Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.4 (trypsin)
42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Regional (popliteal) lymph node cells (RLNC) from A/Jax mice, inoculated in each hind foot with isogeneic Sarcoma 1 tumor cells, demonstrated cytotoxicity in vitro at Day 14 of tumor growth but lost this ability by Day 21. These noncytotoxic RLNC were capable of suppressing activity of other cytotoxic lymphoid cells, but after incubation for 24 hr in vitro their cytotoxicity was restored and their suppressive activity was abrogated. RLNC responsible for cytotoxicity were removed by treatment with anti-theta serum plus complement. The suppressive effect of RLNC was found to be mediated by a soluble "blocking" factor which was released into the culture medium after 24 hr incubation. The factor was not detected in culture media from RLNC pretreated with anti-theta serum plus complement prior to incubation. Absorption of RLNC culture supernatants with tumor-bearer spleen cells, but not with normal spleen cells, completely removed the blocking factor, while absorption by Sarcoma 1 cells significantly reduced blocking activity. The factor was trypsin sensitive, was retained on an Amicon XM100 filter, and did not demonstrate the presence of antibody to Sarcoma 1 in a radioimmunoassay. Although the exact nature of the factor has not been established, it appears to be a receptor antigen complex from T-cells of tumor-bearing animals.
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PMID:Immunological activity of regional lymph nodes in tumor-bearing mice. 31 91

Several of the cannabinoids found in marihuana have been shown to inhibit tumor growth and increase the life-span of mice bearing the Lewis lung adenocarcinoma. When trypsin-dispersed isolated Lewis lung cells are incubated in vitro, they maintain their capacity to carry out macromolecular synthesis (RNA, DNA, protein). This process can be inhibited by cytosine arabinoside, actinomycin D, or methyl-1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, whereas cyclophosphamide, an agent that must be bioactivated, was inactive. Inhibition of DNA synthesis as measured by [3H]thymidine uptake into acid-insoluble material was used as an index of cannabinoid activity against isolated Lewis lung cells, L1210 leukemia cells, and bone marrow cells incubated in vitro delta9-, delta8-, 1-hydroxy-3-n pentyl-, and 1-delta8-tetrahydrocannabinol, and cannabinol demonstrated a dose-dependent inhibition of DNA synthesis whereas cannabidiol and 1-hydroxy-3-n-pentylcannabidiol were markedly less inhibitory in our in vitro cell systems. Furthermore, our in vitro observations with these cannabinoids are supported by in vivo tumor inhibition studies. Ring modifications as in cannabichromene or cannabicyclol abolish in vitro activity as does dihydroxylation at the 8beta and 11 positions of 1-delta9-trans-tetrahydrocannabinol. Delta9-trans-tetrahydrocannabinol demonstrated the least toxicity of all inhibitory cannabinoids in vivo; this is supported by its lesser effect on bone marrow DNA synthesis in vitro.
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PMID:The inhibition of DNA synthesis by cannabinoids. 124 11

Work done in our laboratories, using a murine model, indicates that suppression of host immune responses might be due to secretion of soluble factors by tumor cells. The H238 cells (BALB/c embryonic fibroblasts transformed by UV-inactivated herpes simplex virus Type 2) exhibit progressive tumor growth with subsequent decrease in lymphoproliferation. To further study the suppressive effects of a tumor, H238 conditioned medium (CM) was tested for its ability to block murine and human mitogenic and allogeneic lymphocyte responses. PHA, Con A and LPS were used as mitogens. Lymphoproliferation, in the presence of increasing amounts of H238 CM, resulted in a greater degree of suppression of [3H]thymidine ([3H]Tdr) uptake, in both human and mouse systems. The kinetics of proliferation in the presence of concentrated H238 CM (cCM) showed that depression was evident regardless of the time of cCM addition, thereby affecting it at any stage of the cell cycle. Treatment of H238 cCM using acid (pH 2.3), base (pH 9.6), trypsin (100 micrograms/ml), heat (56 degrees C, 100 degrees C) and freeze-thawing, restored PHA-stimulated lymphoproliferation. Dialysis of H238 cCM showed that the molecular weight of the suppressor lies between 15 and 25 kDa. Northern blot analysis demonstrated the presence of a TGF-beta transcript in H238 cells. Neutralization of the H238 cCM with monoclonal antibody to TGF-beta resulted in complete abrogation of suppressive activity in spleen cell lymphoblastogenesis. These results suggest that TGF-beta appears to be the main inhibitor of immune responses found in this HSV-2-induced murine tumor cell line. Such tumor-induced modulations may contribute to the outcome of immunotherapy in the tumor-bearing host.
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PMID:Suppression of immune responses by herpes virus type 2-transformed murine tumor cells. 166 30

