Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Most malignant cells exhibit increased plasminogen activator activity which, in turn, leads to the formation of the fibrinolytically active enzyme, plasmin. Since solid tumours in man are surrounded by a fibrin network, the fibrinolytic activity of the tumour may influence tumour growth and metastasis. In the present study plasminogen activator activity, as assessed in purified extracts, was compared in benign hyperplasia of the prostate (group A, n = 6), non-metastasizing+ prostatic carcinoma (group B, n = 26), and in prostatic carcinoma with bone metastasis (group C, n = 10). Plasminogen activator activity was significantly higher in prostatic carcinoma than in hyperplasia, but there was no significant difference in plasminogen activator activity between prostate carcinoma with or without bone metastasis. However, plasminogen activator activity in the bone metastasis cells was significantly higher than in the primary tumour. If a positive correlation between fibrinolytic activity of the tumour and the metastasizing capacity were postulated, particular importance could be attached to bone metastasis in prostatic cancer.
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PMID:[Tissue plasminogen activator activity in early prostatic cancer and in bone metastases of prostatic cancer]. 608 73

19 patients with carcinoma of the prostate and 6 controls with hyperplasia of the prostate, have been investigated to elucidate the relationship between tumor fibrinolytic activity, the degree of malignancy, tumor stage and metastatic spread. Significantly (p less than 0.001) higher tissue plasminogen activator activities were found in metastatic carcinoma compared to nonmetastatic carcinoma or hyperplasia of the prostate. Antibodies against human urokinase caused inhibition of urokinase and plasminogen activator activity from human prostatic carcinoma or hyperplasia. Antibody inhibition studies as well as physicochemical characteristics of the plasminogen activator produced by prostatic hyperplasia and carcinoma tissue indicate that this plasminogen activator is identical or similar to urokinase.
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PMID:Tissue plasminogen activator activity in prostatic cancer. 608 49

In the five kinds of human cultured cells derived from ovarian adenocarcinoma (HOC-21), ovarian malignant teratoma (HOTC 3), carcinoma of the uterine endometrium (HEC-1B), squamous cell carcinoma of the uterine cervix (SKG-1) and choriocarcinoma (BeWo), the intracellular presence of lactic dehydrogenase (LDH), alkaline phosphatase (AlP), human chorionic gonadotropin (HCG), alpha-fetoprotein (AFP) and plasminogen activator were investigated. The results were as follows. 1) BeWo-, HOC-21-and HOTC 3-cells revealed high activity of intracellular presence of lactic dehydrogenase (LDH), alkaline phosphatase (AlP), human chorionic gonadotropin (HCG), alpha-fetoprotein (AFP) and plasminogen activator were investigated. The results were as follows. 1) BeWo-, HOC-21-and HOTC 3-cells revealed high activity of intracellular LDH in this order, however none of HEC-1B-and SKG-1-cells did. 2) The activity of intracellular AlP was higher in BeWo-cells than in HOC-21-cells. The isozymes of AlP detected in these cells were found to be heat-stable. The others revealed no activity of AlP. 3) The presence of HCG-beta was confirmed in both BeWo- and HOTC 3-cells. The intracellular levels of HCG-beta were found to be higher in BeWo- cells than in HOTC 3-cells. HCG-beta was observed to leak into culture medium not from HOTC 3-cells but from BeWo-cells. It was not detected in the other cultured cells. 4) No AFP was detected in any of these five cultured cells. 5) Plasminogen activator was detected in HOC-21, HEC-1B-and SKG-1-cells in contrast to HOTC 3-and BeWo-cells which were negative for plasminogen activator. These results suggest that the various marker substances detected in the human cultured cells originated from various carcinomas of sexual organs may reflect biological functions of these tumor cells and, furthermore, can apply as tumor markers to the clinical diagnosis of the diseases.
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PMID:[Studies on marker substances in cell lines derived from various human gynecologic tumors (author's transl)]. 617 49

Using a fluorometric assay based on the activation of human plasminogen, plasminogen activator (PA) activity was measured in cytosolic and lysosomal extracts prepared from normal, benign hyperplastic (BPH), and carcinomatous human prostates. In all three types of prostatic tissue, the lysosomal extracts had much higher concentrations of PA activity than did the cytosolic extracts. The mean PA activity in lysosomal extracts of the carcinomatous prostates was 170% and 85% higher than that measured in normal and BPH prostates, respectively (Student's t-test, p less than .05). With prostatic carcinoma and BPH specimens there was an inverse (negative) relationship between lysosomal PA activity and the nuclear concentration of androgen-receptors (correlation coefficient, -0.84). By comparison in specimens of human breast tumors, there were weakly positive correlations between PA activity and either estrogen (ER) or progestin (PR) receptors (correlation coefficients of + 0.23 and + 0.54, respectively). While as a group ER+, PR+ breast tumors had higher PA activity that ER+, PR- or ER-, PR- tumors, the differences were not statistically significant (Student's t-test, p greater than .05). Thus in breast tumors, it is uncertain whether high levels of PA activity are indicative of hormonal dependence. However, our findings with prostatic tumors infer that in contrast, high concentrations of this enzyme may reflect a malignant phenotype characterized by a decrease in both androgen responsiveness and differentiation.
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PMID:Plasminogen activator activity in human prostate and breast tumors: relationship to steroid receptors. 618 52

