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)

This paper describes the growth of HEp-3, a human epidermoid carcinoma, in the chick embryo. When inoculated onto the chorioallantoic membrane, the tumor grows locally with a doubling time of 21 to 24 hr and disseminates widely in the embryo proper, metastasis to the lung and heart being especially prominent. The tumor secretes large amounts of plasminogen activator (PA) both in vivo and in vitro. This enzyme of human origin can be easily identified in a mixture containing both human and chicken PA's, since each PA has a marked preference for the homologous plasminogen. Thus the presence of human PA in tissues and body fluids can be used as a quantitative marker for HEp-3 metastasis both in embryos and in newly hatched chicks. Two assays for metastasis are described; their respective sensitivities are less than 4 x 10(4) and less than 500 HEp-3 cells per 17-day chick embryo lung (or approximately 1 HEp-3 cell per 400 and per 3 x 10(4) lung cells), respectively. These assays revealed that tumor growth and metastasis are sensitive to embryo age, inoculation onto the chorioallantoic membrane at 10 days being optimal for both. Tumor size, the length of the latent period that precedes the appearance of lung metastasis, and the number of metastatic cells in the lungs are all influenced by inoculum size. Generally, but not uniformly, an increased level of lung metastasis is correlated with tumor size on the chorioallantoic membrane. The attractive features of this system for quantitative study of metastasis are reproducibility rapidity, sensitivity, convenience, and cost.
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PMID:Experimental model for quantitative study of metastasis. 719 62

It has been reported previously that antisera produced in non human primates against many cultured human melanoma lines recognize tumor-associated antigens on the melanoma cells. The reactivity correlated with other parameters of malignancy, such as rapidity of tumor growth in nude mice and release of plasminogen activator. In this study we have investigated whether these antisera also react with non melanoma cancer lines and searched for a correlation between this reaction and the other parameters of malignancy. There was cross-reactivity of the ten sera with 4-43% of the 46 non melanoma lines compared to 62-100% of the 16 melanoma lines, indicating a preferential reactivity with melanoma lines. For the non-melanoma lines no correlation was found between the release of plasminogen activator, the degree of tumorigenicity in the nude mouse or the reactivity of surface antigens as detected with antimelanoma sera.
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PMID:Tumor production in the nude mouse, fibrinolytic activity and cross-reactivity with antimelanoma sera of various human tumor cell lines. 720 96

Suramin, an anticancer agent in current clinical trials, is a prototype of a pharmacological antagonist of growth factors, including basic fibroblast growth factor (bFGF). Suramin inhibited angiogenesis in the chick chorioallantoic membrane assay in a dose-dependent fashion. Suramin, 200 mg/kg i.v., inhibited rat corneal angiogenesis induced by bFGF-impregnated polymers; addition of heparin stimulated angiogenesis and counteracted the inhibition of suramin. The half-maximal inhibitory concentration (IC50) of suramin was determined for key cellular mechanisms that regulate angiogenesis: (a) low and high affinity cellular binding of bFGF to bovine capillary endothelial (BCE) cells with IC50s, respectively, of 24.3 and 71.5 micrograms/ml; (b) spontaneous migration of bovine pulmonary artery endothelial and normal AG 7680 fetal bovine aortic endothelial cells; bFGF-stimulated migration of BCE and transformed GM 7373 fetal bovine aortic endothelial cells with IC50s of 200-320 micrograms/ml; (c) proliferation of bovine pulmonary artery endothelial cells at > 100 micrograms/ml and of BCE cells at > 250 micrograms/ml; and (d) urokinase-type plasminogen activator activity of GM 7373 endothelial cells stimulated by bFGF with an IC50 of 211 micrograms/ml and of BCE cells stimulated by bFGF at > 100 micrograms/ml, but not plasminogen activator activity induced by phorbol 12-myristate 13-acetate. Suramin inhibited multiple control points of angiogenesis, including those stimulated by bFGF. Because tumor growth is angiogenesis dependent, the clinical efficacy of suramin may relate, in part, to angiosuppression.
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PMID:Suramin, an anticancer and angiosuppressive agent, inhibits endothelial cell binding of basic fibroblast growth factor, migration, proliferation, and induction of urokinase-type plasminogen activator. 751 54

