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)

Human breast cancer cell lines growing as xenografts in athymic nude mice have been used to examine the effects of dietary fat and fatty acids on tumor progression. The estrogen independent MDA-MB-435 cell line has the advantage that it metastasizes consistently to the lungs and forms quantifiable secondary nodules when injected into the mammary fat pads. With these breast cancer cells, the stimulating effects of polyunsaturated omega-6 fatty acids on both primary tumor growth and metastasis were demonstrated; in contrast, the long-chain omega-3 fatty acids were inhibitory. The model can also be adapted to examine dietary fatty acids, and inhibitors of their metabolism, as experimental adjuvant therapy after surgical excision of the primary tumors. Unfortunately, estrogen dependent human breast cancer cells do not metastasize, or do so rarely, in nude mice; in consequence, it is not possible to use the model to study estrogen-fatty acid interactions on the metastatic process. In addition to metastasis from a primary location, intravenous injection of MDA-MB-435 cells into the nude mouse host, particularly when combined with studies using Matrigel-based in vitro invasion assays, permits further dissection of the steps in the metastatic cascade which are influenced by dietary fatty acids. The results obtained by these several approaches have demonstrated distinct roles for the cyclooxygenase and lipoxygenase-mediated products of omega-6 fatty acid metabolism, and suggest new approaches to experimental breast cancer therapy.
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PMID:Dietary fat and breast cancer metastasis by human tumor xenografts. 947 77

The effects of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine H-7 (a cAMP-dependent protein kinase and protein kinase C inhibitor), n-(2-[methylamino]ethyl)-5-isoquinoline-sulfonamide H-8 (a cAMP- and cGMP-dependent protein kinase inhibitor) and indomethacin (IND, a cyclooxygenase inhibitor) on both the spontaneous metastatic ability of 3LL (Lewis lung carcinoma) tumor cells and anti-tumor host response were studied. The study of tumor progression showed that H-7 and H-8 (2 mg kg(-1) day(-1) , i.p., for 8 days) significantly reduced the mean number of metastases (0.8 +/- 0.2 and 1.0 +/- 0.7, respectively, P < 0.05) with respect to the number of lung metastases (4.2 +/- 2.1) observed in the control group. In turn, the highest tumor-specific cytotoxicity response (50% increase vs. non-treated target cells) was observed when both animal and tumor cells were treated with H-8. This suggests that the protein kinase inhibitors could inhibit tumor progression toward lung metastases formation by blocking the immunosuppressor mechanism triggered by agents that increase intracellular cAMP.
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PMID:Effect of the protein kinase inhibitors, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine H-7 and N-(2-[methylamino]ethyl)-5-isoquinoline-sulfonamide H-8 on Lewis lung carcinoma tumor progression. 972 36

A series of 1-imidazolyl(alkyl)-substituted quinoline, isoquinoline, naphthalene, benzo[b]furan, and benzo[b]thiophene derivatives was synthesized as dual inhibitors of thromboxane A(2) synthase (P450 TxA(2)) and aromatase (P450 arom). Dual inhibition of these enzymes could be a novel strategy for the treatment of mammary tumors and the prophylaxis of metastases. The most potent dual inhibitors, 5-(2-imidazol-1-ylethyl)-7,8-dihydroquinoline (31) (P450 TxA(2): IC(50) = 0.29 microM; P450 arom: IC(50) = 0.50 microM) and its 5, 6-saturated analogue 30 (P450 TxA(2): IC(50) = 0.68 microM; P450 arom: IC(50) = 0.38 microM), showed a stronger inhibition of both target enzymes than the reference compounds (dazoxiben: IC(50) = 1.1 microM; aminoglutethimide: IC(50) = 18.5 microM). For the determination of the in vivo activity, the influence of selected compounds on serum TxB(2) concentration was examined in rats. Compound 30 (8.5 mg/kg body weight) led to a reduction of the TxB(2) serum level of 78%, 71%, and 51% after 3, 5, and 8 h, respectively (dazoxiben: 60%, 34%, and 36%). Selectivity was studied toward some enzymes of the steroidogenic and eicosanoid pathways. P450 17 was inhibited by selected compounds only at high concentrations. Compound 30 inhibited P450 scc by 13% (25 microM). Compound 31 did not affect cyclooxygenase and lipoxygenase.
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PMID:1-imidazolyl(alkyl)-substituted di- and tetrahydroquinolines and analogues: syntheses and evaluation of dual inhibitors of thromboxane A(2) synthase and aromatase. 1079

