Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The suppression and eradication of primary tumors and distant metastases is a major goal of alternative treatment strategies for cancer, such as inhibition of angiogenesis and targeted immunotherapy. We report here a synergy between two novel monotherapies directed against vascular and tumor compartments, respectively, a tumor vasculature-specific antiangiogenic integrin alphav antagonist and tumor-specific antibody-interleukin 2 (IL-2) fusion proteins. Simultaneous and sequential combination of these monotherapies effectively eradicated spontaneous liver metastases in a poorly immunogenic syngeneic model of neuroblastoma. This was in contrast to controls subjected to monotherapies with either an antiangiogenic integrin alphav antagonist or antibody-IL-2 fusion proteins, which were only partially effective at the dose levels applied. Furthermore, simultaneous treatments with the integrin alphav antagonist and tumor-specific antibody-IL-2 fusion proteins induced dramatic primary tumor regressions in three syngeneic murine tumor models, i.e., melanoma, colon carcinoma, and neuroblastoma. However, each agent used as monotherapy induced only a delay in tumor growth. A mechanism for this synergism was suggested because the antitumor response was accompanied by a simultaneous 50% reduction in tumor vessel density and a 5-fold increase in inflammatory cells in the tumor microenvironment. Subsequently, tumor necrosis was demonstrated only in animals receiving the combination therapy, but not when each agent was applied as monotherapy. The results suggest that these synergistic treatment modalities may provide a novel and effective tool for future therapies of metastatic cancer.
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PMID:Synergy between an antiangiogenic integrin alphav antagonist and an antibody-cytokine fusion protein eradicates spontaneous tumor metastases. 999 69

The antiangiogenic activity and antitumor efficacy of a newly developed matrix metalloproteinase (MMP) inhibitor were examined. N-biphenyl sulfonyl-phenylalanine hydroxiamic acid (BPHA) potently inhibits MMP-2, -9, and -14, but not MMP-1, -3, or -7. In contrast, (-)BPHA, an enantiomer of BPHA, was inactive against all MMPs tested. Daily oral administration of 200 mg/kg BPHA, but not (-)BPHA in mice resulted in potent inhibition of tumor-induced angiogenesis, primary tumor growth, and liver metastasis. The growth inhibition activity of BPHA was 48% and 45% in a B16-BL6 melanoma and F2 hemangio-endothelioma model, respectively. BPHA also showed 42% inhibition of the liver metastasis of C-1H human colon carcinoma cells. These results indicate that selective MMP inhibition is correlated with antiangiogenic and antitumor efficacy and that the selective MMP inhibitor BPHA has therapeutic potential.
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PMID:Correlation of antiangiogenic and antitumor efficacy of N-biphenyl sulfonyl-phenylalanine hydroxiamic acid (BPHA), an orally-active, selective matrix metalloproteinase inhibitor. 1009 53

Several lines of evidence indicate that sialosyl Le(a), tumor-associated carbohydrate antigen present on human colon carcinoma cells, is involved in formation of metastases. To study the role of this carbohydrate structure in development of metastases, we have used the clone of human colon carcinoma CX-1 cells transfected with antisense expression vector containing fragment of cDNA for alpha1,3/4-fucosyltransferase (FT III), which is involved in synthesis of sialosyl Le(a) tetrasaccharide. It has been reported previously that, in contrast to the parental cells, the antisense-transfected CX-1.1AS5 cells do not express sialosyl Le(a) and do not adhere to E-selectin-expressing CHO cells. In the present work we have studied the formation of liver metastases by CX-1.1AS5 cells after their orthotopic or intrasplenic implantation into athymic nu/nu mice. After orthotopic implantation of sialosyl Le(a)-negative colon carcinoma CX-1.1AS5 cells, the number of mice with liver metastases was markedly lower (21% of mice) in comparison with their number after implantation of the parental CX-1.1 cells (86% of mice). However, no differences in ability to form colonies in liver were observed between parental CX-1.1 cells and antisense-transfected CX-1.1AS5 cells after intrasplenic inoculation. The liver metastases were formed in 89% and 84% of mice, respectively. Our data support the thesis on the importance of sialosyl Le(a) antigen expression in the development of liver metastases by colon cancer cells, and indicate the role of transplantation route and primary tumor localization in formation of metastases.
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PMID:Metastatic potential of human CX-1 colon adenocarcinoma cells is dependent on the expression of sialosyl Le(a) antigen. 1021 80

