Search PubMed⌕ Search

Biomedical subjects

Z Fuks

Publications and source records attributed to Z Fuks.

At least 181 records · Page 10Linked to original sources
PubMed1987

Role of heparanase in platelet and tumor cell interactions with the subendothelial extracellular matrix.

Dissemination of neoplastic cells within the body involves invasion of blood vessels by tumor cells. Since platelets have been shown to contribute to this process, we studied the interaction in vitro of platelets and malignant cells with the vascular endothelium and its underlying basement membrane-like ECM. A metastatic subline (ESb) of the methylcholanthrene-induced DBA/2 T-lymphoma invaded the vascular endothelium at a higher rate than its parental nonmetastatic (Eb) subline. ESb cells also exhibited a much higher ability to degrade the proteoglycan scaffold of the ECM by means of a specific HS degrading endoglycosidase (heparanase). The interaction of platelets with this ECM was associated with platelet activation, aggregation, and degradation of HS by means of the platelet heparanase. Degradation of ECM-HS was facilitated by proteolytic activity that produced a more accessible substrate for further cleavage by heparanase. A similar enhancement was exerted by plasminogen via the activity of the tumor cells or ECM associated PAs. Heparin and chemically modified heparins that lack anticoagulant activity inhibited degradation of the ECM-HS by heparanase. Interaction of platelets and lymphoma cells with ECM covered with vascular endothelial cells was investigated by SEM and by determination of ECM-HS degradation products. SEM studies demonstrated that platelets may adhere to minor gaps between adjacent endothelial cells and degrade the ECM-HS. Platelets were also shown to recruit lymphoma cells into these interendothelial gaps, suggesting that by binding to ECM and release of heparanase, platelets may play an active role in tumor cell invasion and metastasis. Our observation that nonanticoagulant heparins may interfere with heparanase-mediated degradation of ECM-HS suggests a potential therapeutic use for such heparins in neoplastic disorders.

Animals↗
PubMed1987

Inhibition of heparanase-mediated degradation of extracellular matrix heparan sulfate by non-anticoagulant heparin species.

Incubation of human platelets, human neutrophils, or highly metastatic mouse lymphoma cells with sulfate-labeled extracellular matrix (ECM) results in heparanase-mediated release of labeled heparan sulfate cleavage fragments (0.5 less than Kav less than 0.85 on Sepharose 6B). This degradation was inhibited by native heparin both when brought about by intact cells or their released heparanase activity. Degradation of heparan sulfate in ECM may facilitate invasion of normal and malignant cells through basement membranes. The present study tested the heparanase inhibitory effect of nonanticoagulant species of heparin that might be of potential use in preventing heparanase mediated extravasation of bloodborne cells. For this purpose, we prepared various species of low-sulfated or low-mol-wt heparins, all of which exhibited less than 7% of the anticoagulant activity of native heparin. N-sulfate groups of heparin are necessary for its heparanase inhibitory activity but can be substituted by an acetyl group provided that the O-sulfate groups are retained. O-sulfate groups could be removed provided that the N positions were resulfated. Total desulfation of heparin abolished its heparanase inhibitory activity. Heparan sulfate was a 25-fold less potent heparanase inhibitor than native heparin. Efficiency of low-mol-wt heparins to inhibit degradation of heparan sulfate in ECM decreased with their main molecular size, and a synthetic pentasaccharide, representing the binding site to antithrombin III, was devoid of inhibitory activity. Similar results were obtained with heparanase activities released from platelets, neutrophils, and lymphoma cells. We propose that heparanase inhibiting nonanticoagulant heparins may interfere with dissemination of bloodborne tumor cells and development of experimental autoimmune diseases.

Animals↗
PubMed1986

Different effects of aspirin, dipyridamole and UD-CG 115 on platelet activation in a model of vascular injury: studies with extracellular matrix covered with endothelial cells.

Cultured endothelial cells produce an extracellular matrix (ECM) which activates platelets, similarly to deendothelialized vascular segments. Platelet-rich plasma (PRP) was incubated with endothelial cells cultures seeded in various densities on ECM. The interaction of the platelets with this artificial intima was evaluated by phase microscopy and by thromboxane A2 (TXA2) and prostacyclin (PGI2) measurement. Large platelet aggregates were formed on exposed ECM. Platelets aggregation but not adhesion on the ECM was markedly inhibited by the presence of endothelial cells. Pretreatment of the endothelial cells with 0.1 mM aspirin reduced their PGI2 synthesis and was associated with platelet aggregation on the ECM. 10 microM dipyridamole markedly inhibited platelet activation by ECM when the drug was added to citrated whole blood before PRP preparation. UD-CG 115 which elevates cyclic AMP in cardiac muscle, inhibited platelet aggregation and TXA2 production induced by ECM, in the presence as well as in the absence of endothelial cells, without any effect on endothelial PGI2 production.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Growth of human mammary carcinoma cells from biopsy specimens in serum-free medium on extracellular matrix.