Previous retrospective studies suggest that the phase of the menstrual cycle at surgery (proliferative versus secretory) for breast cancer may significantly affect patient survival. Fluctuations during the menstrual cycle of the expression of genes involved in metastases in breast cancer tissue have also been reported. We hypothesized that the menstrual phase may also affect similar changes in gene expression of other cancers. We focused our attention on cancer of the uterine cervix because the hysterectomy specimen obtained at original surgery for the cancer can be used retrospectively to determine cycle phase. We analyzed tumor specimens from 36 premenopausal cervical cancer patients who had undergone hysterectomy as their primary treatment. We used reverse transcription-PCR to quantify gene expression during the different phases of the menstrual cycle as determined from the endometrial specimen. We explored a panel of genes that may affect metastatic propensity, namely, metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-2 (TIMP-2), cyclooxygenase 1 and 2 (COX-1 and COX-2), and vascular endothelial growth factor (VEGF). A significantly higher level of TIMP-2 and COX-2 gene expression (P = 0.007 and 0.030, respectively) was detected during the proliferative phase compared to the secretory phase of the cycle. The expression of the other genes was not significantly affected by the stage of the menstrual cycle. The finding that TIMP-2 and COX-2 expression in cervical cancer may be affected by the stage of the menstrual cycle supports the hypothesis that ovarian hormones may affect the expression of genes involved in metastasis. These findings need to be replicated, and their implications for tumor angiogenesis, invasion, and metastatic propensity need to be explored both in human studies and in experimental models.
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PMID:Expression of metastases-associated genes in cervical cancers resected in the proliferative and secretory phases of the menstrual cycle. 1115 16

Non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to reduce the risk and mortality of colorectal cancer (CRC). Although the exact mechanisms remain unclear, the inhibition of cyclooxygenase (COX) by NSAIDs appears to abort, if not prevent, CRC carcinogenesis or metastatic tumor progression. The aim of our study was to investigate the association between COX-2 expression and CRC tumor cell invasiveness. The differences in immunoblot-detectable COX-2 protein contents in primary CRCs, metastatic hepatic lesions and corresponding normal mucosa from the same individual were evaluated in 17 patients. Three different colon cancer cell lines, SW620, Lovo, HT-29 and a metastatic variant of HT-29, HT-29/Inv3, were employed to evaluate COX-2 expression and prostaglandin E(2) (PGE2) production in relation to their invasive abilities in vitro. The effects of a COX-2-selective inhibitor, etodolac, on cell proliferation and invasive activity were also determined. The results showed that 15 of 17 (88%) metastatic CRC cells from the liver and 14 of 17 (82%) primary CRC tissue exhibited much higher levels of COX-2 than corresponding adjacent normal mucosa from the same patient. Among those patients with relatively high COX-2 expression in the primary tumors, almost all exhibited even higher levels of COX-2 in their hepatic metastases. Among the 4 colon cancer cell lines, HT-29/Inv3 manifested the highest COX-2 expression, PGE2 production and in vitro invasive activity. The selective COX-2 inhibitor, etodolac, could especially exert cytotoxicity and markedly suppress the invasive property and PGE(2) production, although not the COX-2 protein level, in HT-29/Inv3 cells. Our results imply that COX-2 expression may be associated with the invasive and metastatic properties of CRC tumor cells.
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PMID:Tumor invasiveness and liver metastasis of colon cancer cells correlated with cyclooxygenase-2 (COX-2) expression and inhibited by a COX-2-selective inhibitor, etodolac. 1127 97

