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)

Angiostatin, a proteolytic fragment of plasminogen, inhibits the growth of primary and metastatic tumors by suppressing angiogenesis. When used in combination with ionizing radiation (IR), angiostatin demonstrates potent antitumor synergism, largely caused by inhibition of the tumor microvasculature. We report here the temporal interaction of angiostatin and IR in Lewis lung carcinoma (LLC) tumors growing in the hind limbs of syngeneic mice. Tumors with an initial mean volume of 510 +/- 151 mm3 were treated with IR alone (20 Gy x 2 doses on days 0 and 1), angiostatin alone (25 mg/kg/day divided twice daily) on days 0 through 13, or a combination of the two as follows: (a) IR plus angiostatin (days 0 through 13); (b) IR plus angiostatin (days 0 and 1); and (c) IR followed by angiostatin beginning on the day after IR completion and given daily thereafter (days 2 through 13). By day 14, tumors in untreated control mice had grown to 6110 +/- 582 mm3, whereas in mice treated with: (a) IR alone, tumors had grown to 2854 +/- 338 mm3 (P < 0.05 compared with untreated controls); and (b) angiostatin alone, tumors had grown to 3666 +/- 453 mm3 (P < 0.05 compared with untreated controls). In combined-treatment groups, in mice treated with: (a) IR plus longer-course angiostatin, tumors reached 2022 +/- 282 mm3 (P = 0.036 compared with IR alone); (b) IR followed by angiostatin, tumors reached 2677 +/- 469 mm3 (P > 0.05 compared with IR alone); and (c) IR plus short-course angiostatin, tumors reached 1032 +/- 78 mm3 (P < 0.001 compared with IR alone). These findings demonstrate that the efficacy of experimental radiation therapy is potentiated by brief concomitant exposure of the tumor vasculature to angiostatin.
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PMID:Potentiation of the antitumor effect of ionizing radiation by brief concomitant exposures to angiostatin. 986 23

AC-7700, a novel combretastatin A-4 derivative, suppresses the growth of solid tumors by inhibiting tumor perfusion. We evaluated the antitumor activity of AC-7700 on solid tumors in two experimental models, an advanced tumor model (murine colon 26 (c26) adenocarcinoma, colon 38 (c38) adenocarcinoma, MethA fibrosarcoma, Sarcoma 180 (S180), Lewis lung carcinoma (3LL), human LS180 adenocarcinoma) and an orthotopically transplanted tumor model (c26), compared with that of cisplatin (CDDP). The maximum tolerable dose (MTD) of CDDP suppressed early-stage c26 and c38 tumor growth when treatment was started after the tumor volume (TV) reached 0.2-0.5 cm3, but it showed reduced activity against the same tumors at an advanced growth stage when TV exceeded 2 cm3. At its MTD, AC-7700 was active against all tumors tested except 3LL in both early and advanced growth stages, reducing the tumor mass and having a curative effect in advanced c38 tumors. AC-7700 was also effective on orthotopically transplanted c26 tumors, showing a comparable activity to that on subcutaneous tumors. Unlike flavon acetic acid, which damages tumor vasculature by inducing endogenous tumor necrosis factor-alpha production, AC-7700 potently suppressed the growth of advanced c26 tumors in athymic as well as euthymic mice. These results suggest that AC-7700 is a novel antivascular agent that may have potent activity against advanced-stage cancer in the clinical setting.
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PMID:A novel combretastatin A-4 derivative, AC-7700, shows marked antitumor activity against advanced solid tumors and orthotopically transplanted tumors. 1055 33

