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Biomedical subjects

U M Schrell

Publications and source records attributed to U M Schrell.

16 recordsLinked to original sources
PubMed1998

Formation of autocrine loops in human cerebral meningioma tissue by leukemia inhibitor factor, interleukin-6, and oncostatin M: inhibition of meningioma cell growth in vitro by recombinant oncostatin M.

OBJECT: It has been demonstrated that growth of cerebral meningiomas found in humans is controlled by a variety of factors, including growth factors, aminergic agents, neuropeptides, and steroids. To further our knowledge of this process, the authors investigated the presence and function of the cytokines leukemia inhibitory factor (LIF), interleukin-6 (IL-6), and oncostatin M (OSM) on meningioma cell proliferation. METHODS: Active transcription of LIF, IL-6, and OSM, their related receptors (LIF-R, IL-6-R, and gp130), and the consecutive signal-transducing molecules (STAT 1, STAT 3, and STAT 5a) were analyzed in reverse transcriptase-polymerase chain reaction experiments. The presence of endogenous LIF, IL-6, and OSM proteins was demonstrated in the supernatant of cultured meningioma cells using the enzyme-linked immunosorbent assay and Western blot experiments, thus indicating an autocrine signaling pathway for all three cytokines. The biological function of all three cytokines was evaluated by studying their effects on meningioma cell growth. Recombinant LIF and IL-6 showed no significant growth modulating effects; however, recombinant OSM decreased meningioma cell growth by 66%. The antiproliferative potency of OSM was demonstrated by cell count experiments, the [3H]thymidine incorporation assay, and cell cycle analysis. CONCLUSIONS: These in vitro data support the concept that growth of meningioma cells may be modulated by cytokines, and they also indicate that recombinant OSM may be one future candidate for use in the adjuvant treatment of inoperable and recurrent meningiomas.

Acute-Phase Proteins↗
PubMed1997

Hydroxyurea for treatment of unresectable and recurrent meningiomas. II. Decrease in the size of meningiomas in patients treated with hydroxyurea.

In this paper the authors present the first evidence that meningiomas respond to treatment with hydroxyurea. Hydroxyurea was administered as an adjunct chemotherapeutic treatment in patients with recurrent and unresectable meningiomas. Hydroxyurea was used because experimental data demonstrated that it inhibits growth of cultured human meningioma cells and meningioma transplants in nude mice by inducing apoptosis. The authors therefore treated four selected patients with hydroxyurea. All patients had undergone multiple gross resections and all except one received radiotherapy. Three patients with recurrent Grade I meningiomas assessed according to World Health Organization (WHO) guidelines received hydroxyurea because of an increased tumor growth rate, documented by magnetic resonance (MR) imaging, within a 6- or 12-month interval. A fourth patient with a malignant meningioma (WHO Grade III) began a course of treatment with hydroxyurea immediately after his sixth palliative operation without waiting for another relapse to be demonstrated on MR imaging. Because of their location and invasive growth behavior none of the meningiomas could have been removed completely by surgical intervention. All patients received hydroxyurea at a dosage level of 1000 to 1500 mg/day (approximately 20 mg/kg/day). In a man with a large sphenoid wing meningioma invading the right cavernous sinus and the temporal base, the intracranial tumor mass was reduced by 60% during 6 months of treatment. A woman with a large ball-shaped meningioma of the right sphenoid wing invading the cavernous sinus exhibited a 74% decrease of the initial tumor volume in 10 months of treatment with oral hydroxyurea. Serial MR images obtained monthly revealed that the process of size reduction was continuous and proportionate. The shrinkage of the tumor was accompanied by a complete remission of symptomatic trigeminal neuralgia after 2 months and by improved abducent paresis after 5 months. The third patient had a slowly growing meningioma that exhibited a 15% reduction in mass when reassessed after 5 months of hydroxyurea treatment. The fourth patient with the malignant meningioma in the left cerebellopontine angle has had no recurrence for 24 months. Long-term treatment with hydroxyurea may result in full remission of tumors in meningioma patients. The preliminary data indicate that hydroxyurea provides true medical treatment in patients with unresectable and recurrent meningiomas, replacing palliative surgery and radiotherapy in the management of this disease.

Adult↗
PubMed1997

Hydroxyurea for treatment of unresectable and recurrent meningiomas. I. Inhibition of primary human meningioma cells in culture and in meningioma transplants by induction of the apoptotic pathway.

