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S Ladisch

Publications and source records attributed to S Ladisch.

At least 55 records · Page 3Linked to original sources
PubMed1994

Circulating tumor gangliosides enhance platelet activation.

Gangliosides enhance tumor formation in experimental animals, and high circulating concentrations of gangliosides shed by tumor cells are associated with rapid progression of human neuroblastoma. We studied these shed molecules for effects on platelet function, because platelet activation may play a role in the metastatic process. Preincubation of normal platelets in patient (tumor ganglioside-containing) serum resulted in their aggregation upon exposure to a subthreshold concentration (1 microgram/mL) of collagen (up to 34% v < 10% in normal serum) and ATP release (up to 1.1 nmol/2.5 x 10(7) platelets v < 0.2 in normal serum). Because circulating shed tumor gangliosides are lipoprotein-associated, we next assessed the effects of the serum lipoprotein fraction on platelet ATP release. The patient serum lipoprotein fraction (d > 1.210) enhanced ATP release (up to 3.1 nmol ATP), whereas the same fraction of normal serum, and both patient and control lipoprotein-depleted serum fractions (d > 1.210), were inactive (< 0.2 nmol ATP released). Finally, as little as 0.5 mumol/L patient serum gangliosides (purified from the lipoprotein fraction) caused significantly greater ATP release than did normal serum gangliosides (P < .01) and caused maximal release at 50 mumol/L (up to 3.0 nmol ATP released v < or = 0.3 nmol released by platelets exposed to normal serum gangliosides). Purified total human neuroblastoma tumor gangliosides, detected in the patient serum and isolated from LA-N5 cells, were highly active; preincubation of platelets with only 5 mumol/L of these gangliosides resulted in release of 2.5 +/- 0.1 nmol ATP. Thus, neuroblastoma patient serum, the lipoprotein fraction, and, specifically, the serum gangliosides enhance platelet activation. This activity appears to reside particularly in the tumor cell gangliosides, which are shed in vivo.

Adenosine Triphosphate↗
PubMed1994

Ceramide structure predicts tumor ganglioside immunosuppressive activity.

Molecular determinants of biological activity of gangliosides are generally believed to be carbohydrate in nature. However, our studies of immunomodulation by highly purified naturally occurring tumor gangliosides provide another perspective: while the immunosuppressive activity of gangliosides requires the intact molecule (both carbohydrate and ceramide moieties), ceramide structure strikingly influences ganglioside immunosuppressive activity. Molecular species of human neuroblastoma GD2 ganglioside in which the ceramide contains a shorter fatty acyl chain (C16:0, C18:0) were 6- to 10-fold more active than those with a longer fatty acyl chain (C22:0/C24:1, C24:0). These findings were confirmed in studies of ceramide species of human leukemia sialosylparagloboside and murine lymphoma GalNAcGM1b. Gangliosides that contain shorter-chain fatty acids (and are most immunosuppressive) are known to be preferentially shed by tumor cells. Therefore, the results suggest that the tumor cell is optimized to protect itself from host immune destruction by selective shedding of highly active ceramide species of gangliosides.

Animals↗
PubMed1994

Treatment strategy for disseminated Langerhans cell histiocytosis. DAL HX-83 Study Group.

Treatment of Langerhans cell histiocytosis (LCH) remains problematic. To test the hypothesis that rapid initiation and long-term continuation of chemotherapy can improve survival and reduce recurrence and late consequences of disseminated LCH, we have completed a prospective clinical trial (DAL HX-83). One hundred six newly diagnosed patients were stratified into three risk groups (A: multifocal bone disease [n = 28]; B: soft tissue involvement without organ dysfunction [n = 57]; C: organ dysfunction [n = 21]). All patients received an identical initial 6-week treatment (etoposide [VP-16], prednisone, and vinblastine), and continuation treatment for 1 year, slightly adapted according to stratification at diagnosis. It included oral 6-mercaptopurine and eight pulses of vinblastine and prednisone for all patients, plus VP-16 in group B and VP-16 and methotrexate in group C. Eighty-nine percent and 91% of patients in groups A and B and 67% of the most severely affected group C, achieved complete resolution of disease. The speed of resolution was rapid (median 4 months) and independent of disease severity. The frequency of recurrence after initial resolution was low (12%, 23%, and 42% in groups A, B and C); overall fully 77% of patients have remained free of recurrence. Permanent consequences developed after diagnosis in 20% of the patients. Diabetes insipidus after initiation of treatment occurred in only 10% of patients. Mortality (9%) was limited to patients of groups B (two patients) and C (eight patients). Finally, among the 106 patients treated by DAL HX-83 none have developed a malignancy (median follow-up 6 years, 9 months). The shorter duration of active disease, low rate of recurrence and permanent consequences, and improved survival among patients with poor prognosis support the strategy of rapid initiation of a predefined prolonged treatment upon the diagnosis of disseminated LCH.

