Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cancer cells elaborate metalloproteinases which may play a role in invasion and metastasis. The serum level of the M(r) 72,000 type IV collagenase (MMP-2) was measured in 87 lung cancer patients. Stage IV cancer levels were significantly elevated (P less than 0.0001) compared to normal sera. A significant difference (P less than 0.01) was found between enzyme levels in the presence versus the absence of distant metastasis. For 29 patients treated with combination chemotherapy, a positive relationship was noted between response failure and elevated enzyme levels. Serum metalloproteinase levels may provide information relevant to prognosis as well as treatment decisions.
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PMID:Correlation of serum metalloproteinase levels with lung cancer metastasis and response to therapy. 132 94

In this study, we investigated the correlation between the expression of MMP-2 and lymph node metastasis by analyzing 58 cases of primary lung cancer. Furthermore we studied expression of membrane-type MMP (MT-MMP) which was identified as an activator of MMP-2 and its relation to the activation ratio of MMP-2 in tumor tissues. Activated form of MMP-2 was detected specifically in the tumor tissues by zymography, and the activation ratio was significantly higher in 20 cases of the lymph node metastasis positive group than in other 38 cases. Additionally, northern blott analysis showed that MT-MMP was overexpressed in cancer tissues and that the expression of MT-MMP was closely related to the amount of activated form of MMP-2. These results indicated that MMP-2, which is activated by MT-MMP expressed on the surface of tumor cells, play a role in tumor metastasis by degrading surrounding basement membranes.
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PMID:[Expression of membrane-type matrix metalloproteinase (MT-MMP) and activation of MMP-2 in lung cancer]. 763 26

In this study we examined the production of gelatinases A and B (MMP-2 and MMP-9), and their natural inhibitors TIMP-1 and TIMP-2 in cell lines derived from different histologic types of lung cancer. Gelatinolytic activity was measured by zymography and radiolabeled gelatin degradation. Immunocytochemistry and Western blot analysis were performed to corroborate the presence of immunoreactive MMP-2, MMP-9, TIMP-1 and TIMP-2 proteins. The highest gelatinolytic activity was identified in the cell extracts from a small-cell carcinoma cell line. MMP-9 was observed in all samples as a proenzyme, while MMP-2 was present as zymogen in the squamous-cell and in the small-cell carcinomas, and in its active form in one squamous-cell carcinoma cell line. TIMPs were also present in the neoplastic lung cell lines. TIMP-1 was observed in the media of all cells as a 21-kD band, and as TIMP-1 polymers with the exception of the small-cell carcinoma samples. TIMP-2 was found as higher-order molecular immunoreactive complexes that may correspond to proMMP-2/TIMP-2 complexes. These results demonstrate that lung neoplastic cells produce both MMP-2 and MMP-9 and their inhibitors, with the small-cell carcinoma cell extracts showing the highest enzymatic activity. This gelatinolytic activity fits well with the clinical metastatic behavior of this type of lung cancer.
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PMID:72-kD (MMP-2) and 92-kD (MMP-9) type IV collagenase production and activity in different histologic types of lung cancer cells. 957 61

