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)

The plasminogen activators (PAs) are serine proteinases which convert the inactive proenzyme plasminogen into plasmin, a proteinase associated with processes such as fibrinolysis and tissue remodelling. There are two immunologically distinct types of PA: tissue-type (t-PA), the main form involved in thrombolysis, and urokinase-type (u-PA), primarily involved in tissue degradation. Two or possibly more genes encode PA activity, and one locus has been provisionally assigned to chromosome 6 in man. We have isolated cDNA clones which encompass the entire coding sequence of the t-PA gene, and have used these to probe DNA on Southern blots isolated from 18 independent human-rodent somatic cell hybrid lines. The presence of the human gene for t-PA showed complete concordance with human chromosome 8 in the hybrids. In addition, the cDNA clones recognize a restriction fragment length polymorphism, where the two common alleles each have a frequency of approximately 0.5. t-PA and u-PA activities have been found in a wide variety of malignant cells, where they are thought to play a role in metastatic invasion of normal tissue. The results reported here will enable us to investigate whether genetic changes associated with the chromosome encoding t-PA are associated with altered t-PA expression in neoplasia.
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PMID:Assignment of tissue-type plasminogen activator to chromosome 8 in man and identification of a common restriction length polymorphism within the gene. 610 May 60

Bovine capillary endothelial cells have been found to respond to several stimuli by producing increased amounts of plasminogen activator and latent collagenase. These stimulators include the tumor promoter tetradecanoyl phorbol-13-acetate as well as crude preparations from a human hepatoma, bovine retinae, and mouse adipocytes, all of which are known to contain angiogenic factors. Endothelial cells and skin fibroblasts do not respond to these stimuli in the same way, indicating a specificity of the response. In addition, inhibitors of plasmin and vertebrate collagenase have been isolated from cartilage, a tissue resistant to neovascularization. We have proposed that these specific protease inhibitors confer on cartilage its antiangiogenic properties.
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PMID:The involvement of proteases and protease inhibitors in neovascularization. 617 34

Hemostatic function of 129 patients with cancer of the digestive system was studied on the clinical point of view. Activator (A) and inhibitor (I) of fibrinolysis of 94 cancer tissues were determined by Malone's method. The following results were obtained: Latent DIC state was observed in the patients with advanced stage. Great majority of the patients with PT less than or equal to 85%, antithrombin III (AT III) less than or equal to 25 mg/dl, FDP greater than or equal to 5 micrograms/ml, alpha 1 antitrypsin (alpha 1 AT) greater than or equal to 340 mg/dl, plasminogen (plg) less than or equal to 10 mg/dl and alpha 2 plasmin inhibitor (alpha 2 PI) less than or equal to 80%, were eligible only for non-curative operation on the preoperative evaluations. Persistent decreases in PT, AT III, plg and alpha 2 PI mean poor prognosis, which were seen within about 6 months prior to death. In gastric cancer patients, these abnormalities showed correlations with serum choline-esterase, albumin and ferritin, and post-operative changes of these parameters suggested the recurrence. There were I activities in the cancer tissues which were scarcely detected in the normal tissues. Some differences in A/I ratios were observed on types of organs involved, histological types and differentiative degrees. There were no correlations between the hemostatic state and A/I ratios. These results indicate the clinical usefulness of the hemostatic functions of the cancer patients and the fibrinolytic properties of the cancer tissues, and also suggested that tumor bearing state, liver function and non-specific stimulating mechanisms participate in the appearance of the abnormalities.
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PMID:[Hemostatic abnormalities of the patients with cancer. Clinical significance and fibrinolytic properties of the cancer tissues]. 620 15