A method developed for the initiation and maintenance in primary culture of human normal mammary epithelial cells was adopted for the growth of epithelial cells from 45 primary human breast tumors. The cells were grown on a naturally produced extracellular matrix (ECM) or on regular tissue culture plastic in a serum-free medium containing growth supplements and high-density lipoprotein (HDL). Successful enzymatic dissociation of the tumor biopsy into organoid structures and cell aggregates was crucial for subsequent cell attachment and growth. Fifty-five percent of the biopsy specimens were successfully dissociated and 87% of these gave rise to actively dividing epithelial cells forming monolayer cultures. In contrast, only 21% of the biopsies which were not optimally dissociated yielded growing cultures. Variations in sample size, duration of enzymatic digestion, and tumor composition affected the outcome of tumor dissociation. Omission of serum from the culture medium prevented the growth of fibroblasts, while plating on ECM greatly improved and in some cases was essential for cell attachment and subsequent outgrowth. The epithelial nature of the cells was verified by their cuboidal and closely apposed morphology and positive staining with antikeratin antibodies. The growth and subculture requirements and the expression of the B38.1 tumor marker were compared in human mammary epithelial cells derived from solid tumors, pleural effusion and normal breast tissue.

Antibodies, Neoplasm↗
PubMed1986

The treatment of single brain metastasis from non-oat cell lung carcinoma. Surgery and radiation versus radiation therapy alone.

Between 1978-1980, 104 patients with single brain metastases (SBM) from non-small cell lung carcinoma (NSCLC) were treated at Memorial Sloan-Kettering Cancer Center (MSKCC). These included 35 patients treated with surgical resection and radiation (S + ERT) and 69 patients treated with conventional external beam radiation therapy alone (ERT). Surgical resection was combined with whole brain (WBRT) and focal radiation in 83% and 17% of patients, respectively. In the ERT group, all patients received WBRT. Both treatment groups were similar with regard to age, sex, stage distribution, location and size of SBM, and time to relapse from initial diagnosis of NSCLC. The histologic examination, however, revealed adenocarcinoma predominating in those patients receiving S + ERT and epidermoid carcinoma in those receiving ERT. Follow-up treatment, symptomatic, and CTT response rates were evaluated. With S + ERT, the overall subjective and objective responses were 80% and 87%, respectively, and with ERT, 83% and 72% (of the 47 patients available for follow-up CT scans), respectively. Survival data indicate a significant advantage of S + ERT over ERT with a median survival of 16 months versus 4 months (P less than 0.0001). Three major factors, however, may have contributed to this difference: (1) patients in the S + ERT group generally received more aggressive initial treatment to the primary disease in the lung (72%) compared to the ERT group (36%); (2) in the S + ERT group, extracranial disease was absent at the time of SBM diagnosis in 49% of the S + ERT group compared to 26% in the ERT group; and (3) distant metastases were present in only 6% of the surgical patients yet, they were present in 49% of those treated with radiation alone. In one subset of patients, however--those with a radically treated primary and no extracranial disease--S + ERT resulted in a median survival of 33 months with 33% of the population still alive with no evidence of disease compared to 12 months and 0%, respectively, with ERT alone. Moreover, intracranial relapse was the cause of death in only one S + ERT patient (9%), yet it accounted for 50% of the ERT deaths. These data suggest that an aggressive approach to SBM in such favorable prognostic patients may indeed improve survival.

Adenocarcinoma↗
PubMed1986

Elevation of erythrocyte zinc- and free protoporphyrins with metastatic spread in cancer patients.

A sensitive fluorometric method for the evaluation of erythrocyte levels of zinc-protoporphyrin (ZPP) and free-protoporphyrin (FPP) in diluted whole blood was used to survey patients with carcinomas in different stages o metastatic dissemination. ZPP levels in patients with primary tumor or with no evidence of metastatic disease were not different from those of normal donors. However, significantly higher ZPP levels were found in patients with carcinomas in correlation with evidence of metastatic disease, irrespective of the histological origin of the tumor. FPP levels were elevated in all stages of malignancy but were found 4 times higher than the normal levels in patients with metastatic malignancies. Similar increases in ZPP and FPP were detected in patients with inflammatory processes, suggesting a common effector of erythropoiesis in these pathological conditions and in metastatic diseases. Simultaneous detection of higher than normal ZPP and FPP levels in the blood of cancer patients may serve as an additional marker of metastatic dissemination in patients without clinical evidence of infectious or autoimmune diseases.

Adult↗
PubMed1986

The potentiation of radiation response on murine tumor by fludarabine phosphate.