We studied AG3340, a potent metalloproteinase (MMP) inhibitor with pM affinities for inhibiting gelatinases (MMP-2 and -9), MT-MMP-1 (MMP-14), and collagenase-3 (MMP-13) in many tumor models. AG3340 produced dose-dependent pharmacokinetics and was well tolerated after intraperitoneal (i.p.) and oral dosing in mice. Across human tumor models, AG3340 produced profound tumor growth delays when dosing began early or late after tumor implantation, although all established tumor types did not respond to AG3340. A dose-response relationship was explored in three models: COLO-320DM colon, MV522 lung, and MDA-MB-435 breast. Dose-dependent inhibitions of tumor growth (over 12.5-200 mg/kg given twice daily, b.i.d.) were observed in the colon and lung models; and in a third (breast), maximal inhibitions were produced by the lowest dose of AG3340 (50 mg/kg, b.i.d.) that was tested. In another model, AG3340 (100 mg/kg, once daily, i.p.) markedly inhibited U87 glioma growth and increased animal survival. AG3340 also inhibited tumor growth and increased the survival of nude mice bearing androgen-independent PC-3 prostatic tumors. In a sixth model, KKLS gastric, AG3340 did not inhibit tumor growth but potentiated the efficacy of Taxol. Importantly, AG3340 markedly decreased tumor angiogenesis (as assessed by CD-31 staining) and cell proliferation (as assessed by bromodeoxyuridine incorporation), and increased tumor necrosis and apoptosis (as assessed by hematoxylin and eosin and TUNEL staining). These effects were model dependent, but angiogenesis was commonly inhibited. AG3340 had a superior therapeutic index to the cytotoxic agents, carboplatin and Taxol, in the MV522 lung cancer model. In combination, AG3340 enhanced the efficacy of these cytotoxic agents without altering drug tolerance. Additionally, AG3340 decreased the number of murine melanoma (B16-F10) lesions arising in the lung in an intravenous metastasis model when given in combination with carboplatin or Taxol. These studies directly support the use of AG3340 in front-line combination chemotherapy in ongoing clinical trials in patients with advanced malignancies of the lung and prostate.
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PMID:Broad antitumor and antiangiogenic activities of AG3340, a potent and selective MMP inhibitor undergoing advanced oncology clinical trials. 1041 35

Expression of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2 was studied in non-small-cell lung cancer (NSCLC). Activity of MMP-2 and MMP-9 by gelatin zymography and expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 mRNAs were examined in 11 lung cancer cell lines which included six small-cell lung cancer (SCLC) cell lines. Localization of MMP-2, MMP-9, TIMP-1, and TIMP-2 was examined by immunohistochemistry in 43 resected NSCLC (22 adenocarcinomas, 17 squamous cell carcinomas, 4 large cell carcinomas) using specific anti-human monoclonal antibodies. Expression of MMP-2 mRNA was detected in 5 (100%), MMP-9 in 1 (20%), TIMP-1 in 4 (80%), and TIMP-2 in 5 (100%) of 5 NSCLC cell lines examined. MMP-2 gelatinolytic activity also was detected in all five NSCLC cell lines, whereas MMP-9 activity was detected in only one cell line. In 43 patients, MMP-2, MMP-9, TIMP-1, and TIMP-2 immunoreactivity was demonstrated in 19 (44%), 9 (21%), 15 (35%), and 29 (67%) excised tumors, respectively. All stromal fibroblasts in tumor samples stained positive for MMP-2. There was a correlation between TIMP-2 immunoreactivity and disease stage (42% stage I versus 88% stages II, III, and IV) (p = 0.0024). Both cancer cell lines and NSCLC tumor samples frequently expressed MMP-2, MMP-9, TIMP-1, and TIMP-2; MMP-2 in particular was highly expressed in malignant cells and surrounding fibroblasts. These findings suggest that MMP-2 plays a more important role in invasion of NSCLC than MMP-9 and that TIMP-2 may have clinical relevance in NSCLC.
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PMID:Expression of matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases in non-small-cell lung cancer. 1047 26

