Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of the extracellular matrix. The MMPs have been implicated in the processes of tumor growth, invasion, and metastasis; are frequently overexpressed in malignant tumors; and have been associated with an aggressive malignant phenotype and adverse prognosis in patients with cancer. A number of MMP inhibitors are being developed for the treatment of cancer. The most extensively studied class of MMP inhibitors includes collagen peptidomimetics and nonpeptidomimetic inhibitors of the MMP active site, tetracycline derivatives, and bisphosphonates. The hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat, which bind covalently to the zinc atom at the MMP-active site, were the first MMP inhibitors to be studied in detail. Marimastat is currently being studied in randomized clinical trials. The nonpeptidic MMP inhibitors were synthesized in an attempt to improve the oral bioavailability and pharmaceutical properties of the peptidic inhibitors. Several members of this class of compounds are undergoing evaluation in phase III clinical trials. The tetracyclines and, particularly, the nonantibiotic chemically modified tetracyclines, interfere with several aspects of MMP expression and activation and inhibit tumor growth and metastases in preclinical models. A representative agent of this class, Col-3, is currently undergoing phase I clinical trials. The development of the MMP inhibitors, like that of other targeted and predominantly antiproliferative compounds, poses a challenge because the paradigms that have governed the design of clinical oncology trials may not be relevant to this new class of agents. The anticipated need for long-term administration of these drugs, together with their cytostatic mechanism of action, will require novel clinical trial design strategies.
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PMID:Development of matrix metalloproteinase inhibitors in cancer therapy. 1115 86

Inhibitors of matrix metalloproteinases (MMPs), enzymes involved in the processes of tumor growth, angiogenesis, invasion and metastasis, represent a promising new potential approach to cancer therapy. Several synthetic inhibitors of MMPs have been developed, many of which are currently in clinical trials. This review will describe some inhibitors of MMPs, presenting results of preclinical studies and, where available, their current clinical status as well. Issues concerning the use of MMP inhibitors, the design of clinical trials and the assessment of clinical response will also be addressed.
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PMID:Preclinical development of metalloproteasis inhibitors in cancer therapy. 1116 19

The tumor microenvironment, or stroma, is known to contribute to tumor progression. Two recent studies have shown that the stromal protein matrix metalloproteinase MMP-9 has a role in the early stages of tumor growth and angiogenesis.
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PMID:Tumor progression: defining the soil round the tumor seed. 1116 92

Tetracyclines (TCs) and their non-antimicrobial analogs (CMTs) have therapeutic potential to inhibit tissue destructive disease processes, such as cancer invasion and metastasis, by inhibiting certain matrix metalloproteinases. Enhanced matrix metalloproteinase-2 (MMP-2; gelatinase A) activity has been correlated to cancer invasiveness, and membrane type MMP (MT1-MMP) expressed by tumor cells is involved in localizing and activating pro-MMP-2, a pathway believed to mediate cancer induced tissue breakdown. CMT-3 (6-demethyl, 6-deoxy, 4-dedimethylamino TC) has been shown to experimentally suppress prostate cancer, colon adenocarcinoma and melanoma invasiveness in cell culture and to inhibit tumor growth and metastasis in vivo and was used in the current in vitro study. Confluent MT1-MMP transfected COS-1 cells were harvested, washed thoroughly, subjected to N(2) cavitation and cell membrane enriched fractions were isolated by sequential centrifugations. This MT1-MMP preparation exhibited (i) pro-MMP-2 activating activity as shown by molecular weight shift of this gelatinase from 72 kDa to 62 kDa using gelatin zymography, and (ii) the ability to degrade both [(3)H-methyl] gelatin and casein at 37 degrees C. Adding CMT-3 at final concentrations of 5--20microM inhibited MT1-MMP gelatinolytic and caseinolytic activity, blocked MT1-MMP activation of pro-MMP-2, and decreased invasiveness (using the Matrigel system) of HT-1080 fibrosarcoma cells. The inhibition of MT1-MMP by CMT-3 may partially explain the inhibition of cancer cell -mediated tissue breakdown and invasiveness by this non-antimicrobial tetracycline analog.
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PMID:CMT-3, a non-antimicrobial tetracycline (TC), inhibits MT1-MMP activity: relevance to cancer. 1117 80

