Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinases-2 (MMP-2) and -9 (MMP-9) facilitate tumor invasion and metastasis via basement membrane degradation. In colorectal cancer (CRC) specimens, MMP production is largely stromal in origin, implicating monocytes (M phi s) and fibroblasts. We hypothesize that CRC cells induce stromal cell MMP production. This study examines the differential effect of metastatic and non-metastatic CRC cells on M phi MMP production. The human M phi line THP-1 was co-cultured with either a non-metastatic human CRC cell line (SW620-P) or a metastatic clone (SW620-S5) established by serial cecal transplantation of SW620-P in nude mice. Conditioned medium MMP activity and cellular MMP mRNA expression were assessed by gelatinase zymography and Northern blot analysis, respectively. Neither CRC line released MMP-2 or MMP-9. Isolated THP-1 M phi s produced basal levels of both MMP-2 and MMP-9. The level of MMP-9 activity was increased moderately by co-culture of M phi s with the metastatic SW620-S5 clone, but decreased by the non-metastatic SW620-P cells. MMP-2 activity was greatly augmented by co-culturing M phi s with SW620-S5 cells, but was not affected by SW620-P cells. The stimulatory effect of SW620-S5 cells on MMP-2 secretion was confirmed by Western blot analysis. Both isolated and co-cultured M phi s expressed MMP-2 mRNA while SW620-S5 cells under similar conditions did not, implicating M phi s as the source of increased MMP-2 activity. Since the induction of MMP-2 activity was not associated with a parallel increase in M phi MMP-2 mRNA, the modulation of M phi MMP-2 release appears to be post-transcriptionally regulated. Metastatic CRC cells are distinct from non-metastatic cells in their ability to induce M phi MMP release. This observation emphasizes the role of M phi-derived MMPs in facilitating CRC invasion and metastasis and suggests modulation of stromal cell MMP production by CRC cells in a paracrine fashion.
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PMID:Metastatic colorectal cancer cells induce matrix metalloproteinase release by human monocytes. 852 14

In vivo antitumor activity of pirarubicin (THP) and epirubucin (EPI) in combination with doxifluridine (5'-DFUR) and cisplatin (CDDP) were examined using mouse P388 leukemia. THP (1.25-7.5 mg/kg) or EPI (1.25-15 mg/kg) was given intravenously on day 1, and then 5'-DFUR (125 or 250 mg/kg/day) and CDDP (4 mg/kg) were given orally on days 1-4 and intravenously on day 5 after tumor inoculation, respectively. Both THP and EPI enhanced the antitumor of a combination of 5'-DFUR and CDDP. The enhancement by THP was additive or synergistic, while that by EPI was additive. Cured animals were observed in the combination of THP with the two drugs, but not in that of EPI. Thus, in combination with 5'-DFUR and CDDP, THP was more effective against P388 leukemia than was EPI. The combination therapy using THP, 5'-DFUR and CDDP may be a novel chemotherapeutic approach to a variable type of tumors in clinical trials.
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PMID:Antitumor effects of pirarubicin and epirubicin in combination with doxifluridine and cisplatin against mouse P388 leukemia. 859 Apr 41