The human melanoma cell lines M21 and MSM-M2 are shown to produce two similar competitive inhibitors of trypsin, a serine proteinase. These proteinase inhibitors inhibited the serine proteinases trypsin and kallikrein with similar efficiency but did not inhibit plasmin (a serine proteinase) or papain (a thiol proteinase). Active synthesis of the inhibitors during cell culture was indicated by the requirement for cell viability, the increase in inhibitory activity of the supernatant with time, and the incorporation of 35S-methionine into the inhibitors. The two inhibitors were stable to heat (70 degrees C) and extremes of pH. Their molecular weights were estimated at 670 and 250 kD, respectively. A screening of the supernatants of five other human melanoma cell lines by HPLC showed that they all released a similar trypsin inhibitory factor not detected in human or bovine serum. The isolation of these proteinase inhibitors facilitates a study of their putative role in tumor growth.
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PMID:Serine proteinase inhibitors produced by human melanoma cell lines. 230 65

Hypercalcemia is one of well-recognized paraneoplastic syndromes and occurs occasionally in patients with oral cancers. Because bone is the richest source of calcium in the body, it has been proposed that humoral bone resorbing factors which are released by tumors are responsible for the pathogenesis of hypercalcemia. In the present study, partial purification and identification of bone resorbing humoral factors were carried out employing VX2 squamous cell carcinoma which has been known to induce hypercalcemia in rabbits. In addition, extra- and intra-cellular mechanisms which are operating to confer autonomous growth on VX2 cancer cells were also studied. VX2 carcinoma induced marked hypercalcemia not only in rabbits but also in nude mice in parallel with tumor enlargement. Administration of indomethacin (INDO), a prostaglandin (PG) synthesis inhibitor, before onset of the hypercalcemia prevented an elevation of serum calcium levels and growth of the tumor. INDO, however, failed to decrease serum calcium levels and tumor growth when administered after development of the hypercalcemia and tumor enlargement. These results indicate that not only PGs but other humoral factors are involved in the pathogenesis of the hypercalcemia seen in VX2 cancer-bearing animals. VX2 cancer cells in culture retained their cancerous phenotypic properties, synthesized PGE2, PGF2 alpha and 6-keto PGF1 alpha and secreted highly levels of PGE2, a powerful bone resorber, into the culture medium in a time- and cell density-dependent manner. The culture supernatants also contained a trypsin- and heat-sensitive bone risorbing factor (BRF) with a molecular weight of approximately 20kD. BRF was presumed to be similar to parathyroid hormone related protein (PTHrP) from its biological and biochemical behaviors. Both PGE2 and PTHrP promoted VX2 cell growth, thus suggesting that these two substances are autocrine growth factors for VX2 cells. Calcium stimulated VX2 cell growth and secretion of PGE2 and BRF (PTHrP) in a concentration-dependent fashion. Stimulation of VX2 cell proliferation by PGE2 and PTHrP was closely correlated with a transient elevation of intracellular free calcium ion ([Ca2+]i). [Ca2+]i elevated transiently in response to PGE2 and PTHrP was shown to be supplied by influx of extracellular free calcium ion ([Ca2+]e) through calcium channel present in plasma membrane. Involvement of protein kinase C in autocrine growth stimulation of VX2 cells by PGE2 and PTHrP was unclear. These results demonstrate that PGE2 and PTHrP secreted by VX2 cancer cells not only induce hypercalcemia but promote VX2 cell growth as autocrine growth factors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Mechanism of hypercalcemia associated with malignancy: interactions between induction of hypercalcemia and autonomous growth in VX2 cancer cells]. 263 47