In the present paper we have characterized the plasminogen activators (PA) synthesized by 25 different human cell lines. Technically easy methods were adopted for concentration and immunological characterization of the activators even in the presence of PA inhibitors. Most cell lines produced u-PA (mol. wt 55,000), melanoma and HeLa cells t-PA (mol. wt 66,000) and two carcinoma cell lines and normal skin fibroblasts produced no detectable PA. The classical 125I-fibrin method was compared to a caseinolytic assay and some of the discrepancies between results obtained with the two methods were shown to be due to cell-derived NaDodSO4-sensitive proteinase inhibitors in culture media. Additionally, synthesis and uptake by the cells of the wide-spectrum proteinase inhibitor alpha-2-macroglobulin ( alpha 2M ) were studied by radioimmunoassay and immunofluorescence. No production of alpha 2M could be measured in any of the malignant cell lines. In normal cells no correlation existed between the production of alpha 2M and the observed inhibition of PA activity, which indicates that other proteinase inhibitors are produced by the cells.
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PMID:Plasminogen activators, activation inhibitors and alpha 2-macroglobulin produced by cultured normal and malignant human cells. 620 45

Many tumors contain elevated levels of plasminogen activator and thus produce elevated levels of the protease plasmin in the milieu of the tumor. We have hypothesized, therefore, that it should be possible to prepare peptidyl prodrug derivatives of anticancer drugs that would be locally activated by tumor-associated plasmin. As an initial test of this hypothesis, we synthesized the peptidyl prodrugs of the anticancer drugs (alpha S, 5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin, AT-125) and N,N-bis(2-chloroethyl)-p-phenylenediamine (phenylenediamine mustard) by mixed anhydride coupling of the parent drug with the protected tripeptide, Boc-D-Val-Leu-Lys(Boc)-OH, followed by deprotection with trifluoroacetic acid. The prodrugs showed an increased selective in vitro cytotoxicity for Rous sarcoma virus transformed chicken embryo fibroblasts (which produce elevated levels of plasminogen activator) compared to nontransformed fibroblasts (which produce low levels of plasminogen activator). In the presence of the plasmin inhibitor, p-nitrophenyl p'-guanidinobenzoate at 2 micrograms/mL, the selectivity of the phenylenediamine mustard prodrug was reduced, but there was no effect on the cytotoxicity of the free drug. Furthermore, the prodrug analogue D-valylleucyl-D-lysylphenylenediamine mustard (in which L-Lys has been replaced by D-Lys) was inactive. Finally, the prodrug derivative of acivicin did not display selective toxicity for transformed cells when the cells were cultured in plasminogen-free medium. These results suggest that plasmin hydrolysis is necessary for the activation of the prodrugs. The prodrugs were tested in vivo for antitumor activity. The prodrug of acivicin, like acivicin itself, was inactive against the B16 melanoma, a murine tumor that produces high levels of plasminogen activator. This prodrug was active against the M5076 carcinoma, a tumor that displays only moderate levels of plasminogen activator; however, despite the fact that the prodrug was 2- to 3-fold less toxic on a molar basis than acivicin, there was no evidence of an increased therapeutic index. The prodrug of phenylenediamine mustard was also slightly less toxic than the parent drug, but again there was no evidence for an improved therapeutic index against the B16 tumor.
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PMID:Plasmin-activated prodrugs for cancer chemotherapy. 1. Synthesis and biological activity of peptidylacivicin and peptidylphenylenediamine mustard. 622 Oct 99