Radiolabeled antibodies have shown promise for the treatment of lymphoma and for solid tumor targeting. Campath-1H is a humanized monoclonal antibody that reacts with the CD52 antigen present on human lymphoid and myeloid cells. Campath-1H is a gamma1 (G1) isotype that induces lymphopenia via an Fc-mediated mechanism(s). Isotype switches were engineered, and the resulting antibodies were expressed in NS0 mouse myeloma cells and biosynthetically radiolabeled with [35S]methionine. The forms included G1, G4, and a G4 variant that contained alanine substitutions at (EU numbering) Leu-235, Gly-237, and Glu-318. All isotypes bound antigen equivalently as assessed by target cell binding in vitro. The G4 variant had a greatly reduced capacity to interact with Fc receptor by virtue of reduced binding to THP-1 human myeloid cells and by a 1000-fold increase in EC50 to intermediate antibody-dependent cellular cytotoxicity. The pharmacokinetics of the isotypes were compared in CD-1 (nu/nu) mice bearing an experimental antigen-expressing tumor. The plasma half-life and tumor uptake were increased for the G4 variant. The G4 variant showed significantly less spleen, liver, and bone uptake but similar uptake in the lung, kidney, and stomach and lower tissue-to-blood ratios. Immunogenicity was assessed after repeated monthly administrations of unlabeled antibody in BALB/c mice. A 50% reduction in the incidence of anti-globulin response was observed for the G4 variant. These properties suggest that antibodies with reduced Fc receptor interaction merit additional study as potential targeting vehicles relative to other isotypes for radioimmunotherapy or situations where diminished normal tissue binding contributes to efficacy.
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PMID:Improved biodistribution, tumor targeting, and reduced immunogenicity in mice with a gamma 4 variant of Campath-1H. 861 27

Integrin-mediated signals play an important but poorly understood role in regulating the growth and behavior of tumor cells. In monocytes and monocytic leukemia cells, integrin-mediated adhesion results in a strong induction of a set of immediate early genes that are characteristic of monocytic differentiation and contain consensus NF-kappa B elements in their 5' regulatory regions. To investigate the role of integrin signaling in control of differentiation in a human monocytic leukemia cell line, THP-1 cells were transiently transfected with an NF-kappa B driven CAT reporter gene. Adhesion to fibronectin or cross-linking of beta1 integrins resulted in an NF-kappa B-dependent induction of CAT activity. To evaluate whether integrin signaling in this system intersects with the Ras signal transduction cascade, THP-1 cells were cotransfected with the NF-kappa B reporter and with plasmids that direct the synthesis of normal or mutant forms of Ras or Raf. We found that Ras or Raf dominant negative mutants did not inhibit integrin-mediated activation of the NF-kappa B-driven reporter. However, cotransfection with activated Ras, or with several other cytoplasmic oncogenes, blocked this process. This suggests that in monocytic leukemia cells, an antagonism exists between the mitogenic signals provided by oncogenes and the signals generated by integrin ligation. This antagonism may play an important role in regulating the balance between proliferation and differentiation in monocytic leukemias.
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PMID:Integrin signaling to NF-kappa B in monocytic leukemia cells is blocked by activated oncogenes. 862 4

A 46-year-old male with unresectable hepatocellular carcinoma (HCC) comprised of severe liver dysfunction was treated by intra-arterial infusion chemotherapy through an implantable reservoir. During 39 months, a total amount of THP-ADR 420 mg, ADR 70 mg and CDDP 350 mg was infused. Through the therapy, the tumor size on the lateral segment was well controlled, and serum AFP and PIVKA-II levels were also lowered. No severe side effect was observed. The patient was treated on an outpatient basis, and a good quality of life during therapy was maintained. This case suggests that THP-ADR may play an important role in a combined intraarterial chemotherapy for advanced HCC.
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PMID:[A case of hepatocellular carcinoma treated by intra-arterial infusion chemotherapy using THP-adriamycin]. 875 11

The 92 kDa matrix metalloproteinase (gelatinase B, MMP-9) plays a major role in the facilitation of tumor metastasis and in inflammatory disorders characterized by excessive matrix protein destruction. MMP-9 is transcriptionally induced in multiple cell types by exposure to the inflammatory mediators bacterial endotoxin, interleukin-1 (IL-1) or tumor necrosis factor-alpha (TNF-alpha). CT-2519, (1-(5-isothiocyanatohexyl)-3,7-dimethylxanthine), a synthetic small molecule from an anti-inflammatory compound library, was evaluated for its effect on endotoxin and cytokine-induced MMP-9 synthesis by a monocytic leukemic cell line, THP-1, and a monocyte/macrophage line, RAW 264.7. CT-2519 dose-dependently inhibited endotoxin and cytokine-induced synthesis of MMP-9 by these cells. Furthermore, both MMP-9 secretion and matrix invasion by cells of a human fibrosarcoma cell line, HT-1080, were inhibited by CT-2519 in a dose-dependent manner. Northern blot analyses and studies utilizing MMP-9 promoter constructs indicated that the inhibitory action of CT-2519 occurs at the level of transcriptional suppression. Given the observation that cellular activation by endotoxin, IL-1 and TNF-alpha may be mediated, at least in part, through induction of certain species of phosphatidic acid (PA), the effect of CT-2519 on lipid levels was analyzed. CT-2519 effectively reduced endotoxin-mediated increases in particular cellular lipid levels. Pharmacologic modulation of cytokine-dependent gene products, such as MMP-9, may offer an important therapeutic approach to the treatment of neoplastic and inflammatory disorders.
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PMID:Pharmacological inhibition of gelatinase B induction and tumor cell invasion. 875 12