Studies with four different transplantable murine tumors demonstrated that surgical instruments contaminated by contact with a tumor mass could produce tumors in a surgical wound. Eighty-seven per cent of mice with wounds made by invisibly contaminated scissors developed tumors. Irrigation with water did not prevent tumor growth. Before spilled tumor cells can invade and grow into a recurrence in the wound site, they must first attach to underlying extracellular matrix. We have devised a simple in vitro assay to identify inhibitors of tumor-cell attachment to develop therapeutic compounds that can prevent tumor-cell reimplantation. Various test compounds, including proteases (trypsin and Dispase), known modulators of matrix metabolism (proline analogues, cycloheximide, heparin, cortisone, cortexolone, and heparin-steroid combinations), large molecular weight polymers (agarose, dextran, polyethylene oxide), and synthetic fibronectin peptides were tested for their ability to inhibit mouse melanoma (B16-F10) cell attachment to gelatinized dishes. Most of these compounds had little or no effect on tumor-cell adhesion when cells were plated in serum-containing medium. However we identified three compounds that inhibited tumor-cell attachment in a reversible fashion: (1) a specific inhibitor of collagen deposition (L-azetidine-2-carboxylic acid); (2) a bacterial neutral protease (Dispase); and (3) synthetic fibronectin peptides that contained the arginine-glycine-asparate (RGD) sequence that is responsible for cell binding. Dispase and the RGD-containing peptides also inhibited cell implantation and prevented tumor formation in a surgical wound. We propose that inhibitors of attachment might be used either alone or with other biologic modifiers to prohibit implantation of free tumor cells at the time of surgery and thus, to prevent local tumor recurrence.
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PMID:Inhibition of tumor-cell attachment to extracellular matrix as a method for preventing tumor recurrence in a surgical wound. 268 68

Conditioned medium from Reuber H-35 or Fao hepatoma cells contains autocrine factors that both stimulate DNA synthesis and activate acetyl-coenzyme A (CoA) carboxylase in serum-deprived Fao cells. The factor(s), which appears within 4 h of serum-free culture, also increases the cell number and the mitotic index. The effects of the conditioned medium are insulinomimetic, both with respect to stimulation of DNA synthesis and acetyl-CoA carboxylase activity. However, no induction of tyrosine aminotransferase activity or stimulation of aminoisobutyric acid uptake is seen in response to the conditioned medium. Insulin over a 4-h period does not increase the concentration of DNA synthesis stimulating activity that is observed in the medium. This activity is dialyzable and is resistant to acid treatment or to heating to 60-100 degrees C and to trypsin digestion; it is not extracted with chloroform/methanol nor adsorbed by charcoal or by a C18 reverse-phase column. Fractionation of the conditioned medium derived from Reuber H-35 hepatoma cells by gel filtration chromatography reveals two low molecular weight (less than 1000) compounds that both stimulate DNA synthesis in Fao hepatoma cells. The larger compound (peak I) also stimulates the activity of acetyl-CoA carboxylase. The stimulatory effects of the peak I compound are destroyed by nitrous acid deamination, periodate oxidation, and methanolysis. Biosynthetic labeling studies indicate the probable presence of glucosamine, galactose, and perhaps phosphate in the peak I-activating material. No significant incorporation of either myoinositol or mannose into the active material has been observed. These data, taken together, are consistent with a glycan structure for this autocrine factor, which bears strong resemblance to similar insulinomimetic factors generated in BC3H1 myocytes and H-35 hepatoma cells in response to insulin and on digestion of membranes with a phosphatidylinositol-specific phospholipase C. Further characterization of this factor may provide insight into different pathways of insulin action and could provide a strategy to check autocrine-stimulated tumor growth.
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PMID:An autocrine factor from Reuber hepatoma cells that stimulates DNA synthesis and acetyl-CoA carboxylase. Characterization of biologic activity and evidence for a glycan structure. 289 65

