Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have reported that particle-mediated interleukin 12 (IL-12) gene transfer into the skin overlying the local tumor inhibits systemic metastases. To further characterize this effect, we compared the antitumor and antimetastatic effects of IL-12 cDNA delivered at the local tumor site versus at a site distant from the primary tumor, in a spontaneous metastasis model of LLC-F5 tumor. Local IL-12 gene delivery into the skin overlying the intradermal tumor (local IL-12 treatment) on days 7, 9, and 11 after tumor implantation resulted in the most suppression of the growth of the primary LLC-F5 tumor, whereas IL-12 gene transfer into the skin distant from the tumor (distant IL-12 treatment) was less effective. In contrast, both local IL-12 and distant IL-12 treatment, followed by tumor excision, inhibited lung metastases to a similar extent, resulting in significantly extended survival of test mice. The results of in vivo studies using depleting anti-asialo GM1 antibody and anti-CD4/anti-CD8 monoclonal antibodies, or neutralizing anti-interferon gamma (IFN-gamma) monoclonal antibody demonstrated that natural killer (NK) cells, CD8(+) T cells, and IFN-gamma contributed to the antimetastatic effects in both treatment groups. Furthermore, the levels of mRNA expression of vascular endothelial growth factor and matrix methalloproteinase 9 at the tumor microenvironment were suppressed after both local and distant IL-12 treatment. These results suggest that the current particle-mediated IL-12 gene delivery in the spontaneous LLC-F5 metastasis model can confer antimetastatic activities, irrespective of the gene transfection site, via a combination of several mechanisms involving CD8(+) T cells, NK cells, IFN-gamma, and antiangiogenesis.
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PMID:Interleukin 12 gene transfer into skin distant from the tumor site elicits antimetastatic effects equivalent to local gene transfer. 1117 52

Of the numerous growth factors and cytokines that have been shown to have angiogenic effects, vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), appears to be a key factor in pathological situations which involve neovascularization as well as enhanced vascular permeability. Our aim was to design a low molecular weight synthetic molecule that potently and selectively blocks the VEGF/VEGF receptor system after oral administration, suitable for the chronic therapy of VEGF-dependent pathological neovascularization. PTK787/ZK 222584 is a potent inhibitor of VEGF receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, like the PDGFR-beta tyrosine kinase, c-Kit and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families such as EGFR, FGFR-1, c-Met and Tie-2 or intracellular kinases like c-Src, c-Abl, PKC-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of KDR, and endothelial cell proliferation, migration and survival in the nanomolar range in cell based assays. In concentrations up to 1 microM, PTK787/ZK 222584 does not have any cytotoxic or anti-proliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF- and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once daily oral dosing (25-100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown subcutaneously in nude mice, as well as a murine renal carcinoma and its metastases in syngeneic, orthotopic models. Histological examination of tumors reveals inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 also significantly inhibits ascites formation induced by a human ovarian carcinoma grown in the peritoneum of nude mice as well as pleural effusion induced by a human lung adenocarcinoma in nude mice. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent, or impair hematopoetic recovery following concomitant cytotoxic anti-cancer agent challenge. These studies indicate that compounds that inhibit the effects of VEGF, such as PTK787/ZK 222584, have the potential to provide a novel, effective and well-tolerated therapy for the treatment of solid tumors. These agents may also provide a new therapeutic approach for the treatment of other diseases where angiogenesis plays an important role.
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PMID:Inhibition of vascular endothelial growth factor (VEGF) as a novel approach for cancer therapy. 1118 30

Angiogenesis has been acknowledged as an important requirement for growth and metastasis of tumors. Complete or partial suppression of vascular growth by a number of different strategies has been consistently associated with suppression of tumor expansion and even reduction of tumor burden. Consequently, identification of the molecular pathways of the angiogenic response has been a major focus of interest in academia and industry. The development of tumor-specific anti-angiogenic therapy was also catalyzed by the finding that inhibitors of angiogenesis appeared immune to the development of drug resistance by the tumor cells, a major restrain in current chemotherapy. Although the full identification of players and their cross-talk is still at its infancy, it appears that partial blockade of one of the steps in the angiogenesis cascade, is sufficient to affect capillary morphogenesis. Thus, suppression of specific integrin pathways or vascular endothelial growth factor signaling have been shown effective in the suppression of tumor-mediated angiogenesis and have led to subsequent initiation of clinical trials. In addition to the generation of antibodies or chemical mimetics to interfere with particular steps during vascular organization, several endogenous (or physiological) molecules have also been identified. The list of endogenous modulators of angiogenesis is growing and can offer additional and important tool for the generation of therapies to restrain tumor vascularization. This review will focus one group of such molecules which include the thrombospondins and metallospondins, two families of proteins linked by the presence of a conserved anti-angiogenic functional domain.
Cancer Metastasis Rev 2000
PMID:Endogenous regulators of angiogenesis--emphasis on proteins with thrombospondin--type I motifs. 1119 Oct 55