Neovascularization is a prerequisite for tumor growth. Thus, selective destruction of the tumor vasculature should prevent tumor expansion. We have established a method to identify proteins that are specifically expressed on the surface of endothelial cells in tumors. CD31-positive endothelial cells were isolated from Lewis lung carcinoma lung metastases as well as from normal lung tissue. cDNAs derived from these cells were subjected to a subtractive hybridization procedure, and cDNAs overrepresented in tumor-derived endothelial cells were isolated; those encoding surface proteins were selected using a signal sequence trap assay. One isolated cDNA encoded H/T-cadherin. In this report, we show that mouse H/T-cadherin is overexpressed on endothelial cells of several tumors, whereas it is expressed only on a subset of endothelial cells in healthy organs. On the basis of the expression of H/T-cadherin in lung metastases of different tumors, we suggest that different tumors can have a differential influence on the expression of endothelial cell surface proteins.
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PMID:Increased expression of H/T-cadherin in tumor-penetrating blood vessels. 1098 67

A technique that can measure tumor blood flow easily, accurately and economically is required to study tumor angiogenesis and angiogenesis inhibition. Using dye extraction colored microspheres, we measured tumor blood flow in Sato lung carcinoma (SLC) and ascites hepatoma LY80 in rats. Colored microspheres were infused into tumor-bearing rats via a catheter in the left ventricle. After removal of the tumor and the liver, the tissue samples were dissolved, and the microspheres were isolated. Dye was extracted, and the dye concentration was quantified by spectrophotometry. The dye concentration per gram of tumor was compared with that per gram of liver as follows (AU = absorbency units): [AU per gram of tumor] / [AU per gram of liver] X 100 = (%). Tumor blood flow corrected for wet weight was calculated as follows: [blood flow to tumor] = [AU per gram of tumor] X [reference withdrawal rate] / [AU per gram of reference blood]. Tumor blood flow rate was divided by tumor weight to yield ml. min-1g-1. The tumors were also examined histologically, and casts of the tumor vasculature were prepared with silicone rubber. Blood flow 2 weeks after transplantation was equivalent to 1/10 and 1/2 at 1 week in SLC and LY80 tumors, respectively (SLC, P=0.009, n=10; LY80, P=0.05, n=10). These decreases in tumor blood flow were associated with underlying pathological and vascular change. Blood flow in LY80 tumors negatively correlated with tumor volume (P=0.009, n=10). We concluded that the colored microsphere method, initially developed to measure organ blood flow, is also useful for estimating tumor blood flow in rats.
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PMID:Measurement of tumor blood flow using colored dye extraction microspheres in two rat tumor models. 1117 86

The promise of cancer immunotherapy is that it will not only eradicate primary tumors but will generate systemic antitumor immunity capable of destroying distant metastases. A major problem that must first be surmounted relates to the immune resistance of large tumors. Here we reveal that immune resistance can be overcome by combining immunotherapy with a concerted attack on the tumor vasculature. The functionally related antitumor drugs 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and flavone acetic acid (FAA), which cause tumor vasculature collapse and tumor necrosis, were used to attack the tumor vasculature, whereas the T-cell costimulator B7.1 (CD80), which costimulates T-cell proliferation via the CD28 pathway, was used to stimulate antitumor immunity. The injection of cDNA (60-180 microg) encoding B7.1 into large EL-4 tumors (0.8 cm in diameter) established in C57BL/6 mice, followed 24 h later by i.p. administration of either DMXAA (25 mg/kg) or FAA (300 mg/kg), resulted in complete tumor eradication within 2-6 weeks. In contrast, monotherapies were ineffective. Both vascular attack and B7.1 immunotherapy led to up-regulation of heat shock protein 70 on stressed and dying tumor cells, potentially augmenting immunotherapy. Remarkably, large tumors took on the appearance of a wound that rapidly ameliorated, leaving perfectly healed skin. Combined therapy was mediated by CD8+ T cells and natural killer cells, accompanied by heightened and prolonged antitumor cytolytic activity (P < 0.001), and by a marked increase in tumor cell apoptosis. Cured animals completely rejected a challenge of 1 x 10(7) parental EL-4 tumor cells but not a challenge of 1 x 10(4) Lewis lung carcinoma cells, demonstrating that antitumor immunity was tumor specific. Adoptive transfer of 2 x 10(8) splenocytes from treated mice into recipients bearing established (0.8 cm in diameter) tumors resulted in rapid and complete tumor rejection within 3 weeks. Although DMXAA and B7.1 monotherapies are complicated by a narrow range of effective doses, combined therapy was less dosage dependent. Thus, a broad range of amounts of B7.1 cDNA were effective in combination with 25 mg/kg DMXAA. In contrast, DMXAA, which has a very narrow range of high active doses, was effective at a low dose (18 mg/kg) when administered with a large amount (180 microg) of B7.1 cDNA. Importantly, combinational therapy generated heightened antitumor immunity, such that gene transfer of B7.1 into one tumor, followed by systemic DMXAA treatment, led to the complete rejection of multiple untreated tumor nodules established in the opposing flank. These findings have important implications for the future direction and utility of cancer immunotherapies aimed at harnessing patients' immune responses to their own tumors.
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PMID:Vascular attack by 5,6-dimethylxanthenone-4-acetic acid combined with B7.1 (CD80)-mediated immunotherapy overcomes immune resistance and leads to the eradication of large tumors and multiple tumor foci. 1128 Jul 51