Because routine histopathological examination of primary non-small cell lung cancer does not predict disease outcome, we correlated disease outcome with the expression level of multiple genes that regulate distinct steps of the metastatic process in 60 formalin-fixed, paraffin-embedded, archival specimens of stage I lung carcinoma from patients undergoing curative surgery at the M. D. Anderson Cancer Center. The expression of E-cadherin (related to cell cohesion), type IV collagenase [matrix metalloproteinase (MMP)-2 and MMP-9, related to invasion], and three angiogenic molecules, basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor, and interleukin 8, were examined by a colorimetric in situ mRNA hybridization technique. The expression levels of the individual genes analyzed by a Cox univariate analysis were not prognostic. In contrast, the ratio between expression of type IV collagenases (mean of the expression of MMP-2 and MMP-9) and E-cadherin, the MMP:E-cadherin ratio (measured at the periphery of each tumor), was significantly higher in patients with recurrent disease than in patients who remained disease free (P = 0.00003). Longer overall survival and reduced disease recurrence rates were significantly associated with a lower MMP:E-cadherin ratio (<2) by a Kaplan-Meier survival analysis (P = 0.0002 and P = 0.0001, respectively). Multiple covariate analyses of overall and disease-free survival also concluded that the MMP:E-cadherin ratio was a significant prognostic factor when corrected for age (P = 0.0001). Determination of this gene expression ratio in individual human lung cancers might therefore be used to direct tailored treatment for individual patients with resectable lung cancer.
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PMID:Differential expression of E-cadherin and type IV collagenase genes predicts outcome in patients with stage I non-small cell lung carcinoma. 1074 98

The immunoreactive protein for the tissue inhibitor of the metalloproteinase (TIMP)-1 and -2 as well as for the matrix metalloproteinase (MMP)-2 and -9 was quantified from the sera/plasma of 90 lung cancer patients and 20 control subjects with enzyme linked immunoassays (ELISA) using specific monoclonal antibodies. Free MMP-2 and that bound to the inhibitor, the MMP-2/TIMP-2 complex were measured separately using different ELISAs. For the detection of MMP-9, TIMP-1 and TIMP-2, the total protein was measured to quantify both free and complex forms. Serum protein levels for TIMP-1, TIMP-2 and the MMP-2/TIMP-2 complex differed significantly in patients with lung cancer when compared to controls. TIMP-1 levels were found to be higher in lung cancer than in controls, whereas TIMP-2 and MMP-2/TIMP-2 complex levels were lower in lung cancer than in the sera of the control subjects. High TIMP-1 (> 300 ng/ml) or MMP-9 (> 30 ng/ml) correlated to poor cumulative survival in lung cancer patients (log rank P < 0.05). High TIMP-1 indicated a poor prognosis, especially in squamous cell cancer and in NSCLC patients with stage III: 66% and 70%, respectively, of the patients with low TIMP-l serum levels survived for more than one year, when only 25% and 20%, respectively, of the patients with high serum levels for TIMP-1 protein survived at that time. 56% of lung cancer patients with a plasma MMP-9 level < 30 ng/ml survived for 12 months when only 31% of the lung cancer patients with high MMP-9 plasma levels survived for more than one year. Also this difference was significant (log rank analysis, P < 0.05). Our results suggest that the factors of the metalloproteinase system might be important in lung cancer progression. TIMP-1 as well as MMP-9 could serve as prognostic markers, and their values could be investigated in the follow-up of lung cancer patients when selecting patients for systemic chemotherapy or other treatment modalities.
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PMID:Serum matrix metalloproteinases -2, -9 and tissue inhibitors of metalloproteinases -1, -2 in lung cancer--TIMP-1 as a prognostic marker. 1081 Apr 41

It has been shown that the type IV collagenase with its two subtypes, 72 kDa/ MMP-2 and 92 kDa/MMP-9, plays an important role in tumor invasion and metastasis formation that occur through a mechanism of proteolytic degradation of collagen IV in the basement membrane. One possible method to specifically inhibit the function of the targeted protein of a cell is to express intracellular antibody combining site that can block the function or prevent the expression of the targeted molecule. Accordingly, intracellular antibodies against type IV collagenase may have a therapeutic use against tumor invasion and metastasis. As described in our previous reports, an anti-type IV collagenase monoclonal antibody (3D6) was obtained using the hybridoma approach, and its functional single-chain Fv fragment (scFv) named M97 was constructed based on recombinant phage display techniques. In this study, the endoplasmic reticulum (ER)-retained scFv antibody fragment was used to inhibit the function of type IV collagenase. For expression in mammalian cells, the assembled scFv M97 gene with ER retention signal encoding 6 additional amino acid (SEKDEL) was reamplified by PCR. The amplified fragments were cloned into the pcDNA3.1 vector containing the CMV early-intermediate promoter/enhancer. The resulting plasmid was sequenced and then introduced by the lipofectamine method into PG cells, a highly metastatic human lung cancer cell line and G418-resistant cells were obtained by G418 selection. After transfection, the M97 mRNA expression was observed and the type IV collagenase expression was downregulated significantly as measured by ELISA. The biological behavior of PG cells, such as the ability of in vitro invasion of colony formation on soft agar through Matrigel, were also inhibited by scFv M97 transfection. The results indicate that intracellular antibody technology represents a novel and efficient way to selectively abrogate the activity of type IV collagenase, at least in vitro. We are presently exploring the efficacy of this approach in a xenograft model of human lung cancer.
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PMID:Antineoplastic effect of intracellular expression of a single-chain antibody directed against type IV collagenase. 1090 9