In the present study, a cytostatic tumor growth inhibitory peptide and a tumor growth promoting peptide with molecular weights of 20,000-30,000 Da have been identified in the supernatant fraction of unfertilized ova from Shad. The factors can be separated by gel chromatography, thus indicating that the factors are individual molecules. Both of the factors are nondialyzable, heat stable, and resistant to trypsin digestion and periodate oxidation.
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PMID:A tumor growth inhibitory factor and a tumor growth promoting factor isolated from unfertilized ova of shad (Alosa sapidissima). 293 May 39

We have recently shown that the integrity of the polyamine pathway is essential but not sufficient for expression of the mitogenic effect of estradiol (E2) in the N-nitrosomethylurea-induced rat mammary tumor grown in vitro in the soft agar clonogenic assay. To elucidate the mechanism of E2 action in this system, we tested whether E2 may stimulate tumor growth through induction of secretory growth factor(s), as already proposed for human breast cancer cell lines in culture. Furthermore, we investigated the potential interaction between such "autocrine" control of tumor growth by E2 and the polyamine pathway. Conditioned medium obtained from E2-treated tumors (E2-CM) but not from control tumors (C-CM) consistently stimulated colony formation when added to N-nitrosomethylurea-mammary tumors plated in soft agar under serum-free media conditions. Such growth-promoting effects of the E2-CM was found to increase with increasing protein concentrations of the medium and was abolished by pretreatment of the medium with concanavalin A, heat, and trypsin. The addition of the polyamine biosynthetic inhibitor alpha-difluoromethylornithine (1 mM) totally abolished the colony-stimulating effect of the E2-CM. Exogenous administration of spermidine (0.1 mM) reversed the inhibitory effect of alpha-difluoromethylornithine on colony formation and restored the action of the E2-CM. Although the addition of polyamines alone did not affect the number of colonies formed, the administration of spermidine was found to significantly enhance in a dose-dependent fashion the colony-stimulating effect of suboptimal concentrations of E2-CM. Attempts to identify the E2-inducible growth factor in the E2-CM and in N-nitrosomethylurea-mammary tumor specimens using monoclonal antibodies raised against the Mr 52,000 E2-inducible protein gave negative results. We conclude that autocrine stimulation of tumor growth by E2 is not limited to human breast cancer cell lines but also occurs in individual experimental mammary tumors grown in soft agar. Our results show that the polyamines must be present for the expression of this "autocrine" control of tumor growth by E2. Finally, the identity of the E2-induced growth factor operating in our system remains to be determined.
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PMID:Autocrine stimulation by estradiol-regulated growth factors of rat hormone-responsive mammary cancer: interaction with the polyamine pathway. 308 Dec 52

These experiments were designed to test whether autocrine/paracrine mechanisms are involved in the growth-promoting action of progesterone (Pg) in the N-nitrosomethylurea-induced rat mammary tumor cultured in vitro in soft agar clonogenic assay. In support of our hypothesis, we observed that conditioned media obtained from Pg-treated tumors (Pg-CM), consistently stimulated colony formation in our system to the same degree as Pg itself (approximately 140% of control). Treatment with heat, trypsin, and concanavalin A abolished the colony-stimulating effect of Pg-CM, thus suggesting the possible glycoprotein nature of the Pg-inducible growth factor(s). The growth-promoting action of Pg-CM was rather specific since CMs obtained from tumors exposed to a variety of other steroid hormones rarely stimulated colony formation and usually only to a modest degree. Administration of the polyamine biosynthetic inhibitor, alpha-difluoromethylornithine, abolished the colony-stimulating effect of Pg-CM. The inhibitory effect of alpha-difluoromethylornithine was reversed in a dose-dependent fashion by exogenous administration of spermidine, which entirely restored the growth-promoting action of Pg-CM. Addition of increasing amounts of spermidine, however, did not potentiate Pg-CM action under our experimental conditions. Our results indicate that autocrine/paracrine mechanisms may mediate, at least in part, the colony-stimulating effect of Pg in our system. The polyamine pathway plays an essential role in the expression of such control of tumor growth by Pg.
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PMID:Polyamines and autocrine control of N-nitrosomethylurea-induced rat mammary tumor growth in vitro by progesterone. 313 Jan 83


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