies of breast xenografts in nude mice suggest that this secondary resistance to TAM may reflect the development of enhanced sensitivity to the estrogenic properties of TAM. In the current study, we examined the hypothesis that TAM could also induce a state of hypersensitivity to estradiol (E2) itself. Oophorectomized nude mice with MCF-7 cell xenografts received 25-mg implants of TAM [long-term TAM treated (LTTT) mice] or cholesterol (C-MCF-7) over a 5-month period (phase 1). The LTTT group regressed to a lesser extent than did C-MCF-7 tumors. After 4 months of TAM exposure, the LTTT tumors begin to regrow, as did the C-MCF-7, as assessed by slope analysis. At 5 months, TAM or vehicle implants were removed, and the LTTT and C-MCF-7 subgroups were given vehicle or two doses of E2 to test estrogen sensitivity (phase 2). We used our “E2 clamp” technique to maintain levels of plasma E2 at either 1.25 or 20 pg/ml. Neither group responded to the very low concentrations of E2 (1.25 pg/ml) or vehicle. The LTTT tumors but not C-MCF-7 tumors exhibited a growth response on exposure to 20 pg/ml E2 during 7 weeks, as demonstrated with mixed models analysis. These studies provide evidence that long-term TAM exposure enhances sensitivity to the estrogenic effects of TAM and also to E2 itself.
Adenovirus-Mediated Retinoblastoma 94 Gene Transfer Induces Human Pancreatic Tumor Regression in a Mouse Xenograft Model
Authors: Roig Josep Maria , Molina Miguel Angel , Cascante Anna , Calbó Joaquim , Carbó Neus , Wirtz Uwe , Sreedharan Sunil , Fillat Cristina , Mazo Adela 
Published: September 2005

Abstract
Purpose: Gene transfer of a truncated variant of the retinoblastoma (RB) gene encoding a Mr 94,000 protein that lacks the NH2-terminal 112 amino acid residues, termed RB94, has been shown to inhibit proliferation of several human tumor cell types. We have assessed its therapeutic effectiveness on pancreatic cancer, one of the most aggressive and therapy-resistant types of cancer. For this purpose, preclinical studies aimed to evaluate the therapeutic potential of RB94 gene transfer in pancreatic cancer were carried out.
Experimental Design: We have compared the antiproliferative effects of adenovirus-mediated gene transfer of RBwt and RB94 at the in vitro and in vivo levels in three RB-positive human pancreatic tumor cell lines: (a) NP-9; (b) NP-18; and (c) NP-31. We have also examined their effects on cell cycle and their capacity to induce apoptosis.
Results: In vitro results indicate that RB94 gene transfer has stronger antiproliferative effects compared with RBwt. RB94 transduction correlated with accumulation at the S-G2 phase of the cell cycle in the three cell lines tested and induction of apoptosis in two of them. In vivo studies show significant decreases in the growth rate of tumors treated with Ad-RB94 when compared with those treated with Ad-RBwt. Moreover, terminal deoxynucleotidyl transferase-mediated nick end labeling analyses of Ad-RB94-treated tumor sections revealed that only RB94 is able to significantly induce apoptosis.
Conclusions: RB94 gene expression has antiproliferative effects also in human pancreatic tumor cells, being more effective than wild-type RB in preventing tumor growth.
Reduced Growth, Increased Vascular Area, and Reduced Response to Cisplatin in CD13-Overexpressing Human Ovarian Cancer Xenografts
Authors: van Hensbergen Yvette , Broxterman Henk J. , Rana Sareena , van Diest Paul J. , Duyndam Monique C. A. , Hoekman Klaas , Pinedo Herbert M. , Boven Epie 
Published: September 2005

Abstract
Purpose: Expression of aminopeptidase N/CD13 can be detected in several solid tumor types. Thus far, the role of CD13 in ovarian cancer has not been studied. We have investigated the expression pattern and biological function of CD13 in ovarian cancer.
Experimental Design: First, we studied the expression of CD13 in ovarian cancer tissue of 15 patients representing three different histological types (5 patients each) by immunohistochemistry. We then stably transfected the IGROV-1 human ovarian cancer cell line with a CD13 expression vector and examined the biological effect of CD13 in vitro and in vivo.
Results: The expression of CD13 in ovarian cancer was associated with the histological subtype: CD13 expression in tumor cells was observed in 80–100% of the patients with a serous or mucinous carcinoma and in only 20% of the clear cell carcinoma patients. In all patients’ tumor samples, CD13-positive blood vessels were present. CD13 overexpression in IGROV-1 cells did not affect in vitro cell growth and sensitivity to doxorubicin, cisplatin, or gemcitabine. CD13 overexpression reduced invasion in Matrigel, which appeared to be independent of the aminopeptidase activity of CD13. Furthermore, the growth rate of IGROV-1/CD13 xenografts was reduced. The area of the vessel lumens was enlarged in a small percentage of vessels in the CD13-overexpressing xenografts. In addition, the CD13-overexpressing tumors were less sensitive to cisplatin.
Conclusions: CD13 is expressed in tumor as well as endothelial cells in human ovarian cancer. Our results suggest that CD13 overexpression affects ovarian cancer growth, vascular architecture, and response to chemotherapy. Further elucidation of the mechanism of the observed effects of CD13 is warranted to better understand its role in the pathophysiology of ovarian cancer.
A Phase II Trial with Pharmacodynamic Endpoints of the Proteasome Inhibitor Bortezomib in Patients with Metastatic Colorectal Cancer
Authors: Mackay Helen , Hedley David , Major Pierre , Townsley Carol , Mackenzie Mary , Vincent Mark , Degendorfer Pam , Tsao Ming-Sound , Nicklee Trudey , Birle Diana , Wright John , Siu Lillian , Moore Malcolm , Oza Amit 
Published: September 2005