The fungal metabolite trichodimerol (BMS-182123) has demonstrated inhibition of lipopolysaccharide (LPS)-stimulated tumor necrosis factor-alpha (TNF-alpha) secretion in various in vitro macrophage models (human and murine) including primary and tumor cell lines. When challenged with LPS, differentiated THP-1 monocytic cells secrete elevated levels of the cyclooxygenase products prostaglandin E2 (PGE2), thromboxane B2, and prostaglandin F2alpha (PGF2alpha). Studies directed at elucidating the mechanism of action of BMS-182123 as a TNF-alpha inhibitor revealed that the compound has a profound inhibitory effect on prostanoid secretion in response to LPS challenge. The key enzymes in prostaglandin synthesis are the constitutive cyclooxygenase, prostaglandin H synthase-1 (PGHS-1), and the mitogen-induced cyclooxygenase (PGHS-2), which is induced upon LPS stimulation in THP-1 cells. BMS-182123 did not inhibit the cyclooxygenase activity of PGHS-1 in an in vitro assay, suggesting that inhibition is due to a blockade in synthesis of cyclooxygenase enzyme. Western blot analysis of microsomal pellets from THP-1 cells stimulated with LPS (with or without BMS-182123 pretreatment) provided convincing evidence that the inhibition of prostaglandin synthesis is a result of suppressed synthesis of PGHS-2 enzyme. Northern blot analysis of THP-1 RNA demonstrated that BMS-182123 inhibits the induction of PGHS-2 at the level of transcription.
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PMID:Trichodimerol (BMS-182123) inhibits lipopolysaccharide-induced eicosanoid secretion in THP-1 human monocytic cells. 877 89

Synthetic oligodeoxyribonucleotides (ODNs) designed to selectively inhibit the transcription or translation of specific genes are being used to modulate the activity of the targeted gene. Because multiple copies of mRNA can be transcribed from one actively expressed gene, ODNs that target double-stranded DNA and form triple helices upon binding with the gene itself have an advantage over ODNs that target the gene product (mRNA) in an antisense fashion. For the present studies, we designed four different triple helix-forming phosphodiester ODNs (TFOs) targeted to the tumor necrosis factor (TNF) gene and examined their effect on production of TNF and on cellular growth of tumors in which TNF acts as an autocrine growth factor. The ODNs J-109-50 and J-108-57 were designed to interact with polypurine oligonucleotides corresponding to the binding sites for nuclear factors kB (-237 to -208) and Sp1 (-58 to -33), respectively; J111-51 was designed to interact with a polypurine oligonucleotide in the third intron (+1429 to +1456) of the TNF gene. To enhance the cellular penetration and prevent degradation by cellular nucleases, the TFOs were modified at their 3' ends by either a cholesterol side chain or a propanolamine blocking group. Treatment of the human promonocytic cell line THP-1 with TNF-TFOs at a nontoxic concentration (2 microM) reduced the production of TNF. All of the TNF-TFOs tested were effective, and control-irrelevant TFOs were ineffective in inhibiting TNF production. The activity of the most efficacious TNF-TFOs also correlated with a decrease in TNF mRNA as observed by using reverse transcriptase PCR assays. In several tumors in which TNF acts as an autocrine growth factor, we examined the antiproliferative activity of J111-51. We found that in the human glioblastoma tumor cell line U-251, TNF-induced growth was blocked by J111-51 in a dose-dependent manner. Thus, overall results demonstrate that oligonucleotides directed to the specific regions of TNF can be designed, which may have a potential in cancer therapy.
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PMID:Triple helix-forming oligodeoxyribonucleotides targeted to the human tumor necrosis factor (TNF) gene inhibit TNF production and block the TNF-dependent growth of human glioblastoma tumor cells. 891 51