Tumor cells are elusive targets for immunotherapy due to their heterogeneity and genetic instability. Here we describe a novel, oral DNA vaccine that targets stable, proliferating endothelial cells in the tumor vasculature rather than tumor cells. Targeting occurs through upregulated vascular-endothelial growth factor receptor 2 (FLK-1) of proliferating endothelial cells in the tumor vasculature. This vaccine effectively protected mice from lethal challenges with melanoma, colon carcinoma and lung carcinoma cells and reduced growth of established metastases in a therapeutic setting. CTL-mediated killing of endothelial cells indicated breaking of peripheral immune tolerance against this self antigen, resulting in markedly reduced dissemination of spontaneous and experimental pulmonary metastases. Angiogenesis in the tumor vasculature was suppressed without impairment of fertility, neuromuscular performance or hematopoiesis, albeit with a slight delay in wound healing. Our strategy circumvents problems in targeting of genetically unstable tumor cells. This approach may provide a new strategy for the rational design of cancer therapies.
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PMID:A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth. 1245 72

A number of cancer vaccine and gene therapy approaches are being evaluated in patients with lung cancer. Cancer vaccine strategies include GM-CSF gene-modified cancer cells, liposomal MUC1 peptide, anti-idiotype antibody targeting GD3, Mage-3 peptide, and mutant p53 pulsed dendritic cells among others. Preliminary human trials have demonstrated immune responses as well as tumor regression in late stage disease. The largest human gene therapy experience in lung cancer is with intratumoral gene replacement therapy, predominantly with p53, but such approaches are limited to locoregional disease control. Earlier stage gene therapy programs targeting the immune system or tumor vasculature hold promise as systemic therapies for treatment of advanced, disseminated disease.
Lung Cancer 2003 Aug
PMID:Lung cancer vaccines and gene therapy. 1286 69

Receptor tyrosine kinase activation contributes to cell viability during cytotoxic therapy. The novel broad spectrum receptor tyrosine kinase inhibitor, SU11248, inhibits vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor, c-kit, and fetal liver tyrosine kinase 3. In this study, we maintained SU11248 plasma levels beyond the completion of radiotherapy to determine whether tumor regrowth can be delayed. The antiangiogenic effects of SU11248 were demonstrated using human umbilical vein endothelial cells in vitro. Apoptosis increased and clonogenic survival decreased when SU11248 was used in combination with radiation from 0 to 6 Gy on endothelial cells. In vivo tumor growth delay was increased in C57B6J mice with Lewis lung carcinoma or glioblastoma multiform (GL261) hind limb tumors. Mice were treated with daily i.p. injections (40 mg/kg) of SU11248 during 7 days of radiation treatment (21 Gy). Combined treatment with SU11248 and radiation significantly reduced tumor volume as compared with either treatment alone. Concomitant reduction in vasculature was confirmed using the dorsal vascular window model. The vascular length established using images taken from a consistent quadrant in the window show the combination therapy was more effective in destroying tumor vasculature than either treatment alone. SU11248 maintenance administration beyond the completion of radiotherapy results in prolongation of tumor control. In summary, SU11248 enhances radiation-induced endothelial cytotoxicity, resulting in tumor vascular destruction and tumor control when combined with fractionated radiotherapy in murine tumor models. Moreover, inhibition of angiogenesis well beyond radiation therapy may be a promising treatment paradigm for refractory human neoplasms.
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PMID:SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models. 1287 99