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

Tumor-promoting phorbol esters have been reported to greatly increase plasminogen activator (PA) activity produced in numerous cell types. Many of these studies have employed a widely used fibrinolysis assay for PA activity that involves large-scale dilution of cell lysates or conditioned medium (CM) into buffer containing plasminogen and the plasmin substrate 125I-fibrin. This assay indicates that phorbol ester and the mitogens epidermal growth factor (EGF) and thrombin all stimulate secretion of PA activity in our human foreskin fibroblast cultures. However, these effects are not observed in a modified fibrinolysis assay employing undiluted conditioned culture medium unless the medium is first treated at pH 3, which inactivates the secreted protease inhibitor, protease nexin (PN). Moreover, a direct assay for plasminogen activator activity based on cleavage of 125I-plasminogen indicates that conditioned culture medium contains little if any active plasminogen activator either before or after treatment of the cultures with phorbol ester or EGF. Phorbol ester and mitogens do stimulate secretion of (a) an inactive PA that can be activated by plasmin and (b) PN, which inhibits both the activated form of the PA and plasmin. Secretions of the inactive PA and PN are further correlated in that release of both is stimulated most by phorbol ester, somewhat less by EGF, and least by thrombin. Significantly, these effects are not accompanied by increases in total protein secretion. We propose that fibroblasts secrete PA in an inactive form in the presence of PN to confine PA activity to an as yet undefined location or event.
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PMID:Phorbol ester and mitogens stimulate human fibroblast secretions of plasmin-activatable plasminogen activator and protease nexin, an antiactivator/antiplasmin. 622

Radiomodifying action of fibrinolysin was studied during radiation treatment in experimental transplanted tumors. It has been established that the application of fibrinolysin prior to radiation increases the inhibition of the growth rate of Pliss lymphosarcoma and Sarcoma 45, as evidenced by the decrease of the tumor volume, the increase of the dose change factor and the animals survival.
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PMID:Enhancement of the radiation effect by fibrinolysin and quantitative pattern of the change of tumor radiosensitivity. 623 71

We carried on an investigation of proteases associated to human tumors by immunohistological techniques. Most of our work dealt with the plasmin system (plasminogen, its two activators and the two plasmin inhibitors, a 2 antiplasmin and a 2 macroglobulin). We found an antigen reacting with anti plasminogen serum in all the 30 colorectal adenocarcinomas we studied by immunofluorescence. This antigen was mainly plasminogen, as we could not detect active plasmin by a histochemical technique on sections of the same tumors. However it is likely that plasminogen present at the surface of tumor cells and on the contour of tumor foci, mainly in invasive areas, can be converted into plasmin, which in turn plays an important role in the degradation of basement membrane antigens. This makes easier tumor invasiveness and release of isolated tumor cells, ready for metastasizing. Plasmin action is likely of short duration and within short range, as this enzyme is rapidly neutralized by its inhibitors, both present at high concentration in the peritumoral stroma. Cathepsin B was characterized by immunoperoxidase method in many colorectal tumors. However our results are preliminary, so we cannot draw any conclusion on the role of this enzyme in tumor invasiveness.
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PMID:Proteases in human tumors. 624 Sep 98

Many types of malignant cells and human tumors display increased concentrations of the protease plasminogen activator that converts plasminogen to the highly active protease, plasmin. Because plasmin rapidly cleaves various low molecular weight compounds coupled to appropriate peptide specifiers, we hypothesized that coupling of such peptide specifiers to anticancer drugs might create "prodrugs" which would be locally activated by tumor-associated plasmin and consequently would be less toxic to normal cells. To provide an initial test of this concept we have synthesized peptidyl prodrugs of the structure D-Val-Leu-Lys-X in which the peptidyl portion has been designed to allow the prodrug to serve as an excellent plasmin substrate and X is an anticancer drug-either the glutamine analog (alphaS,5S) alpha-amino-3-chloro-4,5-dihydro-5-isoxazole-acetic acid (AT-125) or the alkylating agent N,N-bis(2-chloroethyl)-p-phenylenediamine (phenylenediamine mustard). Treatment of these prodrugs with plasmin generated the free peptide and the free drug, demonstrating that these prodrugs are plasmin substrates. The prodrugs and free drugs were tested in an in vitro system against either normal chicken embryo fibroblasts, which display a low level of plasminogen activator, or their virally transformed counterparts, which produce high levels of plasminogen activator. In each case the peptidyl prodrugs displayed at least a 5-fold increase in selectivity for the transformed cells compared to the free drug. The greater selectivity of action of the peptidyl prodrugs against transformed cell cultures suggests that these or similar prodrugs that are substrates for tumor-associated proteases may show increased therapeutic effectiveness in the treatment of tumors that produce sufficiently increased amounts of plasminogen activator.
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PMID:Protease-activated "prodrugs" for cancer chemotherapy. 624 27