Adolescent↗
PubMed1994

LCH-I: a randomized trial of etoposide vs. vinblastine in disseminated Langerhans cell histiocytosis. The Histiocyte Society.

An international randomized trial in Langerhans cell histiocytosis (LCH) has been initiated by the Histiocyte Society. This report reviews the rationale, design, and progress of LCH-I, which compares etoposide (VP-16) and vinblastine in the treatment of disseminated LCH. Data on the risk of etoposide-associated (therapy-induced) malignancy, in the setting of histiocytosis, are reviewed. The available evidence leads to the recommendation that the study of etoposide in LCH should be continued.

Drug Administration Schedule↗
PubMed1994

Treatment of Langerhans cell histiocytosis--evolution and current approaches.

Optimal treatment of Langerhans cell histiocytosis remains problematic. The absence of controlled studies and the lack of standard diagnostic and evaluation criteria have impeded therapeutic progress even though knowledge of basic aspects of LCH have advanced. Historical analysis of outcome suggests little improvement until very recently, but marked differences in outcome according to extent of disease. Consequently, major and now successful efforts have been made to stratify LCH patients into different 'risk groups'. Recent findings suggest that combination chemotherapy for multisystem disease is beneficial and that VP-16 is a useful new agent for treating LCH, despite controversies regarding its side effects. The first randomised international treatment study, LCH-1, being conducted by the Histiocyte Society, should resolve some of these controversies. Other experimental therapies may be considered for children with severe, unresponsive LCH.

Biological Factors↗
PubMed1994

Modulation of human myelopoiesis by human gangliosides.

Cell surface gangliosides are potent modulators of cellular proliferation. We hypothesize that gangliosides shed by tumor cells modulate hematopoiesis and contribute to human tumor-associated suppression of hematopoiesis. To test this hypothesis, we determined the effects on myeloid colony formation by human bone marrow mononuclear cells of total gangliosides isolated from human brain and of seven highly purified individual ganglioside species (GM1, GM2, GD1a, GD1b, GD2, GD3, and GT1b). Total human brain gangliosides and certain individual species, GD1a, GD1b, and GT1b, significantly inhibited myeloid colony formation (number as well as size). The most complex molecules, GD1a, GD1b, and GT1b, were the most inhibitory, suggesting that the degree of inhibition is related to ganglioside structural complexity. To extend these findings, we also investigated certain tumor-derived (neuroblastoma) gangliosides, which we found inhibited both myeloid colony formation and 3H-thymidine incorporation by human bone marrow mononuclear cells. These data suggest a role for gangliosides, which are shed by proliferating cells, in the regulation of human hematopoiesis and may explain the bone marrow hypoplasia observed in association with many human malignancies.

Bone Marrow↗
PubMed1993

Biosynthesis and shedding of murine lymphoma gangliosides.

Ganglioside biosynthesis and subsequent shedding are a potential mechanism contributing to tumor cell escape from the host immune response. As a first step in identifying active molecular species, structural characterization and quantification of the purified individual cellular and shed gangliosides of YAC-1 murine lymphoma cells were undertaken. These studies uncovered three striking changes in ganglioside metabolism in cells passaged in vivo, compared with cells cultured in vitro. (i) Marked inhibition of GalNAcGM1b synthesis: GM1b was present in an equal proportion to its biosynthetic product GalNAcGM1b in vitro, but was present in a 6-fold higher concentration in vivo. (ii) Marked inhibition of NeuGc synthesis: NeuGc, present in vitro in an up to 7-fold higher concentration than its biosynthetic precursor NeuAc, was decreased in relative concentration in vivo (1:1). (iii) Selectivity of shedding: ganglioside shedding in vitro was generalized with respect to both carbohydrate structure and ceramide structure (mainly d18:1-C24:1 and d18:1-C16:0), while in vivo, there was selective shedding of gangliosides containing NeuGc and the shorter chain fatty acid. The reduced synthesis of NeuGc and of GalNAcGM1b in vivo, and the selective shedding of more polar ganglioside species, also in vivo, show that the extracellular environment can markedly affect cellular ganglioside metabolism.