Two bleomycin (BLM)-containing agents (BLM-PLA, BLM-SOL) were prepared, and the drug distribution and antitumor effect were studied. BLM-PLA is an agent in which BLM is incorporated into biodegradable low-molecular-weight polylactic acid, and BLM-SOL is an aqueous solution of BLM. BLM-PLA or BLM-SOL was subcutaneously administered in the back of rats. When BLM-PLA was implanted, high BLM activity of the connective tissues near the implants was maintained for 2 weeks. On the other hand, BLM activity was very low when BLM-SOL was administered. The effects of BLM-PLA, BLM-SOL and nontreatment on tumor growth and survival time were compared using subcutaneous tumor of Yoshida sarcoma in 21 rats each. The survivors and mean survival time in BLM-PLA group, BLM-SOL group and nontreatment group was 14 and 44.6 days, 5 and 23.7 days, and 0 and 11.3 days, respectively. BLM-PLA was superior to BLM-SOL in both drug distribution and antitumor effect, and consequently BLM-PLA could be a useful tool in loco-regional chemotherapy.
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PMID:[Drug distribution and antitumor effect of bleomycin incorporated in poly DL-lactic acid in rats]. 752 49

Nude mice have been subcutaneously inoculated with human tumorigenic fibrosarcoma cells (HT-1080) producing urokinase-type plasminogen activator (u-PA) or with human tumorigenic melanoma cells (G-361) producing tissue-type plasminogen activator (t-PA). Human u-PA (hu-PA) and t-PA (ht-PA) were found in the plasma and in the tumors of mice injected with HT-1080 or G-361 cells, respectively. Metastases containing ht-PA were observed in different organs of mice transplanted with G-361 cells, while mice injected with HT-1080 cells did not develop metastases. These data would suggest a relationship between the metastatic potential of G-361 cells and t-PA. The parallel increase of the levels of endogenous murine PAs (m-PA) activities might play a crucial role in the early stages of tumor growth and metastasis, since the biological effects of the PAs produced by the transplanted tumor cells can not be dissociated from those of the PAs induced in the host.
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PMID:Plasminogen activators in nude mice xenotransplanted with human tumorigenic cells. 767 29

Recently, a novel class of angiostatic steroids which block angiogenesis in several systems has been described. Since the elaboration of proteases is believed to be an important component of angiogenesis, we tested whether these steroids blocked the fibrinolytic response of endothelial cells to the angiogenic protein, basic fibroblast growth factor [bFGF]). Cultured bovine aortic endothelial (BAE) cells were incubated with bFGF and/or medroxyprogesterone acetate (MPA), an angiostatic steroid which has been shown to inhibit vascularization, collagenolysis, and tumor growth. When bFGF (3 ng/ml) was added to confluent monolayers of BAE cells, plasminogen activator (PA) activity in the medium was increased threefold. In contrast, MPA at 10(-6) M, 10(-7) M, 10(-8) M, and 10(-9) M decreased PA levels in the medium by 83%, 83%, 75%, and 39%, respectively. The stimulation of PA levels in BAE cells by bFGF (3 ng/ml) was abrogated by the presence of 10(-6) M MPA. This decrease in PA activity was found to be mediated by a significant increase in plasminogen activator inhibitor type-1 (PAI-1) production. MPA, therefore, negated one of the important enzymatic activities associated with the angiogenic process. In contrast to the decreased levels of secreted PA in cultures exposed simultaneously to MPA and bFGF, cell-associated PA levels remained high, consistent with earlier observations indicating that PAI-1 does not inhibit cell-associated PA. Thus, angiostatic steroids may exert their inhibitory effects on angiogenesis by increasing the synthesis of PAI-1. This, in turn, inhibits PA activity and, therefore, plasmin generation, which is essential for the invasive aspect of angiogenesis.
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PMID:Mechanism of action of angiostatic steroids: suppression of plasminogen activator activity via stimulation of plasminogen activator inhibitor synthesis. 768 43

Malignant cells possess a high degree of proteolytic activity in which the plasminogen activator system plays an important role. An increased expression of urokinase type plasminogen activator (uPA) is of significance for degradation of the extracellular tumor matrix, facilitating invasiveness and growth. Inhibition of the active site of uPA makes it possible to evaluate the significance of uPA in tumor growth. We report here experiments on a uPA-producing human prostate xenograft (DU 145) using a competitive inhibitor of uPA, p-aminobenzamidine. In vitro experiments with DU 145 cells showed that p-aminobenzamidine caused a dose-dependent inhibition of uPA activity. DU 145 cells were inoculated s.c. in SCID mice and, once tumors were established, treatment with p-aminobenzamidine added to drinking water was started and lasted for 23 days. Mice receiving 250 mg/kg/day of p-aminobenzamidine showed a clear decrease in tumor-growth rate compared to the non-treated mice, resulting in 64% lower final tumor weight. In addition, uPA-antigen levels in the membrane fractions of DU 145 tumors from p-aminobenzamidine-treated mice were found to be decreased by 59%. We also show that p-aminobenzamidine has an anti-proliferative effect in cell culture at low cell number, correlating with a dose-dependent decrease in uPA production. In conclusion, we show that a low-molecular-weight uPA-inhibitor, p-aminobenzamidine, has a growth-inhibitory effect on a solid uPA-producing tumor.
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PMID:The urokinase inhibitor p-aminobenzamidine inhibits growth of a human prostate tumor in SCID mice. 775 60