Specimens of the rabbit V2 carcinoma were maintained in organ culture to study the secretion of proteinases. Elastase-like, chymotrypsin-like, plasminogen activator-like, cathepsin B-like and collagenase activities were assayed with sensitive fluorimetric techniques. Of these enzymes, the only activities that were secreted in considerable amounts in primary cultures of tumor tissue were collagenase and a cysteine proteinase resembling cathepsin B. Co-cultures of intraperitoneally grown tumor and normal subcutaneous tissue of the rabbit resulted in significantly higher production of the cysteine proteinase and collagenase compared to the sum of the activities of the separate tissues. Explants of subcutaneous tissue of tumor-bearing rabbits secreted significantly more cysteine proteinase and collagenase than explants from normal animals. Explants from normal subcutaneous tissue stimulated with tumor-conditioned culture medium secreted both enzymes in higher amounts compared to the controls. The cysteine proteinase was similar in some properties to rabbit liver cathepsin B, but the enzyme from the tumor-host system showed a remarkable stability to a moderately alkaline pH. We suggest that a diffusible factor, derived from the tumor or immigrated cells, promotes an increased synthesis and secretion of collagenase and cysteine proteinase in the host, and that both enzymes may play cooperative roles during invasion of the surrounding tissues by the V2 carcinoma.
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PMID:Extracellular cysteine proteinase and collagenase activities as a consequence of tumor-host interaction in the rabbit V2 carcinoma. 632 87

A cell line derived from a human kidney carcinoma produces in vitro the urinary type of plasminogen activator (urokinase). The synthesis of plasminogen activator is enhanced by 12-O-tetradecanoyl-phorbol-13-acetate(TPA); the increase can be followed both in the cell lysate and in the culture medium. The effect requires RNA and protein synthesis as well as the continuous presence of the inducer. Immunofluorescence and immunoprecipitation experiments with monospecific antiurokinase IgG show that kidney carcinoma cells synthesize a 50,000-dalton urokinase and TPA enhances the synthesis of the same molecular species. Hybridization of the total cellular RNA to a human urokinase cDNA probe shows that TPA increases the urokinase mRNA level.
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PMID:Transcriptional induction of urokinase in cultured human kidney carcinoma cells by tetradecanoyl-phorbol-acetate. 638 32

The human carcinoma HEp3 grows on the chorioallantoic membrane and metastasizes to the chicken embryo with kinetics that are quantitatively predictable. We have used this experimental system to test whether plasminogen activator produced by the tumor is required for metastasis. Rabbit antibodies were raised against human urinary urokinase; these cross-reacted with and blocked the catalytic activity of HEp3-PA but did not inhibit chicken PA. When administered intravenously to embryos that had received an inoculum of HEp3 cells, the anti-urokinase antibodies did not inhibit tumor growth at the site of primary inoculation on the chorioallantoic membrane, but they either prevented or strongly inhibited metastasis to the embryo lung. Antibody treatment delayed the onset of pulmonary metastasis, indicating that plasminogen activator is required during early stages of the process.
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PMID:Antibodies to plasminogen activator inhibit human tumor metastasis. 641 88

Small colonic adenocarcinomas can be found in focal areas within benign tumors (adenomas), strongly suggesting an adenoma-to-carcinoma sequence. The induction of plasminogen activator (PA) secretion by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) has been used to order histologically distinct classes of human colonic adenomas in primary culture into a sequence from the most benign to the most advanced premalignant state. This ordering is based on the observation that each of five carcinomas examined in an earlier study by E. A. Friedman (Cancer Res., 41: 4588-4599, 1981) and each of seven carcinomas tested in this study released PA in response to TPA, inducing easily scored morphological alterations. Benign tumors either resembled carcinomas in their response to TPA or exhibited no morphological changes. The most benign adenomas by histopathology criteria were the small pure tubular adenomas without dysplasia. Six of seven of these adenomas did not secrete PA in response to TPA. We concluded that malignant cells had acquired the ability to respond to TPA by PA secretion, while tubular adenoma cells were not an advanced enough preneoplastic stage to so respond. TPA treatment of two cultured villous adenomas, one with infiltrating carcinoma and one with focus of moderately dysplastic cells, in the presence of low serum to decrease the plasmin concentration, demonstrated that only a subpopulation of cells secreted PA. Local areas of the monolayer were morphologically altered by the protease, forming clusters of cells loosely attached to the dish. The presence of such subpopulations within cultured adenomas was demonstrated by screening an additional five villous adenomas, 15 villotubular adenomas, and 11 tubular adenomas. The presence of dysplastic cells in 23 of 24 cases correlated with PA secretion. A subpopulation of villous cells, in the absence of dysplastic cells in each of three cases, also secreted PA. We conclude that, during tumor evolution, this villous subpopulation is the first preneoplastic cell type to acquire responsiveness to TPA by PA secretion. This property is maintained as the cells further evolve through premalignant dysplastic stages to carcinoma.
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PMID:A model for human colon carcinoma evolution based on the differential response of cultured preneoplastic, premalignant, and malignant cells to 12-O-tetradecanoylphorbol-13-acetate. 642 77


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