Animals↗
PubMed1993

Detection of complex gangliosides in human amniotic fluid.

Gangliosides are possibly very potent immunosuppressive molecules. Here we show that human amniotic fluid contains high concentrations of a number of previously unnoted, structurally complex and highly polar gangliosides. These unusual molecules are present early in pregnancy (first trimester), increase in concentration with gestational age, and reach maximum levels (0.8 microM) at term. Since similar gangliosides have been detected in human placenta, trophoblast, and amnion, we suggest that these molecules are shed into the amniotic fluid bathing these tissues.

Amnion↗
PubMed1992

Immunosuppression by human gangliosides: I. Relationship of carbohydrate structure to the inhibition of T cell responses.

Causes of cellular immunodeficiency frequently associated with cancer remain poorly understood. One possible mechanism is tumor cell membrane shedding of immunosuppressive molecules, such as the sialic acid-containing glycosphingolipids, gangliosides. To explore this interesting hypothesis and establish structure-activity relationships, we examined the effects of a series of highly purified human gangliosides on T cell function. In all, ten individual molecular species of two major biosynthetic pathways were compared for their ability to inhibit human T cell proliferative responses. They include GM1, GD1a, GD1b, and GT1b (the predominant normal brain species), and GM4, GM3, GM2, GD3, GD2 and GQ1b. Strikingly, each HPLC-purified molecule, from the simplest monosialoganglioside to the most complex polysialoganglioside, had potent inhibitory activity; even the ganglioside with the most elemental carbohydrate structure (GM4, one sialic acid linked to a monosaccharide) strongly inhibits T cell proliferative responses to tetanus toxoid (ID90 = 1.5 microM). The data also reveal a complex interplay between elements of oligosaccharide structure in determining immunosuppressive activity. Sialic acid is critical to maximal activity, and (i) immunosuppression is most potent in gangliosides containing a terminal sialic acid. (ii) Total desialylation almost abolishes activity and (iii) partial alteration (lactone formation) reduces activity. (iv) Activity is generally but not always higher with higher numbers of sialic acid residues/molecule, and (v) some larger neutral glycosphingolipids retain measurable immunosuppressive activity. Overall, the potent inhibition by gangliosides supports the hypothesis that shedding of these molecules by tumors creates a highly immunosuppressive microenvironment around the tumor, thereby inhibiting the function of infiltrating host leukocytes and contributing to diminished T cell responses in cancer.

Carbohydrate Conformation↗
PubMed1992

Localization of shed human tumor gangliosides: association with serum lipoproteins.

Tumor gangliosides are biologically active (immunosuppressive and tumor-enhancing) cell surface molecules which are shed into the circulation in vivo. However, the mechanism of transport of these molecules (i.e., in solution or bound to proteins or other lipids) is not known. To resolve this question we traced, by direct chemical detection, the serum localization of a specific human tumor ganglioside, GD2, shed by neuroblastoma cells. Sera from patients with tumors were separated into the lipoprotein fractions [very low-density lipoprotein, low-density lipoprotein (LDL), and high-density lipoprotein] and lipoprotein-depleted serum. All three lipoprotein fractions contained GD2. 73% of the total GD2 was present in the LDL fraction, while very low-density lipoprotein and high-density lipoprotein contained 21 and 6%, respectively. Significantly, lipoprotein-depleted serum, which would contain both albumin-bound and free ganglioside, was devoid of GD2. Thus, shed neuroblastoma tumor gangliosides are exclusively associated with the serum lipoprotein (and predominantly LDL) fractions in vivo. These findings have implications for the immunological detection of these molecules and the development of approaches to their removal.

