Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endostatin is a potent inhibitor of angiogenesis currently in phase I clinical trials. Imaging technologies that use near-infrared fluorescent probes are well suited to the laboratory setting. The goal of this study was to determine whether endostatin labeled with a near-infrared probe (Cy5.5) could be detected in an animal and whether it would selectively localize to a tumor. Endostatin was conjugated to Cy5.5 monofunctional dye and injected into mice bearing Lewis lung carcinoma tumors (350 mm2). Mice were imaged at various time points while under sedation using a lightproof box affixed to a fluorescent microscope mounted with a filter in the near-infrared bandwidth consistent with Cy5.5 fluorescence. After i.p. injection, endostatin-Cy5.5 was absorbed producing a near-infrared fluorescent image within the tumors at 18 h reaching a maximum at 42 h after injection. No signal was emitted from mice injected with unlabeled endostatin or Cy5.5 dye alone or those that received no injection. Further results show that a dose response exists with injection of endostatin-Cy5.5. Mimicking the clinical route of administration, an i.v. injection had a peak signal emission at 3 h but also persisted to 72 h. Finally, to determine the intratumoral binding site for endostatin, we performed immunofluorescence on tumor specimens and demonstrated that endostatin binds to tumor vasculature and colocalizes with platelet/endothelial cell adhesion molecule 1 expression. This study demonstrates that endostatin covalently bound to Cy5.5 will migrate from a distant i.p. injection site to a tumor. These data indicate that endostatin-Cy5.5 is appropriate for selectively imaging tumors in uninjured experimental animals.
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PMID:In vivo tumor imaging in mice with near-infrared labeled endostatin. 1507 92

Four novel oral DNA vaccines provide long-lived protection against melanoma, colon, breast, and non-small cell lung carcinoma in mouse model systems. The vaccines are delivered by attenuated Salmonella typhimurium to secondary lymphoid organs and are directed against targets such as carcinoembryonic antigen, tyrosine-related protein, vascular endothelial growth factor receptor-2 [also called fetal liver kinase-1 (FLK-1)], and transcription factor Fos-related antigen-1 (Fra-1). The FLK-1 and Fra-1 vaccines are effective in suppressing angiogenesis in the tumor vasculature. All four vaccines are capable of inducing potent cell-mediated protective immunity, breaking peripheral T-cell tolerance against these self-antigens resulting in effective suppression of tumor growth and metastasis. It is anticipated that such research efforts will contribute toward the rational design of future DNA vaccines that will be effective for prevention and treatment of human cancer.
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PMID:DNA vaccines suppress tumor growth and metastases by the induction of anti-angiogenesis. 1523 34

The phosphatidylinositol 3'-kinase (PI3k)/protein kinase B (PKB/Akt) signal transduction pathway plays a critical role in mediating endothelial cell survival and function during oxidative stress. The role of the PI3k/Akt signaling pathway in promoting cell viability was studied in vascular endothelial cells treated with ionizing radiation. Western blot analysis showed that Akt was rapidly phosphorylated in response to radiation in primary culture endothelial cells (human umbilical vascular endothelial cells) in the absence of serum or growth factors. PI3k consists of p85 and p110 subunits, which play a central upstream role in Akt activation in response to exogenous stimuli. The delta isoform of the p110 subunit is expressed in endothelial cells. We studied the effects of the p110delta specific inhibitor IC486068, which abrogated radiation-induced phosphorylation of Akt. IC486068 enhanced radiation-induced apoptosis in endothelial cells and reduced cell migration and tubule formation of endothelial cells in Matrigel following irradiation. In vivo tumor growth delay was studied in mice with Lewis lung carcinoma and GL261 hind limb tumors. Mice were treated with daily i.p. injections (25 mg/kg) of IC486068 during 6 days of radiation treatment (18 Gy). Combined treatment with IC486068 and radiation significantly reduced tumor volume as compared with either treatment alone. Reduction in vasculature was confirmed using the dorsal skinfold vascular window model. The vascular length density was measured by use of the tumor vascular window model and showed IC486068 significantly enhanced radiation-induced destruction of tumor vasculature as compared with either treatment alone. IC486068 enhances radiation-induced endothelial cytotoxicity, resulting in tumor vascular destruction and tumor control when combined with fractionated radiotherapy in murine tumor models. These findings suggest that p110delta is a therapeutic target to enhance radiation-induced tumor control.
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PMID:A specific antagonist of the p110delta catalytic component of phosphatidylinositol 3'-kinase, IC486068, enhances radiation-induced tumor vascular destruction. 1525 60