Meningiomas, which invade intracranial bone structures and the adjacent connective tissue, are frequently unresectable because of their aggressive and recalcitrant growth behavior. They have a high recurrence rate, and in approximately 10% of these tumors there is an increased risk of malignancy. Significant morbidity and mortality rates associated with recurrent meningiomas demand nonsurgical approaches. To date, adjuvant hormonal treatment has not proven beneficial. The anticancer drug hydroxyurea was therefore tested for its potential use in the treatment of meningiomas. Early-passaged cell cultures were established from 20 different meningiomas. The addition of 5 x 10(-4) and 10(-3) M hydroxyurea over a period of 5 to 9 days resulted in a remarkable decrease in cell proliferation and even blocked tumor cell growth when compared with untreated cells. A significant arrest of meningioma cell growth in the S phase of the cell cycle was revealed on DNA flow cytometry. Electron micrographs of hydroxyurea-treated tumor cells showed ultrastructural features consistent with apoptosis, and light microscopy demonstrated DNA fragmentation by in situ DNA strand break labeling. Short-term treatment of meningioma cell cultures with hydroxyurea for 24 to 48 hours resulted in discrete oligonucleosomal fragments (DNA ladder), another characteristic sign of apoptosis. In addition to the in vitro studies, tissue from five different meningiomas was transplanted into nude mice followed by treatment with 0.5 mg/g body weight hydroxyurea over 15 days. In situ DNA strand break labeling demonstrated DNA fragmentation in distinct regions with different tumor cell densities in all hydroxyurea-treated meningioma transplants. These data provide evidence that hydroxyurea is a powerful inhibitor of meningioma cell growth, most likely by causing apoptosis in the tumor cells. Thus, hydroxyurea may be a suitable chemotherapeutic agent for the long-term treatment of unresectable or semi- to malignant meningiomas, or for preventing recurrent growth of meningiomas after resection.

Animals↗
PubMed1996

Hormonal dependency of cerebral meningiomas.

Though meningiomas are benign intracranial tumors, a minor group invades the skull base and the connective tissue of the sinus cavernous inducing neurological deficits. These patients can not be cured by surgical treatment. Therefore, the development of an adjuvant medical therapy has been the goal during the last decade. We report here on different medical concepts which are based on steroids, amines, growth factor antagonists and cytokines. In addition, our data give evidence that the growth of intracranial meningiomas is under multifactorial proliferative control.

Brain↗
PubMed1996

Dopamine D1, dopamine D2, and prolactin receptor messenger ribonucleic acid expression by the polymerase chain reaction in human meningiomas.

Previous studies have suggested the presence of high-affinity dopamine D1 receptors and prolactin receptors in human cerebral meningiomas. In this study, using the polymerase chain reaction, we report the presence of the messenger ribonucleic acid (mRNA) for the dopamine D1 and D2 receptors and the prolactin receptor in meningioma tissue specimens and cell cultures derived from meningioma tissue. Dopamine D1 receptor mRNA was present in a majority of female tissue specimens and in all male tissue specimens. D2 receptor mRNA was detected in all specimens examined. Prolactin receptor mRNA was present in a little more than half of the female and male meningioma tumor specimens. The polymerase chain reaction products were directly sequenced to confirm the identity of these receptors in meningiomas and cell cultures. Ligand binding studies confirmed the presence of the dopamine D1 receptor in meningioma tissue specimens. In contrast, receptor studies with the dopamine D2 ligand [125I]4-iodospiperone failed to detect D2 binding in meningioma membrane preparations. These results suggest the existence of active dopamine D1 receptors in cerebral meningiomas.

Adult↗
PubMed1995

Inhibition of proliferation of human cerebral meningioma cells by suramin: effects on cell growth, cell cycle phases, extracellular growth factors, and PDGF-BB autocrine growth loop.

The growth of human cerebral meningiomas depends on various growth factors, including epidermal growth factor (EGF), transforming growth factor (TGF)-alpha and TGF-beta, platelet-derived growth factor (PDGF)-BB, insulin-like growth factor (IGF)-I and IGF-II, and acidic and basic fibroblast growth factors. The latter three have been shown to form autocrine loops that are thought to be a major component of uncontrolled growth in meningioma tissue. Suramin is known to prevent binding of a variety of growth factors to their receptors in mammalian tissue, thus abolishing para- and/or autocrine-mediated cell growth. The authors therefore tested the effect of suramin on the proliferation of cultured human meningioma cells. Suramin (10(-5) to 10(-4) M) significantly inhibited the growth of meningioma cells in culture. The maximum effect observed was with the higher dose (10(-4) M), which resulted in a 40% to 70% reduction in cellular proliferation. This effect was observed in all 15 tumor samples studied and was confirmed by [3H]thymidine uptake. In studies using DNA flow cytometry, suramin inhibited meningioma cell proliferation in five tumor samples by arresting cells in the S and G2/M phases of the cell cycle. Growth factor (EGF, IGF-I, and PDGF-BB)-induced cell proliferation was completely abolished in five tumor samples when 10(-4) M suramin was applied to meningioma cells. Western blot analysis of three tumor samples showed that the intracellular PDGF-BB content of meningioma cells was significantly reduced after treating the cells with 10(-4) M suramin. Binding of iodinated growth factors (that is, [125I]EGF, [125I]IGF-I, and [125I]PDGF-BB) to their receptor sites was prevented by suramin in a dose-dependent manner in 10 meningioma membrane fractions. Lowering of the intracellular PDGF content and prevention of extracellular growth factor receptor binding demonstrates that suramin disrupts autocrine loops and paracrine growth stimulation in meningioma tissue. These data provide evidence that growth of cerebral meningiomas in culture is strongly inhibited by suramin at a concentration of 10(-4) M. Suramin acts as a scavenger neutralizing exogenous growth factors; thus it can interrupt autocrine loops and paracrine stimulation of human meningioma cell growth. The evidence favors suramin as a therapeutic option for controlling meningioma proliferation in patients with inoperable and recurrent high-grade meningiomas.

