Polycythemia as a result of ectopic erythropoietin production in benign cystic leiomyoma of uterus.
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Adult↗
Biomedical subjects
Y Zimra
Publications and source records attributed to Y Zimra.
All three receptors for vascular endothelial growth factor (VEGF) are expressed on B-chronic lymphocytic leukemia (CLL) cells.
B-chronic lymphocytic leukemia (B-CLL) cells have a long survival owing to an alteration in the normal pathways of apoptosis. CLL cells have been found to produce and secrete vascular endothelial growth factor (VEGF). In addition to its major role in angiogenesis, VEGF affects cell survival by interfering with apoptosis. The aim of the present study was to investigate the expression of the VEGF receptors VEGFR-1, VEGFR-2, and VEGFR-3 on B-CLL cells, singly and combined. B-CLL cells were isolated from peripheral blood drawn from patients with CLL. Total VEGF receptor, examined in 13 samples by flow cytometry was present in all cases with mean CD19+/VEGF+ expression of 76% (range 52-92%). Specific receptor expression, examined in 27 samples by immunocytochemical methods, was positive for VEGFR-1 in all 27 patients and for VEGFR-2 and VEGFR-3 in 26 (96%). These findings suggest that the VEGF transduction pathway may be very active in CLL cells, and both its paracrine and autocrine pathways may contribute to their enhanced survival.
Aged↗
Expression of basic fibroblast growth factor is associated with poor outcome in non-Hodgkin's lymphoma.
It is now clear that angiogenesis and angiogenesis factors are important in the pathogenesis of haematological malignancies. High pretreatment levels of serum basic fibroblast growth factor have been shown to be associated with poor prognosis in patients with non-Hodgkin's lymphoma. The aim of this study was to evaluate whether non-Hodgkin's lymphoma cells express basic fibroblast growth factor and/or its receptor (fibroblast growth factor receptor-1) and whether basic fibroblast growth factor expression correlates with basic fibroblast growth factor serum levels, intratumoral microvessel density, and patient outcome. We measured basic fibroblast growth factor by enzyme-linked immunosorbent assay in sera taken from 58 patients with non-Hodgkin's lymphoma before treatment and in 19 of them also after treatment. Pathological specimens at diagnosis were evaluated by immunohistochemistry staining using polyoclonal antibody against factor-VIII-related antigen, basic fibroblast growth factor and fibroblast growth factor receptor-1 to determine the expression of the microvessel count and basic fibroblast growth factor and fibroblast growth factor receptor-1. The lymphoma specimens demonstrated positive staining for basic fibroblast growth factor (in 23%) and fibroblast growth factor receptor-1 (in 58.5%). The patients who expressed basic fibroblast growth factor had a significantly worse progression-free and overall survival than those who did not (P=0.003 and P=0.03 respectively), while patients expressing fibroblast growth factor receptor-1 were less likely to achieve complete remission than those lacking the receptor (33% vs 65%, P=0.047). There was no correlation of basic fibroblast growth factor staining with either serum basic fibroblast growth factor levels or microvessel count. Basic fibroblast growth factor serum levels did not change significantly after treatment These results suggest that non-Hodgkin's lymphoma specimens express basic fibroblast growth factor and its receptor (fibroblast growth factor receptor-1) and this expression is associated with poor patient outcome.
Adult↗
Doxorubicin and a butyric acid derivative effectively reduce levels of BCL-2 protein in the cells of chronic lymphocytic leukemia patient.
B-chronic lymphocytic leukemia (B-CLL) is a disease caused primarily by defects in the apoptosis mechanism. AN-9, a butyric acid (BA) derivative, is a potent differentiating and an anti-cancer drug that induces apoptosis in HL-60 cells. Herein we show the affect of AN-9, alone and in combination with doxorubicin, on cell cultures from B-CLL patients. Cells from 17 patients were cultured and tested for viability, apoptosis, bcl-2 and bax protein expression. Exposure of B-CLL cell cultures to AN-9 was accompanied by apoptosis and a marked viability loss (up to 46%, p=0.0017). AN-9 reduced up to 51% (p=0.0017) the levels of bcl-2 in 57% of the cultures that express bcl-2. The combination of low concentrations of AN-9 and doxorubicin more than additively enhanced apoptosis and reduced bcl-2 levels in B-CLL cultures which were resistant to AN-9. AN-9 enhanced bax expression up to 58%(p=0.008) in cultures from 53% of the patients, but had no effect on bax levels when combined with doxorubicin. In conclusion, AN-9 alone reduced bcl-2 and enhanced bax expression in cultures from B-CLL patients, and the reduction of bcl-2 levels in combination with doxorubicin was greater than additive. These results may be beneficial in possible future combination therapy with AN-9 in B-CLL.