Abstract
Purpose: To evaluate the effects of the proteasome inhibitor bortezomib on tumor growth in patients with advanced colorectal cancer, and to explore the relationship between correlative studies and clinical outcome.
Design: Bortezomib (1.3 mg/m2) was administered i.v. on days 1, 4, 8, and 11 of a 21-day cycle. Tumor response was assessed after every two cycles. Tumor biopsies were done prior to treatment and on day 9 of the first treatment cycle. Biopsies were examined for Ser32/36-IκB, Ser276-nuclear factor κB (NFκB), hypoxia-inducible factor-1α (HIF-1α), carbonic anhydrase IX (CAIX), p53, and microvessel density using immunohistochemistry.
Results: Nineteen patients received 42 cycles (range 1-4) of bortezomib. No objective response was seen; three patients had stable disease at cycle 2, two patients had progressive disease after cycle 1, and 11 patients had progressive disease at cycle 2. Of the three patients with stable disease, one had progressive disease after cycle 4, and two were withdrawn due to toxicity. The median time to progression was 5.1 weeks (95% confidence interval, 5.1-11.1 weeks). There was a significant increase in the expression of HIF-1α relative to its transcriptional target CAIX following bortezomib, and a similar effect was also observed in a companion study using a human tumor xenograft model. Expression of p53, Ser276-NFκB, and Ser32/36-IκB was unchanged.
Conclusion: Single agent bortezomib is inactive in metastatic colorectal cancer. Using this regimen, there was no detectable effect on NFκB, but a significant accumulation of HIF-1α was seen relative to CAIX. This suggests that proteasome inhibition alters the response to tumor hypoxia, and further investigation of this effect is indicated.
Critical Role of Peroxisome Proliferator-Activated Receptor γ on Anoikis and Invasion of Squamous Cell Carcinoma
Authors: Masuda Tomotake , Wada Koichiro , Nakajima Atsushi , Okura Masaya , Kudo Chiho , Kadowaki Takashi , Kogo Mikihiko , Kamisaki Yoshinori 
Published: September 2005

Abstract
Purpose: Peroxisome proliferator-activated receptor γ (PPARγ) plays a important role in various physiological functions. We examined whether PPARγ is expressed in primary squamous cell carcinoma and lymph node metastasis and whether PPARγ is a potential target for tumor therapy.
Experimental Design and Results: A high-level expression of PPARγ was observed in tumor cells of human primary squamous cell carcinoma, lymph node metastasis, and squamous cell carcinoma cell lines. Treatment with PPARγ-specific antagonists, but not agonists, caused apoptotic cell death on squamous cell carcinoma cell lines in a concentration-dependent manner. Small interfering RNA for PPARγ also inhibited cell adhesion and growth of squamous cell carcinomas. The phosphorylation of focal adhesion kinase (FAK) was decreased by treatment with PPARγ antagonists, and resulted in decreases in phosphorylation of Erk and mitogen-activated protein kinase. Furthermore, PPARγ antagonists decreased the adhesion of squamous cell carcinomas into fibronectin-coated plates, indicating the inhibition of interaction between squamous cell carcinomas and fibronectin. Expression of integrin α5, a counter adhesion molecule for fibronectin, was inhibited by the treatment with PPARγ antagonists. These results indicate that the decrease in integrin α5 and following inhibition of cell adhesion may cause the inhibition of FAK signaling pathways. PPARγ antagonists also strongly inhibited invasion of squamous cell carcinoma via down-regulation of CD151 expression.
Conclusions: The cell death caused by the PPARγ antagonists was a result of direct interference with cell adhesion “anoikis” involving intracellular FAK signaling pathways. These results imply a potentially important and novel role for the inhibition of PPARγ function via the use of specific antagonists in the treatment of squamous cell carcinoma and the prevention of tumor invasion and metastasis.
S100P Promotes Pancreatic Cancer Growth, Survival, and Invasion
Authors: Arumugam Thiruvengadam , Simeone Diane M. , Van Golen Kenneth , Logsdon Craig D. 
Published: September 2005

Abstract
Purpose: In the current study, we examined the functional significance and mechanism of action of S100P in pancreatic cancer cells.
Experimental Design: S100P levels were increased in Panc-1 cells, which do not express S100P, by transfection with an S100P cDNA and S100P levels were reduced in BxPC3 cells, which express high levels of S100P, by small interfering RNA gene silencing. Effects of these manipulations on cell proliferation, resistance to apoptotic insults, cell migration, and invasion were estimated in vitro using standard assays. The influences of S100P on tumor growth in vivo were studied using xenograft mouse models. To identify the mechanisms involved in these responses, coimmunoprecipitation studies were conducted with S100P with receptor for advanced glycation end products (RAGE) and the effects of inhibiting RAGE using an antagonistic peptide were analyzed.
Results: S100P levels correlated with the rates of cell proliferation, survival, migration, and invasion in both cell models in vitro. In vivo, increased S100P levels increased the growth of tumors in mice with s.c.-implanted Panc-1 cells and decreased S100P levels decreased tumor growth after orthotopic implantation of BxPC-3 cells. A direct interaction between S100P and RAGE was indicated by coimmunoprecipitation of these molecules from pancreatic cancer cells. A RAGE antagonist peptide inhibited this interaction and also inhibited the biological effects of S100P on these cells in vitro.
Conclusions: These data suggest that S100P plays a major role in the aggressiveness of pancreatic cancer that is likely mediated by its ability to activate RAGE. Thus, interference with S100P may provide a novel approach for treatment of pancreatic cancer.