Fludarabine phosphate is a synthetic analog of beta-arabinofuranosyl adenine (beta-ara-A), an anti-viral agent. Since beta-ara-A has been shown to be an effective inhibitor of potentially lethal damage (PLD) repair in cell culture system but ineffective in in vivo tumors, we carried out experiments to determine whether fludarabine phosphate which is not inactivated by adenosine deaminase potentiates the radiation effects on in vivo murine tumor. The combined effects of single acute fludarabine phosphate (600 mg/kg) and single dose of X-irradiation (20 Gy) on Meth-A fibrosarcomas in BALB/c mice produced more than 90% tumor control, while the radiation alone resulted in less than 10% tumor control. The radiosensitizing effect by fludarabine phosphate was higher when the drug was administered immediately prior to X-irradiation. The dose modifying factor of fludarabine phosphate is estimated to be 1.6 at 400 mg/kg. Experiments with fractionated irradiation and fludarabine phosphate similarly showed a high rate of tumor control. The present study suggests that inhibitors of PLD repair including several antiviral agents may have potential utility in the treatment of some radioresistant human tumors by radiotherapy.

Animals↗
PubMed1986

Megavoltage radiotherapy using water bolus in the treatment of Kaposi's sarcoma.

Between 1976 and 1983, 28 patients with Kaposi's sarcoma were treated in the Department of Radiation and Clinical Oncology of the Hadassah University Hospital in Jerusalem. Most of the patients (16, i.e. 57%) were Jews of European origin. Eighteen (64.2%) of the patients presented with severe leg edema in addition to multifocal, disseminated skin lesions. Only one patient was free of clinical disease in the lower extremities. Large, ulcerated masses were seen in three patients. The affected limbs were immersed in a water bath and irradiated with two-opposing portals to a total dose of 3000 rads. Total disappearance of the skin lesions was achieved in 89% of the patients, although the limb edema regressed completely in only 56% of the patients.

Adult↗
PubMed1986

Total lymphoid irradiation in refractory systemic lupus erythematosus.

In two patients with systemic lupus erythematosus, conventional therapy was considered to have failed because of persistent disease activity and unacceptable side effects. Both were treated with total lymphoid irradiation without clinical benefit, despite adequate immunosuppression as documented by markedly reduced numbers of circulating T lymphocytes and T-lymphocyte-dependent proliferative responses in vitro. The first patient developed herpes zoster, gram-negative septicemia, neurologic symptoms, and deterioration of lupus nephritis. The second patient developed massive bronchopneumonia, necrotic cutaneous lesions, and progressive nephritis and died 2 weeks after completion of radiotherapy. These observations, although limited to two patients, indicate that total lymphoid irradiation in patients with severe systemic lupus erythematosus should be regarded as strictly experimental.

Adult↗
PubMed1985

Sequential degradation of heparan sulfate in the subendothelial extracellular matrix by highly metastatic lymphoma cells.

A highly metastatic variant (ESb) of a methylcholanthrene-induced T lymphoma elaborates a heparan sulfate (HS) degrading endoglycosidase (heparanase) to a much higher extent than its non-metastatic parental subline (Eb). Whereas a serum-free medium conditioned by either subline contained a trypsin-like serine protease, heparanase activity was detected only in the ESb-conditioned medium (CM). ESb CM was incubated with a naturally produced, sulfate-labelled subendothelial extracellular matrix (ECM) or with a soluble, high-MW labelled proteoglycan first released from the ECM by incubation with Eb CM or with the partially purified ESb protease. Sulfate labelled degradation products were analyzed by gel filtration on Sephrose 6B. The optimal pH for degradation of ECM-bound HS was 6.2 as compared to pH 5.2 for degradation of the soluble proteoglycan. Heparanase-mediated degradation of both ECM-bound and soluble HS was inhibited by heparin. Addition of either trypsin, plasmin or to a lower extent, the purified ESb protease, stimulated between 5- and 20-fold the ESb CM-mediated degradation of ECM-bound HS but had no effect on heparanase-mediated degradation of the soluble proteoglycan. This stimulation was inhibited in the presence of heparin or protease inhibitors. These results indicate that both a protease and heparanase are involved in the ESb-mediated degradation of ECM-bound HS and that one enzyme produces a more accessible substrate for the next enzyme. This sequential cleavage is characteristic of degradation of a multimolecular structure such as the subendothelial ECM and hence cannot be detected in studies with its isolated constituents.

Animals↗
PubMed1985

Correlation of erythrocyte and plasma levels of zinc, copper, and iron with evidence of metastatic spread in cancer patients.