Adult↗
PubMed1992

13-cis-retinoic acid (NSC 122758) in the treatment of children with metastatic neuroblastoma unresponsive to conventional chemotherapy: report from the Childrens Cancer Study Group.

The Childrens Cancer Study Group evaluated daily oral 13-cis-retinoic acid to determine its therapeutic efficacy in 28 children with advanced neuroblastoma refractory to conventional therapy. Cheilitis and fissured lips were the most common side effects; however, fewer than 50% of the patients experienced any toxicity. Two of twenty-two evaluable children demonstrated positive response to therapy. In one case, a child received the drug for 11 months. Seventeen patients demonstrated progressive disease within 28 days of the start of treatment. Three other patients with stable disease, or removed from study at day 28, were considered nonresponsive. Our data demonstrate that, when given as a single daily oral dose of 100 mg/m2, 13-cis-retinoic acid does not have significant activity in children with advanced neuroblastoma.

Adolescent↗
PubMed1992

Immunosuppression by human gangliosides. II. Carbohydrate structure and inhibition of human NK activity.

Gangliosides shed by tumors enhance tumor formation, possibly by suppressing host antitumor immune function, and gangliosides purified from animal tissues and cultured cells inhibit human cellular immune function in vitro. Determination of immunosuppressive activity of highly purified gangliosides, to uncover structure-activity relationships, is therefore important. Here we have studied a series of gangliosides obtained from human tissue and determined their effects on human natural killer (NK) activity. Total gangliosides from human brain tissue were moderately inhibitory; 100 nmol/ml reduced NK activity of human nonadherent PBMC by 43%. The influence of carbohydrate structure upon inhibitory activity was determined by study of eight highly (HPLC) purified individual gangliosides. Of these, we unexpectedly found that the two minor brain gangliosides with the simplest carbohydrate structures, GM2 and GM3, were very active inhibitors (75 and 47%, respectively, at 50 nmol/ml). In contrast, the structurally more complex major species, GM1, GD1a, GD1b, GT1b, and two other minor gangliosides, GD2 and GD3, were inactive. Reduced effector-target binding in a single-cell binding assay by GM2 but not GM3 suggests different mechanisms of inhibition by these two active gangliosides. Since GM2 and GM3 are present in high concentrations in, and are shed by, several common human tumors (e.g., neuroblastoma, melanoma, and glioma), their ability to inhibit NK cytotoxicity supports the hypothesis of a role of shed tumor gangliosides in the enhancement of tumor formation.

Brain Chemistry↗
PubMed1992

Alteration of neuroblastoma ganglioside metabolism by retinoic acid.

Cellular differentiation is often associated with striking changes in ganglioside metabolism. Because retinoic acid causes cellular differentiation in vitro, we have characterized its effect on ganglioside synthesis and shedding by LAN-5 human neuroblastoma cells. Three major observations were made: (a) 20 microM retinoic acid caused a marked (twofold) increase in cellular ganglioside content, with a slight relative enhancement in GD1a and GT1b synthesis, (b) ganglioside shedding increased in parallel with increased cellular ganglioside content, and also, unexpectedly, (c) retinoic acid caused a quantitatively similar increase in content of cell membrane phospholipids, which are also shed. We conclude that enhanced ganglioside synthesis and shedding by retinoic acid are part of a previously undescribed generalized stimulatory effect on membrane lipid metabolism.

Chromatography, Thin Layer↗
PubMed1991

Shedding of human neuroblastoma gangliosides.

Gangliosides shed by tumor cells are implicated in modulating tumor formation. For example, rapid progression of human neuroblastoma tumors is associated with high circulating levels of shed GD2 ganglioside. To elucidate the kinetic and qualitative characteristics of tumor cell ganglioside shedding, which is difficult to accomplish in vivo, we examined this process in LAN-5 human neuroblastoma cells in vitro. Three major gangliosides, GD2, GM2 and GT1b, comprise 82% of the mean total of 38 nmol LBSA/10(8) cells. These molecules are shed very rapidly (1-3 pmol/10(6) cells per h, or approx. 0.5% of the total cell gangliosides per h). Quantitative and qualitative characteristics of ganglioside shedding are remarkably constant over a 40-fold range of cell density. Not only GD2, but every major carbohydrate species is shed, in proportion to its concentration in the cell, with slightly greater shedding of ceramide subspecies containing shorter chain fatty acids. These findings were confirmed in three other neuroblastoma cell lines, LAN-1, IMR and KCNR. We suggest that the high expression and rapid generalized shedding of human neuroblastoma tumor gangliosides results in significant in vivo accumulation of these biologically active molecules during tumor growth.