In brain, breast, and other common human tumors there is a correlation between expression of the transcriptional activator hypoxia-inducible factor 1 (HIF-1) and tumor grade and vascularization. HIF-1 stimulates angiogenesis by activating transcription of the gene encoding vascular endothelial growth factor (VEGF). HIF-1 is a heterodimer consisting of a constitutively-expressed HIF-1beta subunit and an O2- and growth factor-regulated HIF-1alpha subunit. Recent studies have demonstrated that HIF-1alpha expression is increased in tumor relative to normal tissue by two mechanisms. First, decreased intratumoral O2 concentrations provide a physiological stimulus. Second, genetic alterations that activate oncogene products or inactivate tumor suppressor gene products increase HIF- 1alpha expression and/or HIF-1 transcriptional activity independent of the O2 concentration. Taken together, these recent data suggest that increased HIF-1 activity provides a molecular basis for VEGF-induced angiogenesis and other adaptations of cancer cells to hypoxia that are critical for establishment of a primary tumor and its progression to the lethal phenotype.
Cancer Metastasis Rev 2000
PMID:HIF-1: using two hands to flip the angiogenic switch. 1119 Oct 64

We postulate that oncogenes and tumor suppressor genes may influence tumor angiogenesis not only directly (e.g. by upregulating vascular endothelial growth factor) but also through their impact on expression (and/or function) of tissue factor and other elements of the hemostatic system.
Cancer Metastasis Rev 2000
PMID:Impact of oncogenes and tumor suppressor genes on deregulation of hemostasis and angiogenesis in cancer. 1119 Oct 70

Angiogenesis is essential to prostate cancer progression. The first study of antiangiogenic therapy in patients with locally advanced prostate cancer at The University of Texas M. D. Anderson Cancer Center showed that preoperative treatment with a fumagillin analog was safe. Microvascular density correlated with Gleason score, but marked intertumoral and intratumoral changes were observed. Clinical experience with thalidomide (Thalomid), which inhibits angiogenesis induced by both vascular endothelial growth factor and basic fibroblast growth factor, has included observation of "clinical improvement" in patients with androgen-independent prostate cancer and anecdotal responses in patients with metastatic disease refractory to chemotherapy. In an effort to assess the in vivo effect of thalidomide in prostate carcinoma, we have initiated a study of neoadjuvant thalidomide treatment in patients with locally advanced prostate cancer that is to include serial ultrasonographic and pathologic evaluation, as well as serial collection of serum/urine markers that may prove useful surrogate markers of antiangiogenic activity. We have also initiated a phase I/II trial of thalidomide, paclitaxel (Taxol), and estramustine (Emcyt) in patients with metastatic androgen-independent prostate cancer progressing after up to two courses of chemotherapy.
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PMID:Development of angiogenesis inhibition as therapy for prostate cancer. 1120 69

We have previously shown that tumor necrosis factor-alpha (TNF-alpha), which is an important angiogenesis-related factor, was over-secreted in male BALB/c mice under social isolation stress as compared with the control, and closely associated with a remarkable elevation of tumor invasion and metastasis of colon 26-L5 carcinoma cells. In the present study, we explored the effect of isolation stress on the angiogenesis caused by colon 26-L5 carcinoma cells in vivo and in vitro. Social isolation lead to the enhancement of tumor growth after intrahepatic implantation with a fragment of colon 26-L5 tumor. Angiogenic response (number of vessels oriented towards tumor mass) and tumor growth (size) were significantly increased in the socially isolated mouse relative to that in the group-housed mice. Furthermore, higher protein level of hepatic TNF-alpha was found in the stressed mice than that in the control. Expression of mRNA for vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) were also elevated in the tumor regions and liver tissues of the stressed mice in comparison with that in group-housed mice. On the other hand, hepatic sinusoidal endothelial (HSE) cells treated with TNF-alpha exhibited a marked promotion of the migration, invasion, expression of mRNA for matrix metalloproteinase (MMP)-9, and tube-like formation, but no cytotoxicity against the cells in vitro. The above data suggest that the social isolation stress augmented the tumor-induced angiogenesis probably by up-regulating the angiogenesis-related factors, including TNF-alpha, VEGF and HGF, and consequently mediating the functions of endothelial cells such as migration, invasion, and tube-like formation.
Clin Exp Metastasis 2000
PMID:Social isolation stress augments angiogenesis induced by colon 26-L5 carcinoma cells in mice. 1120 31