Aspirin (acetylsalicylic acid) is a widely used anti-inflammatory drug. Recently, aspirin was shown to reduce the risk of development of cancer and mortality from it. Tumor metastasis is the most important cause of cancer death. The aim of the present study was to investigate if aspirin affects the invasion of cancer cells. Matrix metalloproteinases (MMPs) and cell adhesion molecules play important roles in the modulation of tumor invasion. Gelatin-based zymography assay showed that aspirin inhibited MMP-2 activity of SK-Hep-1 cancer cells. Matrigel-based chemoinvasion assay showed that aspirin inhibited in vitro invasion of SK-Hep-1 cancer cells. Aspirin treatment also increased the production of the cell adhesion molecule, E-cadherin, in Hep G2 cancer cells. Aspirin is a cyclooxygenase (COX) inhibitor. Treatment of cells with another COX inhibitor, sulindac, also inhibited MMP-2 activity and increased E-cadherin production of cells. These results indicate that aspirin can modulate both MMP-2 and E-cadherin production and therein may possess antimetastatic effect.
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PMID:Aspirin inhibits matrix metalloproteinase-2 activity, increases E-cadherin production, and inhibits in vitro invasion of tumor cells. 1140 13

The present study evaluated the significance of nitric oxide synthase (NOS), cyclooxygenase (COX) expression and p53 status in 55 patients with gastric adenocarcinoma and relationship of these molecular markers to tumor characteristics and metastatic potential. Immunohistochemical technique was used to identify the cellular location and distribution of the enzymes in the specific cells of gastric tumors. In gastric cancer tissue, the expression of inducible enzymes, iNOS and COX-2, increased significantly with increasing tumor stage (P=0.015, P=0.001, respectively), size (P=0.025, P=0.001, respectively) and the presence of metastases (P=0.002, P=0.015, respectively). The expression of constitutive enzymes, ecNOS and COX-1, followed the opposite pattern. COX-1 was significantly reduced in advanced gastric tumors (P=0.007) and tumors larger than 5 cm (P=0.007). Reduced expression of ecNOS was also observed in advanced gastric tumors; however, this did not reach statistical significance. 53% of gastric tumors showed accumulation of p53. This was significantly higher in advanced tumors (P=0.004), larger than 5 cm (P=0.015) with metastases (P<0.001). Gastric tumors positive for accumulation of p53 had significantly stronger expression of iNOS (P=0.018) and COX-2 (P=0.01) enzymes than tumors negative for this nucleophosphoprotein. We conclude, that tumor-associated nitric oxide production, as well as COX-2 overexpression, may promote gastric cancer progression by providing a selective growth advantage to tumor cells with non-functioning p53.
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PMID:Expression of nitric oxide synthase, cyclooxygenase, and p53 in different stages of human gastric cancer. 1156 94

Docetaxel, a semisynthetic taxane, improves the survival of stage IIIB and IV non-small cell lung cancer patients. However, the 5-year survival remains poor, and few patients experience a complete remission. In this report, we evaluated the effects of exisulind, a novel proapoptotic agent that is a sulfone metabolite of sulindac, in combination with docetaxel on the growth of the human non-small cell lung cancer cell line A549 in vitro and in vivo. Exisulind is a novel sulindac metabolite in that it does not inhibit cyclooxygenase enzymes and has been shown to induce apoptosis in a variety of human cancers by inhibiting cyclic GMP-dependent phosphodiesterase. Exisulind alone increased the fraction of cells in the G(1) phase of the cell cycle from 46% to 65%, whereas it decreased the fraction of cells in the S phase from 38% to 14%. Docetaxel increased the fraction of cells in the S phase from 17% to 19%, and 10 nM docetaxel increased the G2-M phase by 23%. Docetaxel alone induced apoptosis from 11% to 64% at 12-24 h after incubation. The combination of exisulind with concentrations of docetaxel (in concentrations that alone did not alter cell cycle distribution) reduced the G(1) accumulation induced by exisulind, increased the fraction of cells in G(2)-M (9-17%), and increased apoptosis (5-62%). The IC(50) for in vitro growth inhibition by exisulind alone was approximately 200 microM and 2.5 nM for docetaxel. The in vitro combination of exisulind and docetaxel produced an additive to synergistic growth inhibition. In athymic nude rats with A549 orthotopic lung cancers, both exisulind and docetaxel alone moderately prolonged survival, inhibited tumor growth and metastases, and increased apoptosis compared with control animals treated with a carrier. However, the combination of exisulind with docetaxel significantly prolonged survival (P = < 0.0004), inhibited tumor growth and metastases (P = < 0.0001), and increased apoptosis (P = < 0.001) when compared with control animals. These results provide rationale for conducting clinical trials using the combination of exisulind and docetaxel in patients with advanced lung cancer.
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PMID:Exisulind in combination with docetaxel inhibits growth and metastasis of human lung cancer and prolongs survival in athymic nude rats with orthotopic lung tumors. 1189 25