The plasminogen activation system is considered to play an important role in cancer growth and metastasis. Both plasminogen activators (PAs) and their fast-acting inhibitors are produced in tumor cells and their surrounding tissues. In order to clarify the influence of the existence of malignant tumor in urinary tract on the systemic fibrinolytic activity, we designed a study in which we compared the plasma levels of PAs and their inhibitors between before and after radical resection of tumors. Fourteen patients with renal cell carcinoma and 14 patients with transitional cell carcinoma participated in the study. In both groups, plasma levels of tissue-type plasminogen activator and urokinase-type plasminogen activator before the operation were higher than those 15 days after operation. The plasma level of plasminogen activator inhibitor 1 (PAI-1), however, did not change after the operation in the renal cell carcinoma group, and it decreased slightly in the transitional cell carcinoma group although it was not significant. When these values of the groups with or without metastasis were compared to other organs or lymph nodes, the PAI-1 level before operation was significantly higher in the group with metastasis than that without metastasis. In the three groups divided by the degree of atypia, PAI-1 level in the most atypical group was the highest. These results suggest that the fibrinolytic system in the plasma of cancer patients may play an important role in tumor growth and metastasis.
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PMID:Plasminogen activators and plasminogen activator inhibitor 1 in urinary tract cancer. 814 Jun 79

The plasminogen activator urokinase (u-PA) mediates proteolysis by a variety of human tumor cells. Competitive displacement of u-PA from cellular binding sites results in decreased proteolysis in vitro, suggesting that the cell surface is the preferred site for u-PA-mediated protein degradation. We studied the effect of u-PA receptor blockade on the metastatic capacity of human PC3 prostate carcinoma cells, using transfectants which expressed chloramphenicol acetyl-transferase (CAT). Eight weeks after subcutaneous inoculation of these cells into nude mice, CAT activity was detected in regional lymph nodes, femurs, lungs, and brain, thereby mimicking the organ tropism observed for naturally occurring metastases of prostate cancer. In a second transfection, CAT-expressing PC3 cells received cDNA encoding a mutant u-PA (Ser356-->Ala) which lacks enzymatic activity but which retains full receptor binding affinity. Three mutant u-PA expressors, each with < 5% of wild-type cell-associated u-PA activity, were compared in vivo with independently derived controls. Primary tumor growth was similar in each group of animals and all tumors expressed comparable CAT activity. In contrast, metastasis (as assessed by CAT activity) was markedly inhibited when cell surface u-PA activity was blocked. Levels of CAT activity were reduced by a factor of > 300 in regional lymph nodes, 40-100 in brain tissue, and 10-20 in lung tissue. Metastatic capacity was inhibited similarly when animals were given intermittent intraperitoneal injections of a u-PA/IgG fusion protein capable of displacing u-PA activity from the tumor cell surface. Our results indicate that cell surface u-PA activity is essential to the metastatic process. In addition, the assay system employed in these experiments may be generally useful in testing other therapeutic modalities to limit the spread of primary tumors.
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PMID:Prevention of metastasis by inhibition of the urokinase receptor. 838 64

Tumor cell invasion and metastasis is a complex, multistep process that is postulated to require degradation of extracellular matrix at several steps. Urokinase-type plasminogen activator (uPA) is expressed on the cell surface of B16 murine melanoma cells and is thought to contribute to the pericellular proteolysis necessary for tumor cell migration. In vitro modification of B16 melanoma cell surface uPA activity has been shown to alter the invasive and metastatic potential of these murine melanoma cells in vivo. Plasminogen activator inhibitor-1 (PAI-1), a rapid inhibitor of both uPA and tissue-type plasminogen activator (tPA) is the major physiologic regulator of plasminogen activator activity. To test the role of host PAI-1 in the invasive and metastatic capacity of B16 melanoma cells we analyzed local tumor growth and pulmonary metastasis in transgenic mice engineered to overexpress murine PAI-1 in multiple tissues including lung, and in mice completely deficient in PAI-1. No significant difference in the number of pulmonary metastases was observed after intravenous inoculation of tumor cells into PAI-1-overexpressing and PAI-1-deficient mice when compared with wild-type controls. Similarly, in a spontaneous metastasis model, PAI-1-overexpressing and PAI-1-deficient mice demonstrated no difference in primary tumor size or overall survival. These data demonstrate that wide variations of host PAI-1 expression, from complete absence to marked overexpression, does not significantly influence the metastatic potential of B16 melanoma cells in a murine model.
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PMID:Lack of plasminogen activator inhibitor-1 effect in a transgenic mouse model of metastatic melanoma. 863 41


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