A novel strategy achieved the eradication of lung tumor metastases by joint suppression of angiogenesis in the tumor neovasculature and induction of tumor cell apoptosis. This was accomplished by CTLs induced by a DNA vaccine encoding secretory chemokine CCL21 and the inhibitor of apoptosis protein survivin, overexpressed by both proliferating endothelial cells in the tumor vasculature and tumor cells. Oral delivery of this DNA vaccine by doubly attenuated Salmonella typhimurium (dam(-) and AroA(-)) to such secondary lymphoid organs as Peyer's patches in the small intestine, elicited marked activation of antigen-presenting dendritic cells, and an effective CD8(+)T cell immune response against the survivin self-antigen. This resulted in eradication or suppression of pulmonary metastases of non-small cell lung carcinoma in both prophylactic and therapeutic settings in C57BL/6J mice. Moreover, the suppression of angiogenesis induced by the vaccine did not impair wound healing or fertility of treated mice. It is anticipated that such novel DNA vaccines will aid in the rational design of future strategies for the prevention and treatment of cancer.
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PMID:A DNA vaccine targeting survivin combines apoptosis with suppression of angiogenesis in lung tumor eradication. 1569 99

Paclitaxel poliglumex (CT-2103; XYOTAX) is an innovative macromolecular taxane designed to increase the therapeutic index of paclitaxel. This large macromolecule conjugate of paclitaxel and poly-L-glutamic acid accumulates in tumor tissues by taking advantage of the enhanced permeability of tumor vasculature and lack of lymphatic drainage. Paclitaxel poliglumex prolongs exposure to active drug and minimizes systemic exposure. Preclinical studies in animal tumor models demonstrate enhanced safety and efficacy relative to paclitaxel when administered as a single agent or in conjunction with radiation. Clinical pilot studies with paclitaxel poliglumex showed improved outcomes compared to standard taxanes and allowed a more convenient administration schedule. Human pharmacokinetic data are consistent with prolonged tumor exposure to active drug and a limited systemic exposure. Based on these results, three ongoing randomized phase III trials were initiated to test the efficacy of paclitaxel poliglumex in patients with advanced non-small cell lung carcinoma.
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PMID:Paclitaxel poliglumex (XYOTAX; CT-2103): an intracellularly targeted taxane. 1571 Nov 76

The development of tumor vasculature is thought to occur through two complementary processes: sprouting angiogenesis from preexisting blood vessels of the host, and vasculogenesis, which involves the spontaneous development of vessels through specific recruitment, differentiation, and vascular incorporation of circulating endothelial cells (EC), endothelial progenitor cells (EPC), or potentially bone marrow-derived cells. Recent reports, however, have challenged the belief that bone marrow-derived cells contribute to tumor neovascularization, claiming an exclusive role for sprouting angiogenesis in tumor blood vessel development. In the present study, we explored the recruitment behavior of bone marrow-derived lin(-)c-kit(+)Sca-1+ stem cells to subcutaneously implanted Lewis lung carcinoma in a syngeneic bone marrow transplantation model. We observed that although lin(-)c-kit(+)Sca-1+ and their derived cells demonstrate significant recruitment to carcinomas in vivo, they do not appear to functionally contribute to tumor neovascularization. Furthermore, our results support the hypothesis that new vessel formation in carcinomas occurs primarily through endothelialization from adjacent and preexisting vasculature.
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PMID:Bone marrow-derived lin(-)c-kit(+)Sca-1+ stem cells do not contribute to vasculogenesis in Lewis lung carcinoma. 1579 23

With recent Food and Drug Administration approval of the anti-vascular endothelial growth factor (VEGF) antibody for the treatment of colon cancer, it may be possible to achieve similar progress in the treatment of locally advanced lung cancer. Antiangiogenic therapies in the clinic are a reality, and it is important to demonstrate that they can be used safely with conventional modalities, including radiation therapy (RT). Strategies under scrutiny in preclinical and clinical studies include the use of endogenous inhibitors of angiogenesis, use of agents that target VEGF and VEGF receptor signaling, targeting endothelial-related integrins during angiogenesis, and targeting the preexisting immature vessels growing within tumors (ie, vascular targeting). Regardless of the approach, it is necessary to address whether angiogenesis is a consistent phenomenon within the lung parenchyma around a cancer and a relevant target and whether inhibiting angiogenesis will improve current lung cancer therapies without increasing toxicity. Vascular-targeting agents (VTAs) are an interesting class of agents that have the potential to enhance RT, but their clinical promise has yet to be realized. In preclinical models, these agents selectively destroy the tumor vasculature, initiating a rapid centralized necrosis within established tumors. Characteristically, after treatment with VTAs, a rim of viable tumor cells remains at the periphery of the tumor, which remains well perfused and should therefore be relatively sensitive to radiation-induced cytotoxicity. This review will focus on VTAs in the treatment of lung cancer and includes a discussion of combination studies with RT in the laboratory and some of the hurdles in the clinical application of these agents.
Clin Lung Cancer 2005 Nov
PMID:Vascular-targeting agents and radiation therapy in lung cancer: where do we stand in 2005? 1635 11