Antineoplastic Combined Chemotherapy Protocols↗
Bcl-2 expression correlates positively with serum basic fibroblast growth factor (bFGF) and negatively with cellular vascular endothelial growth factor (VEGF) in patients with chronic lymphocytic leukaemia.
A large proportion of B-chronic lymphocytic leukaemia (B-CLL) cells express the anti-apoptotic protein Bcl-2. Basic fibroblast growth factor (bFGF) has been shown to upregulate the expression of Bcl-2 in B-CLL cell lines. Vascular endothelial growth factor (VEGF) has been shown to enhance the survival of endothelial cells by upregulating the expression of Bcl-2. In the present study, we measured serum and cellular levels of bFGF and VEGF in 85 patients with CLL using a commercial quantitative sandwich enzyme immunoassay technique. Levels of Bcl-2 were also assayed concomitantly using Western blot analysis. The mean serum level of bFGF was 53.4 pg/ml (range 0-589) and that of VEGF 459.2 pg/ml (range 33-1793). The mean cellular level of bFGF was 158.3 pg/2 x 105 cells (range 0.8-841) and VEGF, 42.4 pg/2 x 105 cells (range 0-244). A high correlation was found between serum and cellular bFGF levels (P < 0.001), but not between the corresponding VEGF levels. Twenty-nine of 69 patients (42%) evaluated for Bcl-2 level, expressed it. The Bcl-2 level was positively correlated with the serum bFGF level (P = 0.007). However, surprisingly there was a negative correlation between Bcl-2 expression and intracellular VEGF level (P = 0.003). A positive correlation was also found between serum bFGF and disease follow-up time and log white blood cell count. These findings indicate that in CLL there is a correlation between angiogenesis-related factors and apoptosis-related protein expression, and elevated bFGF levels may account for the elevated Bcl-2 levels.
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Microvessel density in chemosensitive and chemoresistant diffuse large B-cell lymphomas.
Preliminary reports involving a number of different kinds of tumors have indicated that microvessel quantification may be useful in predicting disease outcome. The aim of this study was to examine the relationship between microvessel density (MVD) as a parameter of tumor angiogenesis and the response to chemotherapy in diffuse large B-cell (DLBC) lymphomas. A total of 36 DLBC lymphoma patients were evaluated, 23 of them with a chemosensitive; responsive disease (median survival 8y) and 13 with a chemoresistant, refractory disease (median survival 8 months). Microvessel quantification was performed by immunohistochemical staining, using monoclonal antibodies against factor VIII related antigen (F8RA) and against platelet/endothelial cell adhesion molecule-CD31. We found that F8RA stained a significantly higher number of blood vessels (about 2.5 times more) than CD-31; 7 samples were not stained with CD-31 but were positive for F8RA. There was no significant difference between the density of microvessel staining of the two groups. In the chemosensitive DLBC lymphomas positive for F8RA, the mean number of microvessels stained was 54.5 +/- 36.1 per microscopic field (200x) examined (range 6-149) whereas in the chemoresistant group the corresponding mean number was 43.1 +/- 25.5 (range 11-94). F8RA appears to be more sensitive for staining DLBC lymphomas microvessels than CD-31. Our data demonstrate that there is no correlation between tumor MVD and response to chemotherapy in patients with DLBC lymphomas.
Adult↗
Uptake of pivaloyloxymethyl butyrate into leukemic cells and its intracellular esterase-catalyzed hydrolysis.
UNLABELLED: Pivaloyloxymethyl butyrate (AN-9), a butyric acid (BA) prodrug, exhibited low toxicity and significant anticancer activity in vitro and in vivo. The purpose of this study was to elucidate the basis for AN-9 increased anticancer activity compared to BA, by studying the uptake of BA and AN-9 into the cells. METHODS: The uptake rate and level of [14C]-AN-9 and [14C]-BA, labeled on the carboxylic moiety of BA, into HL-60 and MEL leukemic cell lines was measured. The cells were filtered and the retained radioactivity was determined. The dependence of the uptake on the activity of cellular esterases and membrane fluidity was investigated. RESULTS: The uptake level in cells incubated with [14C]-AN-9 increased rapidly, peaked after 30 min in MEL and 1 h in HL-60 cells, and declined thereafter. This decline could be attributed to the hydrolysis of AN-9 by cellular esterases and catabolism of the released BA to CO2. In cells pretreated with an esterase inhibitor and incubated with [14C]-AN-9, the reduction of radioactivity was less precipitous. In cells exposed to [14C]-BA, the intracellular radioactivity level was low and unaffected by treatment with an esterase inhibitor. The uptake of [14C]-AN-9 decreased significantly at 4 degrees C compared to that at 37 degrees C. CONCLUSION: The higher potency of AN-9 compared to BA could be at least partially attributed to the more rapid uptake of the lipophilic AN-9 and the release of BA in the cells.