Inhibition of gelatinolytic activity in implanted tumor tissues by oral administration of N-biphenyl sulfonyl-phenylalanine hydroxamic acid (BPHA), a selective matrix metalloproteinase (MMP) inhibitor, was demonstrated by means of film in situ zymography (FIZ). Active-MMP-2 but not pro-MMP-2 showed gelatinolytic activity in FIZ, whereas both forms of MMP-2 were found to be active in conventional zymography. A mixture of either tissue inhibitors of metalloproteinase-2 or BPHA with active-MMP-2 resulted in inhibition of gelatinolytic activity in FIZ but not in zymography. Thus, FIZ, but not zymography, could detect net MMP activity in tumor tissues. When a specimen from Ma44 human lung cancer xenograft was subjected to FIZ, gelatinolytic activity was markedly detected with precise localization in the tumor tissues. The gelatinolytic activity detected in Ma44 tumor tissues was found to be mainly derived from MMPs because the gelatin-degrading activity was inhibited by pretreatment of the tumor specimen with MMP inhibitors. Oral administration of BPHA but not (-)BPHA, an enantiomer of BPHA lacking MMP inhibitory activity, successfully inhibited the MMP activity localized in Ma44 tumor tissues in both a dose-dependent and time-dependent manner. The data presented in this report showed for the first time that oral administration of synthetic MMP inhibitor could inhibit the net activity of MMP activity in tumor tissues, suggesting the usefulness of the FIZ technique for determining the effective dose of MMP inhibitor in clinical studies.
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PMID:Inhibition of gelatinolytic activity in tumor tissues by synthetic matrix metalloproteinase inhibitor: application of film in situ zymography. 1095 15

We examined the tumorigenic and metastatic potentials of three human non-small cell lung cancer (NSCLC) cell lines, PC-14, A549 or Lu-99 cell lines suspended in Matrigel-containing phosphate-buffered saline were orthotopically implanted into the lungs of nude mice. The formation of a solitary tumor nodule in the lung was observed after the implantation of all cell lines. Intrapulmonary implantation of PC-14 or Lu-99 cells resulted in spontaneous distant metastases. In contrast, A549 cells caused multiple intrapulmonary metastases to the right and left lobes of the lung without producing visible lymphatic metastasis. We also investigated the expression of matrix metalloproteinases (MMPs), urokinase-type plasminogen activator (u-PA), u-PA receptor (u-PAR) and c-MET in these cell lines in vitro and in vivo. Reverse transcription polymerase chain reaction (RT-PCR) analysis showed that the expression of MMP-2 and membrane-type 1 MMP (MT1-MMP) was elevated in PC-14 as compared with the other two cell lines. In contrast, stronger expression of c-MET was observed in A549 than in PC-14 or Lu-99. These results indicate that differential patterns of metastasis of lung cancer might be associated with differential expression of metastasis-associated molecules. Our orthotopic implantation models display clinical features resembling those of NSCLC, and may provide a useful basis for lung cancer research.
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PMID:Solitary lung tumors and their spontaneous metastasis in athymic nude mice orthotopically implanted with human non-small cell lung cancer. 1100 66


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