We have synthesized peptidyl prodrugs of doxorubicin (Dox) designed to be selective substrates of plasmin. Such prodrugs might be locally activated by the elevated levels of plasmin produced near many solid tumors under the action of tumor-associated plasminogen activators. One such prodrug, 3'-(D-Val-Leu-Lys)-Dox, was obtained via a mixed-anhydride coupling with isobutyl chloroformate between the protected peptide Fmoc-D-Val-Leu-N epsilon-Fmoc-Lys-OH and doxorubicin, followed by removal of the Fmoc groups with anhydrous ammonia. Compared to doxorubicin, the prodrug showed about a 7-fold improved selective cytotoxicity against chicken embryo fibroblasts transformed with the Rous sarcoma virus (which produce high levels of plasminogen activator) compared to normal cells (which produce low levels of plasminogen activator). However, the prodrug was a very poor plasmin substrate, and although in vivo tests against the murine B16 melanoma showed that the prodrug was active, the maximum T/C obtained was less than that achieved by doxorubicin even at 25 times the molar concentration of prodrug. Qualitatively similar results were obtained for a far more hydrophobic prodrug, 3'-(Boc-Val-Leu-Lys)-Dox. These results demonstrate that peptidyl prodrugs of doxorubicin designed as plasmin substrates are more selective anticancer agents in vitro than doxorubicin itself but that the bulky anthracycline moiety probably prevents efficient plasmin-catalyzed conversion to the active parent drug, so that, in their present form, these drugs are not potent enough to allow a determination as to whether or not they are more selective in vivo.
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PMID:Plasmin-activated prodrugs for cancer chemotherapy. 2. Synthesis and biological activity of peptidyl derivatives of doxorubicin. 630 53

Plasminogen activators are membrane-associated, arginine-specific serine proteases which convert the inactive plasma zymogen plasminogen to plasmin, an active, broad-spectrum serine protease. Plasmin, the major fibrinolytic enzyme in blood, also participates in a number of physiologic functions involving protein processing and tissue remodelling, and may play an important role in tumor invasion and metastasis. In HTC rat hepatoma cells in tissue culture, glucocorticoids rapidly decrease plasminogen activator (PA) activity. We have shown that this decrease is mediated by induction of a soluble inhibitor of PA activity rather than modulation of the amount of PA. The hormonally-induced inhibitor is a cellular product which specifically inhibits PA but not plasmin. We have isolated variant lines of HTC cells which are selectively resistant to the glucocorticoid inhibition of PA but retain other glucocorticoid responses. These variants lack the hormonally-induced inhibitor; PA from these variants is fully sensitive to inhibition by inhibitor from steroid-treated wild-type cells. Cyclic nucleotides dramatically stimulate PA activity in HTC cells in a time- and concentration-dependent manner. Paradoxically, glucocorticoids further enhance this stimulation. Thus glucocorticoids exert two separate and opposite effects on PA activity. The availability of glucocorticoid-resistant variant cell lines, together with the unique regulatory interactions of steroids and cyclic nucleotides, make HTC cells a useful experimental system in which to study the multihormonal regulation of plasminogen activator.
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PMID:Hormonal regulation of plasminogen activator in rat hepatoma cells. 631 82


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