Identification of the processing/activation of multiple interleukin-1beta converting enzyme (ICE)-like proteases and their target substrates in the intact cell is critical to our understanding of the apoptotic process. In this study we demonstrate processing/activation of at least four ICE-like proteases during the execution phase of apoptosis in human monocytic tumor THP.1 cells. Apoptosis was accompanied by processing of Ich-1, CPP32, and Mch3alpha to their catalytically active subunits, and lysates from these cells displayed a proteolytic activity with kinetics, characteristic of CPP32/Mch3alpha but not of ICE. Fluorescence-activated cell sorting was used to obtain pure populations of normal and apoptotic cells. In apoptotic cells, extensive cleavage of Ich-1, CPP32, and Mch3alpha. was observed together with proteolysis of the ICE-like protease substrates, poly (ADP-ribose) polymerase (PARP), the 70-kD protein component of U1 small nuclear ribonucleoprotein (U1-70K), and lamins A/B. In contrast, no cleavage of CPP32, Mch3alpha or the substrates was observed in normal cells. In cells exposed to an apoptotic stimulus, some processing of Ich-1 was detected in morphologically normal cells, suggesting that cleavage of Ich-1 may occur early in the apoptotic process. The ICE-like protease inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone (Z-VAD.FMK), inhibited apoptosis and cleavage of Ich-1, CPP32, Mch3alpha, Mch2alpha, PARP, U1-70K, and lamins. These results suggest that Z-VAD.FMK inhibits apoptosis by inhibiting a key effector protease upstream of Ich-1, CPP32, Mch3alpha, and Mch2alpha. Together these observations demonstrate that processing/activation of Ich-1, CPP32, Mch3alpha, and Mch2alpha accompanies the execution phase of apoptosis in THP.1 cells. This is the first demonstration of the activation of at least four ICE-like proteases in apoptotic cells, providing further evidence for a requirement for the activation of multiple ICE-like proteases during apoptosis.
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PMID:Processing/activation of at least four interleukin-1beta converting enzyme-like proteases occurs during the execution phase of apoptosis in human monocytic tumor cells. 912 56

Macrophage cathepsin B (CB) is implicated in tissue injury in inflammatory diseases. Lipopolysaccharide (LPS) is an activator of macrophages whose effect on CB is unknown. This study was undertaken to investigate the potential of macrophages as a source of increased CB and to determine if exposure to LPS might stimulate CB levels. As a model we chose the macrophage-like tumor line, THP-1. Incubation with LPS led to a time and dose-dependent increase in CB activity. LPS potentiated interferon-gamma (IFN-gamma)-induced elevations of CB and led to an additive increase in CB activity. Pretreatment of the cells with LPS not only caused a marked stimulation of CB activity over that seen with IFN-gamma alone, but also decreased the concentration and exposure time to the cytokine necessary to achieve maximum induction of the enzyme. The LPS and IFN-gamma induced CB increases were abolished by cycloheximide or actinomycin D in the cultures, indicating that the increases in CB required increased RNA transcription and de novo protein synthesis. Direct measurement of CB mRNA showed increases. These data indicate that although LPS alone appears to induce the production of CB in THP-1 cells, it augments IFN-gamma induced increases, suggesting that two signals are necessary for maximum CB induction in this system.
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PMID:Endotoxin induces increased intracellular cathepsin B activity in THP-1 cells. 913 7


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