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.
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PMID:Social isolation stress augments angiogenesis induced by colon 26-L5 carcinoma cells in mice. 1120 31

Docetaxel is a chemical compound belonging to the taxoid class of anticancer agents. Batimastat (BB-94) is the first matrix metalloproteinase inhibitor entering clinical trials. To improve the treatment of tumors, we studied the combined effects of docetaxel and batimastat on mouse forestomach carcinoma (MFC), and compared them with doxorubicin. In vitro growth curve analysis, MTT assay, and clonogenic assay were used to determine the cytotoxic effect of docetaxel or/and BB-94 on MFC. They showed that docetaxel, but not BB-94, had a significant cytotoxicity and that the effect of docetaxel was not enhanced by BB-94. In an early stage MFC tumor model, an obvious antitumor effect of docetaxel or doxorubicin given iv at maximum tolerated dose (MTD) was observed. Tumor growth inhibition was greater for docetaxel + BB-94 (96.0%) than for doxorubicin + BB-94 (88.0%), docetaxel (89.0%), doxorubicin (68.0%), and BB-94 (33.0%). Docetaxel showed activity against advanced stage MFC tumor in a dose-dependent manner and was more effective at MTD than doxorubicin, with 4/5 regression, 46.5 days tumor growth delay, and 2.8 log10 tumor-cell kill. Our results suggest that docetaxel is an effective new cytotoxic drug against MFC tumor and that BB-94 enhances the antitumor activity of docetaxel in the dose and schedule used.
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PMID:Potentiation of docetaxel antitumor activity by batimastat against mouse forestomach carcinoma. 1121 20

The proper structure of the extracellular matrix, in particular of the basement membrane and the adjacent interstitial matrix, are essential prerequisites for a proper function of tissues. Invasive growth in malignant tumors is associated with a destruction of various matrix structures. Due to extensive recent analyses significant advances have been made in the knowledge of the structure of the extracellular matrix, the composition of its most important constituents, their metabolism and that of matrix degrading enzymes. This information provides insight into the pathophysiology of malignant growth. Thereby, it has been shown that malignant tumor growth is associated with a loss of basement membrane (BM) material which, however, disappears not homogeneously, but affects various BM components to different degree. The loss of an intact BM as the first barrier is therefore the initial step of tumor invasion. Despite this loss there is evidence that the de novo synthesis of BM constituents in tumor and adjacent stromal cells is enhanced. Thus, it is obvious that BM material is degraded during the invasion process to significant degree. In addition, since there is a positive correlation between the amount of retained peritumoral BM and a higher degree of tumor cell differentiation the amount of retained BM material seems to represent a marker for the biological behaviour of the tumor cells. The loss of BM material is well explained by a significant expression of major matrix degrading enzymes, the matrix metalloproteinases (MMPs) both on the mRNA and protein level. Here again, there is considerable data indicating that both tumor and stroma cells are involved in the MMP synthesis. In addition to the loss of BM substances, the interstitial extracellular matrix (ECM) is disarranged. This disarrangement may comprise enhanced de novo synthesis ("desmoplasia") or dissolution by distinct MMPs (collagenases, such as MMP-1) reflecting obviously different reaction statuses of the stromal cells. Finally, significant work has been done on the elucidation of the role of regulating cytokine systems. To this regard, particular attention has been paid to the TGF-beta system and it has been shown that the major three isoforms of TGF-betas are upregulated both in tumor and stroma cells. Since the TGF-beta-effect is mainly mediated by a particular signalling system via the TGF-beta-receptors (TBRs), the investigation of this system has provided considerable insight into the role of TBRs which are now known to represent the most potent tumor suppressor genes. Thus frequent mutations in the TBR-II gene, one of the three TBRs, in various carcinomas suggest that these molecular alterations are responsible for both the loss of the control of cellular proliferation (in tumor cells) and altered matrix metabolism (in tumor and stroma cells). The further analysis of this major cytokine system therefore will provide us with major insights into the molecular abnormalities of invasive tumor growth.
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PMID:Synthesis and degradation of basement membranes and extracellular matrix and their regulation by TGF-beta in invasive carcinomas (Review). 1125 Nov 60

