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Biomedical subjects

T Tursz

Publications and source records attributed to T Tursz.

At least 91 records · Page 5Linked to original sources
PubMed1992

Phase I-II study of vinorelbine (Navelbine) plus cisplatin in advanced non-small cell lung cancer.

32 patients with advanced non-small cell lung cancer previously untreated by chemotherapy were included in a phase I-II study in order to determine the feasibility of the combination of vinorelbine and cisplatin, each administered at its optimal dose, i.e. 30 mg/m2 weekly and 120 mg/m2 every 4-6 weeks, respectively. There were 27 males and 5 females with a mean age of 55 years and a median performance status of 80%. 13 had locally advanced disease and 19 had distant metastases at the time of inclusion. Our study demonstrated the feasibility of this protocol. Dose intensities could be maximised by adapting vinorelbine doses rather than by postponing treatment in the event of neutropenia. Both response rate (33%) and overall survival of the population (median 11 months) justify further studies.

Adult↗
PubMed1992

Human T-cell leukemia virus type I envelope protein maturation process: requirements for syncytium formation.

The human T-cell leukemia virus type I (HTLV-I) envelope protein is synthesized as a gp61 precursor product cleaved into two mature proteins, a gp45 exterior protein and a gp20 anchoring the envelope at the cell membrane. Using N-glycosylation inhibitors and site-directed mutagenesis of the potential glycosylation sites, we have studied the HTLV-I envelope intracellular maturation requirements for syncytium formation. We show here that experimental conditions resulting in the absence of precursor cleavage (tunicamycin, monensin treatments, and use of inhibitors of the reticulum steps of the N glycosylations) also result in no cell surface expression of envelope protein. The lack of syncytium formation observed in these cases is thus explained by incorrect intracellular transport. When the precursor is cleaved in the Golgi stack (no treatment or treatment with inhibitors of the Golgi steps of the N glycosylations), it is transported to the cell surface in all the cases examined. Syncytium formation is markedly reduced, however, when Golgi glycosylations are incorrect, which shows that the sugar moieties are involved in the envelope functions. Site-directed mutagenesis demonstrates that each of the five potential glycosylation sites is actually glycosylated. Glycosylation of sites 1 and 5 is required for normal maturation, whereas that of sites 2, 3, and 4 is dispensable. Glycosylation of each site, however, is required for normal syncytium formation. Altogether, the restraints exerted by the cell for the HTLV-I envelope to be transported and functional are very high, which might play a role in the observed conservation of the envelope amino acid sequence between various strains.

1-Deoxynojirimycin↗
PubMed1992

Consistent transcription of the Epstein-Barr virus LMP2 gene in nasopharyngeal carcinoma.

Two species of the Epstein-Barr virus-encoded latent membrane protein 2, LMP2A and LMP2B, are generated by alternative splicing, each species having a distinct first exon. LMP2 transcription in undifferentiated nasopharyngeal carcinoma (NPC), which is consistently associated with the Epstein-Barr virus, was investigated. Fifteen NPC specimens were analyzed by Northern (RNA) blot and RNA-based polymerase chain reaction; the LMP2A transcript was present in all specimens except one. In some specimens the LMP2B transcript was also detected. Sequence analysis of LMP2 cDNAs obtained from two NPC specimens revealed four mutations in exon 1 of the LMP2A transcript, which were present in both tumors and which resulted in nonconservative amino acid changes. These data suggest that the LMP2 expressed in NPC is distinct from that which is expressed in lymphoid cells.

Amino Acid Sequence↗
PubMed1992

Alterations of the p53 gene in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignancy which is consistently associated with the Epstein-Barr virus (EBV). The structure of the EBV genome in NPC suggests that NPC is a clonal proliferation of epithelial cells which emerges after EBV infection. The disease develops with high incidence in specific populations in discrete geographic locations, implicating possible genetic or environmental cofactors. Mutations of the p53 gene are among the most frequent genetic changes found in a large variety of human tumors. Mutations in p53 have been shown to abrogate the suppressor function of wild-type p53 and thus contribute to the transformed phenotype. To determine if mutation in p53 participates in the development of the malignant clone in NPC, the structure and sequence of p53 in 42 primary, metastatic, and nude mouse-passaged NPC specimens was analyzed. A high frequency (6 of 9) of mutations was detected in the nude mouse-passaged tumors, while only 2 of 15 metastatic and 0 of the 18 primary tumors harbored mutant p53. The p53 mutations included single-point mutations and more extensive changes such as frame shifts, deletion, duplication, or complete loss of coding sequences. These data indicate that alterations of the p53 gene are unlikely to be involved in the initial genetic events leading to the clonal outgrowth in NPC. However, although it is a rare NPC which can be established in nude mice, this growth advantage appears to be conferred on tumors bearing a mutant p53.

Animals↗
PubMed1992

IL-2 phase II trial in metastatic melanoma: analysis of clinical and immunological parameters.