The dose of radiation that can be safely delivered to cancers residing in sensitive areas such as the lungs is limited by concern for normal tissue damage. Therapies that target tumor vasculature have potential to enhance the efficacy of radiotherapy, with minimal risk for toxicity. We constructed a unique plasmid, pXLG-mEndo, containing the mouse endostatin gene. A significantly greater anti-tumor effect was obtained against Lewis lung carcinoma (LLC) in mice when pXLG-mEndo was combined with radiation compared to radiation alone. Here we report results of cellular and cytokine assessments performed one day after treatment. These analyses were done to obtain baseline data on leukocytes that affect angiogenesis, as well as anti-tumor immunity, and to detect possible treatment-related toxicities. White blood cell counts were dramatically elevated in blood and spleens of untreated tumor-bearing mice, primarily due to granulocytosis. Overall, the effect of radiation was more evident than that of the plasmids (pXLG-mEndo and parental pWS4); radiosensitivity of specific lymphocyte subsets was variable (B > T > NK; CD8+ Tc > CD4+ Th). Tumor presence resulted in dramatically elevated interleukin-2 (IL-2) and decreased tumor necrosis factor-alpha (TNF-alpha) in supernatants of activated splenocytes, but had no significant effect on interferon-gamma (IFN-gamma). Administration of pXLG-mEndo, radiation, or both modified the tumor-induced aberrations in IL-2 and TNF-alpha; IFN-gamma production was decreased by radiation. Red blood cell counts, hemoglobin, and hematocrit were low in tumor-bearing mice, but there were no treatment-related differences among groups. Platelet counts were reduced, whereas their volumes were increased in tumor-bearing mice; both parameters were only slightly affected by either pXLG-mEndo or control plasmid injection, however. The data demonstrate in the Lewis lung carcinoma model that tumor-localized endostatin gene therapy and radiation had significant effects on cells and cytokines that can influence angiogenesis, tumor growth, and immune status.
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PMID:Radiation and endostatin gene therapy in a lung carcinoma model: pilot data on cells and cytokines that affect angiogenesis and immune status. 1655 Nov 33

Inhibition of tumor angiogenesis is a promising approach in cancer treatment. The purpose of this study was to evaluate the vascular response of human lung tumor xenografts in vivo to RO0281501, an inhibitor of tyrosine kinase receptors, including vascular endothelial growth factor receptor 2, fibroblast growth factor receptor, and platelet-derived growth factor receptor, using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Human non-small cell lung carcinoma (H460a) xenografts grown s.c. in athymic nu/nu mice were treated p.o. with the antiangiogenic agent RO0281501. Treatment-induced changes in tumor volume, epiphyseal growth plate thickness, and microvessel density assessed by CD31 immunohistochemistry were analyzed. Tumor vascular permeability and perfusion were measured in tumors using DCE-MRI with gadopentetate dimeglumine on a 1.5 T clinical scanner to assess vascular function. Treatment with RO0281501 resulted in significant growth retardation of H460a tumors. RO0281501-treated tumors showed histologic evidence of growth plate thickening and relatively lower microvessel density compared with the controls. Regarding DCE-MRI variables, the initial slope of contrast uptake and Ak(ep) were significantly decreased on day 7 of treatment. RO0281501 is a novel antiangiogenic/antitumor agent, which is active in the H460a xenograft model. Its effects on tumor vasculature can be monitored and assessed by DCE-MRI on a 1.5 T human MR scanner with clinically available gadopentetate dimeglumine contrast, which will facilitate clinical trials with this or similar agents.
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PMID:Preclinical evaluation of tumor microvascular response to a novel antiangiogenic/antitumor agent RO0281501 by dynamic contrast-enhanced MRI at 1.5 T. 1692 15

Antiangiogenic therapy could destroy tumor vasculature and inhibit tumor growth. It might inhibit tumor growth significantly when used as a single treatment modality and its therapeutic benefit may even be greater when used in combination with established treatment modalities such as radiation therapy (RT). In the present report, we investigated the effect of recombinant human plasminogen kringle 5 domain (rhK5) in combination with ionizing radiation on angiogenesis, tumor growth and survival in a murine Lewis lung carcinoma (LLC) tumor model. Combined treatment using rhK5 and radiotherapy displayed obvious suppressive effect on LLC tumor growth as compared with single treatment with either modality (p < 0.05), and resulted in a more additive effect on tumor growth delay in this model. In addition, combined treatment significantly enhanced the survival of mice and no toxic effect, such as weight loss, was observed. The significant antitumor effect of rhK5 plus radiation was associated with a direct suppression effect on early neoangiogenesis and tumor cell apoptosis. Furthermore, the expression of VEGF and HIF-1alpha in tumor tissue correlated well with decreased vessel density. The results suggest that rhK5 significantly enhances the antitumor activity of RT and could be a potent adjuvant therapeutic approach to improve the efficacy of radiotherapy for lung cancer.
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PMID:Combination of human plasminogen kringle 5 with ionizing radiation significantly enhances the efficacy of antitumor effect. 1768 May 63


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