ST1481 (gimatecan) is a novel lipophilic camptothecin with a promising preclinical pharmacological profile. On the basis of its high antitumor efficacy when delivered by the oral route, the compound is suitable for prolonged administration. This schedule of treatment has been reported as the most appropriate to exploit the antiangiogenic effects of cytotoxic drugs. The aim of the study was to investigate the antiangiogenic and antitumor effects of oral ST1481 in human tumor xenografts. In spite of a marginal drug effect against the s.c. growing A549 lung carcinoma following administration with an intermittent schedule (q4dx4 times, maximum tolerated dose: 2 mg/kg), tumor growth was strongly inhibited by a daily low-dose (0.5 mg/kg) prolonged administration. Immunohistochemical analysis showed a reduced number of microvessels in tumors of both treated groups versus controls and a significantly higher reduction in the daily versus the q4dx4-treated tumors (P < 0.0001, by Student's t test). In our experimental model, the relation between microvessel density and tumor size (r = 0.738, by the Spearman rank test) suggests a role of inhibition of tumor vasculature in tumor response. Significant inhibition of tumor angiogenesis (P < 0.0001 versus control tumors) was observed even with a very low drug dose (0.06 mg/kg) in the orthotopically implanted (i.d.) MeWo melanoma, under conditions causing minimal tumor growth inhibition. Additional evidences of the antiangiogenic activity of ST1481 were provided by antimotility effects on endothelial cells, in vivo inhibition of vascularization in the Matrigel assay, and down-regulation of the expression of the proangiogenic basic fibroblast growth factor in A549 tumor cells associated with inhibition of the pathway involving Akt. In conclusion, the available results support the possibility that the antiangiogenic properties of ST1481 contribute to its antitumor potential and that this effect might be enhanced by the continuous low-dose treatment.
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PMID:Antiangiogenic effects of the novel camptothecin ST1481 (gimatecan) in human tumor xenografts. 1457 87

Tumor production of granulocyte-macrophage colony-stimulating factor (GM-CSF) results in the mobilization of CD34(+) progenitor cells into the peripheral blood and tumor tissue. Using the Lewis lung carcinoma (LLC) model, in vitro studies showed that LLC cells could chemoattract CD34(+) cells predominantly through tumor production of VEGF. Addition of LLC-conditioned medium to CD34(+) cells that were cultured under conditions that support myeloid lineage cells skewed the differentiation of these precursor cells toward endothelial cells expressing CD31 and CD144. This differentiation of CD34(+) cells toward endothelial cells was attributed predominantly to angiopoietin-1 in the tumor-conditioned medium. The CD34(+) cells expressed the angiopoietin receptor Tie-2 and their differentiation into endothelial cells was blocked with neutralizing angiopoietin-1 antibodies. In vivo studies showed that infusion of lacZ(+) CD34(+) cells from the bone marrow of transgenic mice into wild-type mice bearing LLC tumors resulted in the accumulation of lacZ(+) cells within the tumor mass, particularly at the tumor's periphery. That these infused CD34(+) progenitor cells could develop into endothelial cells of the tumor vasculature was supported by their acquisition of the endothelial cell markers CD31 or CD144 within the tumor tissue. These studies demonstrate the capacity of tumor to attract CD34(+) cells to the tumor site and to direct the differentiation of these CD34(+) cells into endothelial cells that can become a component of the tumor vasculature.
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PMID:Tumor skewing of CD34+ progenitor cell differentiation into endothelial cells. 1499 72


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