AdmATF is a recombinant adenovirus encoding a secreted version of the amino-terminal fragment (ATF) of murine urokinase (uPA). This defective adenovirus was used in three murine models to assess the antitumoral effects associated with local or systemic delivery of ATF, a broad cell invasion inhibitor that antagonizes uPA binding to its cell surface receptor (uPAR). A single intratumoral injection of AdmATF into pre-established MDA-MB-231 human breast xenografts grown in athymic mice, or into pre-established C57/BL6 syngeneic Lewis lung carcinoma resulted in a specific arrest of tumor growth. Neovascularization within and at the vicinity of the injection site was also suppressed, suggesting that AdmATF inhibited primary tumor growth by targeting angiogenesis. AdmATF also interfered with tumor cell establishment at distant sites: (1) lung dissemination of Lewis lung carcinoma cells was significantly reduced following intratumoral injection at the primary site; and (2) systemic administration of AdmATF inhibited subsequent liver metastasis in a LS174T human colon carcinoma xenograft model. These data outline the potential of using a recombinant adenovirus directing the secretion of an antagonist of cell-associated uPA for cancer gene therapy.
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PMID:Adenovirus-mediated delivery of a uPA/uPAR antagonist suppresses angiogenesis-dependent tumor growth and dissemination in mice. 1032 34

IL-12 is an immuno-regulatory cytokine that has been shown to generate a potent NK and Th1 response in a variety of laboratory models. However, the detailed immune development in the hepatic tumor model by IL-12-mediated gene therapy has not been clarified. In our previous study, intra-tumoral transfer of Adv.mIL-12 (5 x 10(8) pfu) to the MCA26 colon carcinoma liver tumor induced an effective anti-tumor response, extending the median survival time from 29 to over 54 days, while 25% of the animals became tumor-free after a single treatment. In this work, we show that NK cells are responsible for the early, and both NK and T cells for the long-term, Adv.mIL-12-induced immune response. Immunohistopathological analysis of the tumor and in vitro cytotoxicity study of the mononuclear cells of the liver show that NK cells are the first to infiltrate and mediate tumor cell killing, as early as 48 hr after Adv.mIL-12 treatment. In vivo and in vitro depletion of these cells completely abolishes this early anti-tumor response. This activity can be observed in both populations of conventional NK and NKT cells in vitro and in athymic nude mice in vivo. However, the early NK response alone is not sufficient. In vivo T-cell depletion in both the primary tumor treatment and the long-term survival rechallenge study reveals that T cells in addition to NK cells are required in the development of the long-term survival and immunity attributed to Adv.mIL-12 gene therapy in this orthotopic tumor model of colon carcinoma.
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PMID:Role of NK and T cells in IL-12-induced anti-tumor response against hepatic colon carcinoma. 1032 38

We describe a rare case of metastatic intra-suprasellar adenocarcinoma from colonic cancer mimicking a meningioma of the "diaphragma sellae". Autopsy studies indicate breast and lung carcinoma to be the most frequent primary tumor metastasizing this site, particularly in patients with systemic spread. While diabetes insipidus is reported to be one of the commonest symptoms in these cases, the only clinical manifestation of the tumor in our patient was a bitemporal hemianopia, while the primary tumor remained asymptomatic. In the available literature are reported only two pituitary metastasis from operated colon carcinoma. In both cases the diagnosis of the colon cancer preceded the pituitary operation. The clinico-pathological and neuroradiological aspects of this unusual lesion are analyzed in the light of the relevant literature on the topic focusing on recent MRI acquisitions.
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PMID:Diaphragma sellae metastasis from colon carcinoma mimicking a meningioma. A case report. 1044 59