Aberrant expression of tyrosine kinases such as c-erbB and EGFR contributes to the progression of head and neck squamous cell carcinomas (HNSCCs). One mechanism may be potentiation of angiogenesis, since upregulation of vascular endothelial growth factor (VEGF) expression by activation of epidermal growth factor receptor (EGFR) and/or c-erbB-2 has been described. Firstly, we demonstrated expression of all 4 members of the VEGF family in a panel of 15 HNSCC cell lines which over-express one or more c-erbB receptors. We then explored the regulatory roles of three major ligands with different selectivity of binding to c-erbB receptors (namely transforming growth factor-alpha (TGF-alpha), betacellulin (BTC) and heregulin-beta1 (HRG-beta1)) on VEGF-A, B, C and D expression in selected HNSCC lines. Using semi-quantitative reverse transcription-PCR, we showed that all three c-erbB ligands up-regulated VEGF-A mRNA (all isoforms) and VEGF-C (BTC max at 1-10 nM; TGF-alpha and HRG-beta1 max at 10-100 nM) but had no effect on VEGF-B. Interestingly, all ligands simultaneously down-regulated the expression of VEGF-D mRNA. A monoclonal antibody (mAb) which blocks EGFR ligand binding (ICR62) down-regulated the basal levels of VEGF-A (all isoforms) and VEGF-C, had no detectable effects on VEGF-B and increased VEGF-D. ICR62 also reversed the effects of all three erbB ligands (TGF-alpha, BTC and HRG-beta1) on VEGF-A, VEGF-C and VEGF-D expression. An anti-c-erbB-2 mAb (ICR12) showed similar effects on basal or ligand-modulated expression of VEGF in these cell lines, although to a lesser extent. Our results reveal that the four VEGF genes are regulated by c-erbB signaling pathways in a strikingly different manner, suggesting that they serve distinct, although perhaps complimentary (VEGF-A and VEGF-C) or antagonistic (VEGF-D) functions. The EGFR and c-erbB-2 signaling pathway(s) plays a role in VEGF regulation in HNSCC, although EGFR would appear to be dominant in this cell type.
Clin Exp Metastasis 2000
PMID:Vascular endothelial growth factor family members are differentially regulated by c-erbB signaling in head and neck squamous carcinoma cells. 1123 91

Redundant mechanisms mediate colon cancer angiogenesis. Targeting multiple angiogenic factors simultaneously may improve survival of mice with colon cancer metastases. BALB/c mice underwent splenic injection with CT-26 colon cancer cells to generate liver metastases and received administration of either vehicle alone or a tyrosine kinase inhibitor for vascular endothelial growth factor, basic fibroblast growth factor, and platelet-derived growth factor receptors (SU6668). Mice were sacrificed when they became moribund as determined by a blinded observer. In a parallel experiment, groups of mice were sacrificed at earlier time points to better define the kinetics of the effect of SU6668 on angiogenic parameters over time. SU6668 increased median survival by 58% (P < 0.001) and led to a progressive increase in tumor cell and endothelial cell apoptosis that increased over time. In addition, pericyte vessel coverage and tumor vascularity were significantly decreased in mice treated with SU6668. Based on current knowledge of endothelial cell survival, these data suggest that SU6668 may prevent tumor endothelial cell survival directly (vascular endothelial growth factor) and indirectly (pericyte coverage) by affecting endothelial cell survival mechanisms.
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PMID:Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms. 1124 52

We quantitatively evaluated dendritic cell (DC) infiltration in primary colorectal cancers from 44 patients and metastatic colorectal tumors from 13 patients using immunohistochemistry for the DC marker CD83, HLA-DR, and the DC activation molecules CD40 and CD86. Nearly all CD83+ cells were also HLA-DR+, CD40+, and CD86+, indicating that the DCs that infiltrate colon cancer in vivo express the activation and costimulatory molecules associated with a mature DC phenotype. The density of DCs in colorectal cancer primaries was three times lower than that seen in normal colonic mucosa (0.29 versus 0.84 CD83+ cells/ high-power field (hpf), p < 0.001). Dendritic cells were rarely observed in metastatic tumors: DC density in metastases was sixfold lower than in colorectal primary tumors (0.05 versus 0.29 CD83+ cells/hpf, p < 0.001). Because cytokines have been shown, in vitro, to exert potent effects on DCs, we also evaluated the relationship between intratumor DC density and the expression of cytokines by tumor-infiltrating lymphocytes (TILs) and tumor cells. Expression of interleukin-10 and transforming growth factor beta by either TIL or tumor cells was not associated with decreased DC density or decreased expression of CD40 or CD86 on DCs. Tumor expression of vascular endothelial growth factor was associated with a more than twofold increase in DC density (p = 0.01). Patients who had a high proportion of TILs expressing tumor necrosis factor (TNF) had a greater intratumor mature DC density than patients with a low proportion of TNF + TIL (0.54 versus 0.21 CD83+ cells/hpf, p < 0.01).
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PMID:Dendritic cell infiltration in colon cancer. 1126 70


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