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Expression of bcl-2 and bax in cells isolated from B-chronic lymphocytic leukemia patients at different stages of the disease.
B-Chronic lymphocytic leukemia (B-CLL) is an example of a human malignancy caused by alterations in the pathways of programmed cell death. In this disease the anti-apoptotic protein, bcl-2, is overexpressed and may lead to the prolonged survival of a malignant CLL clone. In the present study we examined the expression of bcl-2 and bax, which has an antagonistic role against the function of bcl-2, in cells from CLL patients at different stages of the disease, by immunoblot analysis. A direct association between the stage of the disease and the level of bcl-2 in the patients' cells was observed. At stages A and B, 33% and 29% of patients, respectively, expressed high levels of bcl-2, as opposed to 80% of patients at stage C (p= 0.019). Bax level was not significantly associated with the stage of the disease, although patients at stage C had higher levels of bax. In this study we found a trend of association between bcl-2 and bax levels. Analysis including all patients revealed that 65% of the patients who expressed high levels of bcl-2 had high levels of bax (p = 0.058). Of patients in stage C, 45% expressed high levels of both bcl-2 and bax while 50% and 42% of patients at stages A and B had low levels of both proteins.
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Bcl-2, Bcl-X, Bax, and Bak expression in short- and long-lived patients with diffuse large B-cell lymphomas.
Long-term cure is now possible for approximately 50% of all patients with aggressive non-Hodgkin's lymphoma (NHL). Apoptosis-related proteins play an important role in the chemosensitivity or chemoresistance of tumors. We examined the role of Bcl-2 family proteins in aggressive NHL. We retrospectively selected two groups of patients by clinical outcome: 24 patients with chemoresponsive disease and long survival (median, 88 months); and 20 patients with chemoresistant disease and short survival (median, 8 months). The expression of the apoptosis-regulating proteins, Bcl-2, Bcl-X, Bax, and Bak, in the initial biopsy samples was examined with immunohistochemical methods. Specimens containing >10% immunostained tumor cells were considered immunopositive. An inverse association was found between length of patient survival and expression of Bcl-2, Bcl-X, and Bax. Bcl-2 was expressed in 75% of short-lived patients but in only 42% of the long-lived ones (P = 0.026). Bcl-X expression was also higher in the short-lived patients (40% versus 12.5%; P = 0.036). Unexpectedly, Bax expression was strongly associated with short survival (60% versus 21%; P = 0.008). Several combinations of protein expression, i.e., Bcl-2 with Bax, Bcl-2 with Bcl-X, and Bcl-X with Bax, were different between the groups: a positive expression of these proteins was found in the short-lived patients. Furthermore, a strong association was found between the expression of Bcl-2 and Bcl-X, suggesting that Bcl-X potentiates rather than replaces the effect of Bcl-2 in NHL. In diffuse large B-cell NHL, Bcl-2, Bcl-X, and Bax expression alone or in combination is associated with chemoresistance and shortterm survival.
Adult↗
Butyric acid and pivaloyloxymethyl butyrate, AN-9, a novel butyric acid derivative, induce apoptosis in HL-60 cells.
A novel butyric acid derivative, pivaloyloxymethyl butyrate, AN-9, was previously shown to be a potent differentiating agent. AN-9 exerts a significant anticancer activity in vitro and in vivo. In all the activities examined, AN-9 was more potent than butyric acid. Here we show that AN-9 and butyric acid induce cell death by apoptosis. Exposure of HL-60 cells to butyric acid and AN-9 decreased cell numbers and induced cell differentiation and the appearance of typical apoptotic features. Induction of apoptosis and/or differentiation by AN-9 and butyric acid was dependent on the concentration and the time of exposure to the drugs. The advantage of AN-9 over butyric acid was further confirmed. Apoptosis induced by AN-9 occurred after a shorter exposure and at lower drug concentrations than that induced by butyric acid. Apoptosis by AN-9 was accompanied by reduction in Bcl-2 expression. Preincubation with antioxidants did not protect HL-60 cells from apoptosis induced by AN-9. HL-60 cells that were induced to differentiate by preincubation with retinoic acid or low AN-9 concentrations were more resistant to apoptosis, induced later by high concentrations of AN-9, than were undifferentiated cells.
Antineoplastic Agents↗