Clinically evident metastases of carcinomas to the thyroid gland are rare, particularly from a colorectal primary tumor. We present a case of colonic adenocarcinoma metastatic to the thyroid gland with histopathologic and immunohistochemical findings. A 68-year-old woman with a history of Dukes' stage B colon carcinoma presented a mass in the thyroid gland. The tumor was confirmed to be metastatic adenocarcinoma from the colon. The immunohistochemical findings demonstrated positive staining for cytokeratin 20, low-molecular-weight cytokeratin, villin and carcinoembryonic antigen, but stains were negative for cytokeratin 7 and thyroglobulin.
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PMID:Colonic adenocarcinoma metastatic to the thyroid gland: a case report with immunohistochemical investigation. 1048 29

In metastasis research it would be useful to determine the number of blood borne tumor cells which are released from a primary tumor into the blood circulation. One way to quantify the number of released tumor cells could be to take blood from a vessel which is located close to a primary tumor and is draining the tumor. The number and viability of tumor cells released into the blood stream at any given time could be measured in cancer patients, especially those known to bear a primary, hematogenous metastasizing tumor. Plating efficiency is a precise method for the quantitative determination of the number of colony-forming cells in an adherent cell population. We performed initial in vitro experiments using plating efficiency to count adherent tumor cells within whole human blood. Exploiting the difference in adherence properties of colon carcinoma cells and blood cells in standard cell culture medium, these initial investigations show that it is possible to determine the plating efficiency of colon carcinoma cells within fresh whole human blood.
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PMID:Simple quantitative method for determining the amount of blood-borne tumor cells: initial in vitro results. 1074 79

Patients with metastatic renal and colon carcinoma have a very poor prognosis. In many cases, the tumor recurs after surgical excision and chemotherapy. Therefore, it might be beneficial for cancer patients to induce an immune attack against the tumor by inserting a cytokine gene into the tumor cells. Here, two different techniques for isolation of single tumor cells were compared. An enzymatic solution was superior to an EDTA/DTT isolation solution for establishing tumor primary cultures. In total, 18 primary cell cultures could be established from 68 patients with colon and renal cell carcinoma. Cells were further characterized concerning fibroblast contamination, cell proliferation and HLA-typing. These primary tumor cells might be of value for cytokine gene transfer and in vaccination protocols for cancer patients.
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PMID:Establishment and characterization of colon carcinoma and renal cell carcinoma primary cultures. 1080 22

In colorectal cancer patients, prognosis is not determined by the primary tumor but by the formation of distant metastases. Molecules that have been implicated in the metastatic process are the proto-oncogene product c-Met and CD44 glycoproteins. Recently, we obtained evidence for functional collaboration between these two molecules: CD44 isoforms decorated with heparan sulfate chains (CD44-HS) can bind the c-Met ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF). This interaction strongly promotes signaling through the receptor tyrosine kinase c-Met. In the present study, we explored the expression of CD44-HS, c-Met, and HGF/SF in the normal human colon mucosa, and in colorectal adenomas and carcinomas, as well as their interaction in colorectal cancer cell lines. Compared to the normal colon, CD44v3 isoforms, which contain a site for HS attachment, and c-Met, were both overexpressed on the neoplastic epithelium of colorectal adenomas and on most carcinomas. Likewise, HGF/SF was expressed at increased levels in tumor tissue. On all tested colorectal cancer cell lines CD44v3 and c-Met were co-expressed. As was shown by immunoprecipitation and Western blotting, CD44 on these cells lines was decorated with HS. Interaction with HS moieties on colorectal carcinoma (HT29) cells promoted HGF/SF-induced activation of c-Met and of the Ras-MAP kinase pathway. Interestingly, survival analysis showed that CD44-HS expression predicts unfavorable prognosis in patients with invasive colorectal carcinomas. Taken together, our findings indicate that CD44-HS, c-Met, and HGF/SF are simultaneously overexpressed in colorectal cancer and that HS moieties promote c-Met signaling in colon carcinoma cells. These observations suggest that collaboration between CD44-HS and the c-Met signaling pathway may play an important role in colorectal tumorigenesis.
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PMID:Expression of c-Met and heparan-sulfate proteoglycan forms of CD44 in colorectal cancer. 1107 15


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