Animals↗
PubMed1990

Shed tumor gangliosides and progression of human neuroblastoma.

Shedding of membrane gangliosides is characteristic of human and experimental tumors. Because some shed tumor gangliosides have potent tumor-enhancing properties, significant ganglioside shedding could influence tumor progression. We examined this possibility in a human tumor, neuroblastoma. Ganglioside shedding, measured as circulating tumor-derived GD2 ganglioside, and the outcome of 74 patients with advanced stage (III and IV) disease were studied. Progression-free survival (PFS) was inversely related to circulating GD2 levels at the time of diagnosis (P = .018). By Kaplan-Meier analysis, the quartile of patients having the highest circulating GD2 levels (greater than or equal to 568 pmol/mL) had a strikingly different outcome from the quartile of patients with the lowest (less than or equal to 103 pmol/mL) GD2 levels (P = .013): median PFS was shorter (9 v 28 months), and the long-term survival rate lower (2-year PFS of 24% v 70%). We conclude that more rapid disease progression and lower survival rate are associated with high circulating GD2 levels at diagnosis and speculate that shed neuroblastoma tumor gangliosides play a role in accelerating tumor progression.

Biomarkers, Tumor↗
PubMed1989

Aberrant fatty acyl alpha-hydroxylation in human neuroblastoma tumor gangliosides.

Abnormalities of ganglioside structure characterize the neoplastic state, and aberrant glycosylation has been implicated as underlying many new tumor ganglioside structures. However, variations in ceramide structure can also result in novel tumor gangliosides. To address systematically this aspect of ganglioside metabolism, we have initiated a study of the structures of the ceramide species of an oligosaccharide-homogeneous human tumor-derived ganglioside, GM2. The ganglioside was isolated from neuroblastoma tissue and purified by normal-phase high pressure liquid chromatography. Marked ceramide heterogeneity was observed; 18 individual ceramide species of neuroblastoma GM2 were separated by reversed-phase high pressure liquid chromatography and collected. Their structures were determined by a combination of negative- and positive-ion fast atom bombardment mass spectrometry and collisionally activated dissociation tandem mass spectrometry of the underivatized gangliosides. The striking finding was the detection of alpha-hydroxylation of a significant fraction of each of the major fatty acid species (16:0, 18:0, 20:0, 22:0, and 24:1); alpha-hydroxylated species quantitatively represented almost one-fifth of the total tumor GM2 species. Fatty acyl hydroxylation was also detected in the ceramide of several other human tumor gangliosides. In contrast, as previously known, fatty acyl hydroxylation was not detected in the normal human brain gangliosides GM3, GM2, and GM1. We propose that aberrant fatty acid alpha-hydroxylation is a novel and sometimes quantitatively significant characteristic of human tumor ganglioside metabolism.

Ceramides↗
PubMed1989

Immunosuppressive activity of human neuroblastoma tumor gangliosides.

Gangliosides are shed in substantial amounts by some tumors, including human neuroblastoma, and these molecules modulate experimental tumor formation in vivo. We now demonstrate that neuroblastoma tumor gangliosides have potent immunoregulatory activity. Gangliosides of every one of 17 tumors studied were highly inhibitory for the normal in vitro human lymphoproliferative responses to the soluble antigen, tetanus toxoid; 30 nmol ganglioside/ml caused 43% to greater than 99% inhibition and the mean concentration causing 50% inhibition was only 17.3 nmol/ml. Furthermore, gangliosides isolated from clinically more aggressive tumors (Stage III or IV) were up to twice as immunosuppressive as those of the generally less aggressive tumors (Stage I or II) (p less than 0.05). Taken together with the lack of immunosuppressive activity of normal plasma gangliosides, the potent activity of neuroblastoma gangliosides supports the hypothesis that one mechanism by which these shed molecules may act to enhance tumor formation in vivo is through abrogation of the host cellular immune response at the site of tumor formation.

G(M3) Ganglioside↗