TIMP-2 is a natural matrix metalloproteinase (MMP) inhibitor that prevents the degradation of extracellular matrix proteins. It abolishes the hydrolytic activity of all activated members of the metalloproteinase family and in particular that of MT1-MMP, MMP-2, and MMP-9, which are selective for type IV collagenolysis. Since MMPs have been implicated in both cancer progression and angiogenesis, we generated a recombinant adenovirus to deliver human TIMP-2 (AdTIMP-2) and evaluated its anticancer efficiency in three murine models. Our results demonstrated that overexpression in vitro of TIMP-2 inhibited the invasion of both tumor and endothelial cells without affecting cell proliferation. Its in vivo efficiency has been evaluated in murine lung cancer LLC, and colon cancer C51 in syngeneic mice as well as in human breast cancer MDA-MB231 in athymic mice. Preinfection of tumor cells by AdTIMP-2 resulted in an inhibition of tumor establishment in more than 50% of mice in LLC and C51 models and in 100% mice in the MDA-MB231 model. A single local injection of AdTIMP-2 into preestablished tumors of these three types significantly reduced tumor growth rates by 60--80% and tumor-associated angiogenesis index by 25--75%. Lung metastasis of LLC tumor was inhibited by >90%. In addition, AdTIMP-2-treated mice showed a significantly prolonged survival in all the cancer models tested. These data demonstrate the potential of adenovirus-mediated TIMP-2 therapy in cancer treatment.
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PMID:AdTIMP-2 inhibits tumor growth, angiogenesis, and metastasis, and prolongs survival in mice. 1126 84

The matrix metalloproteinase matrilysin has been implicated in the progression of gastrointestinal and other cancers. The aim of this study was to examine matrilysin mRNA expression and determine whether it is correlated with K-ras mutations and/or progression of pancreatic carcinoma. Using the semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we analyzed 11 pancreatic cancer cell lines and 70 pancreatic adenocarcinoma tissues for matrilysin mRNA expression. The results were correlated with clinicopathological characteristics and K-ras mutations. Significant amounts of matrilysin mRNA were detected in six of the eight cell lines with K-ras mutations but not in the three cell lines with wild-type K-ras. Matrilysin mRNA was detected in 57 (81.4% ) of the 70 tumor tissues and in all of the eight liver metastases, but not in any of the adjacent non-tumorous tissues. Matrilysin expression was significantly correlated with the size of tumor, tumor spreading, lymph node metastasis, advanced pathologic tumor-node- metastasis stage and K-ras mutations. The relative amounts of matrilysin mRNA in tumor tissues increased with increase in tumor stage and were highest in liver metastatic tumor tissues. Our results suggest that matrilysin, the expression of which is correlated with K-ras mutations, plays a key role in tumor growth and progression of pancreatic carcinoma.
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PMID:Association of matrilysin mRNA expression with K-ras mutations and progression in pancreatic ductal adenocarcinomas. 1140 48

The purpose of this study was to determine whether systemic administration of interferon-alpha (IFN-alpha) can inhibit liver metastasis produced in nude mice by human colon cancer cells. KM12L4 (IFN-alpha-sensitive) or KM12L4 IFN(R) (IFN-alpha-resistant) cells were injected into the spleen of nude mice. Seven days later, the mice were treated with subcutaneous (s.c.) injections of IFN-alpha (70,000 units/week) at different dosing schedules (1, 2, or 7 times/week). Significant inhibition of tumor growth, vascularization and expression of basic fibroblast growth factor (bFGF) or matrix metalloproteinase-9 (MMP-9) mRNA and protein occurred in mice given daily injections of IFN-alpha. Kinetic analysis of therapy showed that daily s.c. administrations of 10,000 units of IFN-alpha induced apoptosis in liver metastasis-associated endothelial cells, followed by inhibition of tumor cell division and apoptosis of tumor cells. These data suggest that the antiangiogenic activity of IFN-alpha-2a depends on frequent administration of the optimal biologic dose.
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PMID:Suppression of angiogenesis and therapy of human colon cancer liver metastasis by systemic administration of interferon-alpha. 1142 Jul 51


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