The level of plasma copper (Cu-Pl) and zinc (Zn-Pl) and the level of erythrocyte iron (Fe-RBC), copper (Cu-RBC), and zinc (Zn-RBC) were determined in the blood of 70 normal donors and 138 patients with various solid tumors by diagnostic x-ray spectrometry (DXS), a technique based on x-ray fluorescence spectrometry analysis. There were no significant changes in the mean values of Zn-Pl, Fe-RBC, and Cu-RBC in the patients when compared with those of normal donors. The mean level of Cu-Pl in the normal donors was 1.34 +/- 0.37 micrograms/ml; it was significantly increased in the patients, ranging between 1.47 +/- 0.34 micrograms/ml for patients without evidence of active cancer (NED) and 1.91 +/- 0.76 micrograms/ml for patients with hepatic metastases. The most significant change observed was an increase in the Zn-RBC found in the patients with clinical evidence of metastatic spread. Whereas the Zn-RBC level in the normal donors was 9.85 +/- 1.47 micrograms/g wet weight, and not significantly elevated in the NED patients, it was elevated to values of 11.37 +/- 1.55 micrograms/g (P less than 0.004) for patients with soft tissue and hepatic metastases and was 12.34 +/- 1.65 micrograms/g (P less than 0.001) for patients with bone metastases. The data suggest a clear correlation between Zn-RBC and metastatic spread in nonlymphomatous human cancer.

Bone Neoplasms↗
PubMed1985

Production and characterization of interferon from endothelial cells.

The capacity of cultured bovine aortic, capillary, and corneal endothelial cells as well as of human umbilical cord endothelial cells to produce interferon (IFN) was investigated. The endothelial cells of the two species produced significant amounts of IFN in response to various viruses and poly (I) poly (C). The IFN produced by human umbilical cord endothelial cells was a mixture of alpha- and beta-IFN, as determined by neutralization with antibodies directed against these two types of IFNs as well as by measuring the antiviral activity on heterologous cells. Bovine endothelial cells also produced a mixture of at least two IFN subspecies, one of them labile at pH 2 and active on human cells and the other stable at pH 2 and inactive on human cells.

Animals↗
PubMed1985

Differential structural requirements for the induction of cell attachment, proliferation and differentiation by the extracellular matrix.

The subendothelial extracellular matrix (ECM) mediates the attachment of both human Ewing's sarcoma and colon carcinoma cells. Attachment and flattening of the sarcoma cells was sensitive to heat treatment but not to periodate oxidation of the ECM, whereas the colon carcinoma cells attached and flattened over heated but not periodate-treated ECM. Such differential sensitivity to heat treatment and periodate oxidation was also observed using purified fibronectin and laminin, respectively, but the inhibition of cell attachment was greater than with a similarly treated ECM. It is therefore conceivable that fibronectin and laminin specifically mediate the attachment and flattening of Ewing's sarcoma and colon carcinoma cells to the ECM, but that other constituents may support this attachment either directly or via interaction and stabilization of adhesive glycoproteins in the ECM. The ECM-mediated morphological differentiation of adult rat oligodendrocytes was sensitive to periodate oxidation to a much higher extent than to heat treatment of the ECM. In contrast, both treatments had only a small effect on the ECM-induced proliferation of vascular endothelial cells. These results indicate that different constituents of the ECM may be held responsible for its effects on different parameters of cell behavior, and that various cell types respond differently to a given modification of the ECM.

Animals↗
PubMed1985

Cell interaction with the extracellular matrices produced by endothelial cells and fibroblasts.

The extracellular matrices (ECM) produced by cultured bovine corneal endothelial cells and chick embryo fibroblasts were compared for their induction of cell attachment, proliferation and differentiation. The corneal endothelial ECM (cECM) induced a comparable and rapid attachment and flattening of both human Ewing's sarcoma and colon carcinoma cells which utilize fibronectin and laminin as adhesive glycoproteins, respectively. In contrast, the ECM produced by fibroblasts (fECM) readily supported the attachment and flattening of Ewing's sarcoma cells but had only a small effect on the carcinoma cells. Vascular endothelial cells were stimulated to proliferate by both types of matrices, but to a lesser extent by the fECM. In contrast, the formation of a closely apposed, non-overlapping and contact-inhibited endothelial cell monolayer was only dictated by the cECM. Vascular endothelial cells cultured on fECM grew on top of each other and incorporated [3H]thymidine even late at confluency. Neurite outgrowth (ciliary ganglion cells) and network formation (adult rat oligodendrocytes) were promoted by both types of matrices but in a more consistent manner with the cECM. It is likely that the small amounts of laminin deposited by chick embryo fibroblasts into their ECM are responsible for its efficient induction of neurite outgrowth and for the limited degree of carcinoma cell attachment and flattening. It is thus demonstrated that differences in chemical composition and supramolecular arrangement between cECM and fECM result not only in differences in the attachment, spreading and proliferative responses of cells but also in the expression of their characteristic morphological appearance and differentiated functions.

Animals↗