Lung cancer is a major public health problem and the leading cause of cancer-related death worldwide. Its survival rates have changed little over the past 20 years. The best clinical benefit (ie, survival rates) with combination cytotoxic therapies in non-small-cell lung cancer (NSCLC) may have been reached. The need for improved survival rates in NSCLC has driven the development of novel, rationally designed, targeted therapies. Inhibitors of angiogenesis have been developed and are increasingly studied. Potential targets for therapy include inhibitors of vascular endothelial growth factor receptor, endogenous angiogenesis inhibitors, and cyclooxygenase inhibitors. Combining targeted molecules with traditional cytotoxic therapies usually results in lower required chemotherapy doses and fewer, less severe side effects. A number of ongoing randomized studies are underway to evaluate this idea. It is anticipated that these new targeted therapies will play an important role, along with cytotoxic and radiation therapies, in the management of metastatic disease.
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PMID:Angiogenesis inhibitors in lung cancer. 1204 42

Adenocarcinoma of the mammary gland is the leading type of cancer in women. Among these breast cancers those that are estrogen-responsive respond well to existing therapeutic regimens while estrogen non-responsive cancers metastasize widely, demonstrate a high relapse rate, and respond poorly to therapy. Over-expression of the arachidonic acid-metabolizing enzymes cyclooxygenase-2 and lypoxygenases is frequently observed in breast cancer, particularly the non-estrogen-responsive type, suggesting a role of the arachidonic acid (AA) cascade in the growth regulation of these malignancies. Adenocarcinomas of the lungs, pancreas and colon also frequently over-express AA-metabolizing enzymes, and recent evidence suggests that the growth-regulating AA-cascade in these malignancies is under beta-adrenergic control. Our current experiments have therefore tested the hypothesis that in analogy to these findings adenocarcinomas of the breast are also regulated by beta-adrenergic receptors via stimulation of the AA-cascade. Analysis of DNA synthesis by [3H]-thymidine incorporation assays in three estrogen-responsive and three estrogen non-responsive cell lines derived from human breast cancers demonstrated a significant reduction in DNA synthesis by beta-blockers and inhibitors of cyclooxygenase or lipoxygenases in all cell lines. Analysis of AA-release in one of the most responsive cell lines demonstrated a time-dependent increase in AA-release in response to the beta-adrenergic agonist isoproterenol. Analysis by RT-PCR revealed expression of beta2-adrenergic receptors in all cell lines whereas beta1-adrenergic receptors were not found in two of the estrogen non-responsive cell lines. Our data suggest that a significant subset of human breast cancers is under control of beta-adrenergic receptors via stimulation of the AA-cascade. These findings open up novel avenues for the prevention and clinical management of breast cancer, particularly the non-estrogen-responsive types. Moreover, our findings suggest that cardiovascular disease and adenocarcinomas in a variety of organ systems, including the breast may share common risk factors and benefit from similar preventive and treatment strategies.
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PMID:Beta-adrenergic and arachidonic acid-mediated growth regulation of human breast cancer cell lines. 1206 62


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