Blotting, Western↗
PubMed1994

Meningiomas and neurofibromatosis for the oncologist.

The goal of this review is to understand meningioma, one of the most frequent primary intracranial tumors, from an oncologic and neurosurgical point of view. The epidemiology, pathogenesis, cytogenetics, and molecular genetics are presented. The operative therapeutic possibilities, the recurrence rates in relation to the intracranial tumor localization, and the place of adjunctive therapies is discussed. Although the emphasis of this review is on developments in the past year, some historical references are provided.

Growth Substances↗
PubMed1992

Presence of dopamine D1 receptors and absence of dopamine D2 receptors in human cerebral meningioma tissue.

Preliminary studies have shown that the dopamine D1 receptor is expressed in cerebral meningioma tissue. The current study presents evidence that the iodinated dopamine D1 antagonist [125I]SCH-23982 bound to dopamine binding sites in 33 of the 45 human cerebral meningiomas examined for this. Saturation curves and the linearity of the Scatchard analysis indicate that [125]SCH-23982 binds to a homogeneous population of binding sites. Competition curves reveal the presence of a dopamine D1 receptor by rank order of various dopaminergic and nondopaminergic antagonists ((+)-SCH-23390 greater than (+/-)-SKF-83566 greater than (cis)-flupentixol greater than (+)-butaclamol greater than chlorpromazine greater than 1-sulpiride greater than mianserin greater than (-)-butaclamol). Stereoselectivity was evaluated by (+)- and (-)-butaclamol. The mean (+/- standard deviation) dissociation rate constant was 369 +/- 196 pM with a density of 31.9 +/- 12.5 fmol/mg membrane protein among 33 meningiomas. The dopamine D2 receptor was not present in the 30 meningiomas examined for this. These findings indicate that the dopamine D1 receptor identified is expressed alone and is therefore regulated independent of a D2 receptor in cerebral meningioma tissue. Although the function of the dopamine D1 receptor in cerebral meningiomas has not so far been defined, previous studies have suggested that the D1 receptor might be involved in the control of proliferative growth of meningiomatous tissue.

Adult↗
PubMed1991

Autocrine control of human meningioma proliferation: secretion of platelet-derived growth-factor-like molecules.

We have used cell-culture techniques to investigate growth-factor production by human meningioma cells. Meningioma tissue was dispersed with collagenase and the cells grown to high density in tissue-culture flasks. The cultures were used to generate conditioned medium (MEN-CM), which was used to cultivate IMR32 cells (a human neuroblastoma line) and freshly dispersed primary meningioma cells. MEN-CM profoundly stimulated the in vitro growth of both IMR32 and meningioma cells. In addition, H3-thymidine uptake by cultured meningioma cells was increased in a dose-dependent manner by varying concentrations of MEN-CM. A neutralizing anti-body against platelet-derived growth factor (PDGF) completely abolished the stimulatory effects of MEN-CM, whereas an antibody against TGF-alpha was without effect. The mitogenic activity of MEN-CM, as assayed by promotion of H3-thymidine uptake by cultured meningioma cells, eluted from a Sephadex G-100 column in 3 peaks corresponding to molecular weights of greater than or equal to 150, 56 and 28 kDa. Our results show that proliferation of human meningiomas may be under autocrine control via secretion of PDGF-like molecules.

Cell Division↗
PubMed1991

Loss of heterozygosity on chromosome 3, bands q24----qter, in a diploid meningioma.

Cytogenetic analysis of a meningioma from a 46-year-old female patient exhibited as the sole cytogenetic aberration a deletion on the long arm of one chromosome 3 involving bands 3q24----qter. To verify this finding, RFLP analysis was performed with two polymorphic probes, MOX2 and D3S5. The patient was informative for both single copy probes and demonstrated loss of heterozygosity in the region above whereas chromosome 22 displayed no loss of heterozygosity as judged by a proximal and a distal probe.

Chromosome Banding↗
PubMed1990

Growth of cultured human cerebral meningiomas is inhibited by dopaminergic agents. Presence of high affinity dopamine-D1 receptors.

We have found that microM concentrations of the dopamine agonist bromocriptine significantly decrease the proliferation rate of human meningioma cells in culture (25-56% inhibition). This effect was also seen with direct application of dopamine, as well as the dopamine-D1 agonist (+)-SKF-38393 (both applied in microM concentrations) to meningioma cell cultures. Receptor studies with the dopamine-D1 ligand (125I)SCH-23982 (dopamine-D1 antagonist) indicated that dopamine-D1 binding sites were present in the membranes of meningioma tissue. The mean dissociation constant (Kd) was 325 ( +/- 74.5 SEM) pM and the receptor density (Bmax) was 25.4 ( +/- 1.5 SEM) fmol/mg pellet protein in 5 human meningiomas. The pharmacological specificity was proven by (+)-SKF-38393, ( +/-SKF-83566 or (+)-butaclamol and their inactive isomers (-)-SKF-38393 and (-)-butaclamol in a 1000 fold excess. These results provide evidence that human meningiomas possess high affinity dopamine-D1 receptors and that dopamine agonists have an antiproliferative effect on these tumors in culture. We conclude that the proliferation of cerebral meningiomas may be under dopaminergic control and that dopamine agonists may have a role in the medical treatment of patients with meningiomas.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Hormonal dependency of cerebral meningiomas. Part 1: Female sex steroid receptors and their significance as specific markers for adjuvant medical therapy.

Female sex steroid receptors were examined in 50 human cerebral meningiomas. For estrogen receptors, high-affinity binding sites (dissociation constant (Kd): 0.05 to 0.2 nM) were found in the cytosolic fraction with a capacity of less than 4 fmol/mg protein in 10 meningiomas using a dextran-coated charcoal (DCC) assay. In the same cytosolic fraction, the solid-phase enzyme immunoassay revealed only one cytosol with a positive colorimetric reaction equal to 5 fmol/mg protein. However, in the nuclear compartment, none of the tumors stained positively for estrogen receptors with immunohistochemical techniques. In addition, the most convincing evidence for the absence of estrogen receptors was obtained by in situ hybridization using an oligonucleotide probe complementary to a fraction of the human receptor messenger ribonucleic acid (mRNA). In none of the 50 meningiomas was the expression of estrogen mRNA coding for the estrogen receptor detected. For progesterone receptors, high-affinity binding sites (Kd: 0.3 to 2.6 nM) were found in 49 of the 50 tumors using a DCC assay. In the same cytosols, solid-phase enzyme immunoassay revealed that each tumor was positive for progesterone receptors. However, in the nuclear compartment, only five tumors had partially positive staining for progesterone receptors with immunohistochemical techniques. Within the confines of this study, it is concluded that: 1) the estrogen receptor is generally absent in meningioma tissue, and 2) the progesterone receptor is mainly absent in the nuclear compartment, leading to the conclusion that the cytosolic progesterone receptor may be an inactive form. This study suggests that female sex steroid receptors are not primarily involved in the proliferative rate of cerebral meningiomas and that they are of no current significance as markers for adjuvant medical therapy of most meningiomas.

Adult↗
PubMed1990

Hormonal dependency of cerebral meningiomas. Part 2: In vitro effect of steroids, bromocriptine, and epidermal growth factor on growth of meningiomas.

Cell culture and biochemical techniques have been employed to examine the effects of steroids, bromocriptine, and epidermal growth factor (EGF) on the growth and proliferative potential of meningiomas. In cell culture, the growth of meningiomas was not altered by progestogens, antiprogestogens, or 17beta-estradiol. The progestogen, norethisterone, had no effect on the uptake by meningiomas cell cultures of 3H-thymidine. Furthermore, cytosolic deoxyribonucleic acid (DNA) polymerase activity of meningiomas did not correlate with the progesterone receptor status of the same tumors. In contrast, the androgen antagonists, cyproterone acetate and 11-alpha-hydroxyprogesterone, and the dopamine agonist, bromocriptine, all inhibited the in vitro growth of meningioma cells. The growth of meningioma cell cultures was stimulated by EGF, and there was a positive correlation between the EGF content and DNA polymerase activity in meningioma cytosols. These results demonstrate that female sex steroids do not influence growth of meningiomas in vitro, whereas antiandrogens and bromocriptine have an antiproliferative effect. Consequently, bromocriptine and antiandrogens may have a role in the medical treatment of meningiomas. In addition, these results suggest that EGF may be involved in the genesis and/or progression of meningiomas.

Bromocriptine↗