Twenty-four patients with histologically proven metastatic malignant melanoma were included in a phase II trial of recombinant IL-2 (rIL-2, RU 49637). Twenty million international units (IU)/m2/day were given by continuous intravenous infusion on days 1 to 5, 15 to 18, and 29 to 31, and then monthly for 5 days until disease progression or major intolerance developed. All patients were evaluable for response and toxicity. Toxicity was consistent with one case of myocardial ischemia, 13 cases of grade III and IV hypotension, and 15 cases of proven sepsis. There were 8 objective responses: 4 of them were of short duration as they were observed on day 31 only. An activation of the immune system was detected in all patients. It was demonstrated by an increase in lymphocyte populations, especially in activated NK cells. A tendency for higher numbers of cytotoxic cells was found in patients with objective tumor responses. These results indicate a role for rIL-2 RU 49637 in treating patients with metastatic malignant melanoma. However, further trials are required to determine its optimal dosage and schedule of administration.

Adolescent↗
PubMed1992

[Immunotherapy: current problems and outlook].

Cytokines are soluble mediators involved in cell-cell regulations in the immunological and the hematopoietic systems-genetic engineering now allows the characterization and the availability of recombinant molecules, some of them being recently introduced in clinical trials. Interleukin-2 (IL-2) is the first factor having demonstrated a reproducible therapeutic effect on human metastatic solid tumors, mainly chemo-resistant. High-dose IL-2 alone could achieve about 25% objective responses in metastatic renal cancers, with a low but significant number of complete, relatively long-lasting complete responses. Similar data are obtained in metastatic melanoma. IL-2 is probably acting through the activation of cytotoxic lymphocytes (LAK: lymphokine activated killers). The interest for simultaneous administration of autologous LAK cells generated through in vitro culture with IL-2 is discussed. Cytokine therapy is currently limited by important systemic toxicities, including mainly general symptoms with fever, and a capillary leak syndrome with weight gain, edema and functional renal failure-cardiac are respiratory troubles can be life-threatening. Future trends for cytokine therapy will be: The discovery of new cytokines, and a better knowledge of their synergies, allowing the design of rational associations. A letter understanding of the mechanisms of toxicities, allowing specific prevention of adverse effects not needed for efficient anti-tumor action. Gene therapy, which will lead to important and prolonged release of cytokines by the tumor cells themselves, or by infiltrating peri-tumoral cells, in order to achieve local efficacy and to circumvent systemic toxicities.

Forecasting↗
PubMed1991

A phase II study of the combination of carboplatin and ifosfamide in previously untreated metastatic small cell lung carcinoma.

This Phase II study evaluated the combination of two active agents in small cell lung carcinoma (SCLC): carboplatin and ifosfamide. Thirty previously untreated patients (27 men and 3 women) with a median age of 59 years were included in this study. Twelve patients had one metastatic site and 18 had two or more metastatic sites. The median performance status was 80%. The chemotherapy (CT) regimen administered during the course of this study consisted of carboplatin (300 mg/m2) and ifosfamide (4 g/m2) plus mesna every 4 weeks. All 30 patients were evaluable: 1 achieved a complete remission (CR) and 18 achieved a partial remission (PR) (objective response rate, 63%). The median response time was 3 months and the median survival time was 8 months (range, 1 to 25+ months). Bone marrow toxicity was Grade III in three patients and Grade IV in four patients. The carboplatin and ifosfamide combination was well tolerated. No cross-resistance with the doxorubicin and etoposide regimen was established because 4 of 11 patients responded to this combination (+/- cisplatin) after failing to respond to the ifosfamide and carboplatin regimen. The ifosfamide and carboplatin combination may be considered for inclusion in non-cross-resistant alternating CT schedules.

Adult↗
PubMed1991

[Phase I trial of a recombinant human interleukin 2. Results in patients with disseminated solid tumors].

A phase I trial of Roussel-Uclaf recombinant human interleukin 2 (IL 2) was performed on 31 cancer bearing patients of the Institut Gustave-Roussy, Villejuif, and the Institut Curie, Paris. This study allowed to define a schedule for administration of IL 2 in continuous infusion over 5 day cycles. This schedule is manageable in patients without major visceral failure. It is reproducibly feasible in conventional medical oncology units, without specialized intensive care facilities. Toxicities, although numerous, are acceptable for IL 2 doses below 24,000,000 IU/m2/day. There is a close relationship between secondary effect severity and IL 2 doses received. Main toxicities were: fever with chills, fatigue and general discomfort in 23 patients, nauseas and vomiting in 12, diarrhea in 10 and cutaneous rashes with erythema and dermal vascularitis in 13. One peculiar feature of this study was the minimal occurrence of manifestation related to leaky capillary syndrome prominant in other studies. Oliguria, functional renal failure and edema were observed in only 4 patients with functionally unique kidney. Five patients had severe anemia, 2 grade III thrombocytopenia, 1 grade IV hepatic cytolysis, 4 severe confusion episodes and 2 hypothyroidism with anti-thyroid microsome auto-antibodies. All these toxicities were reversible after withdrawal of IL 2 treatment. During this phase I trial, 3 therapeutic objective responses were observed, all 3 occurring in patients with metastatic melanoma treated with IL 2 doses equal to, or above 16,000,00 IU/m2/d. Recombinant IL 2 Roussel-Uclaf thus can be administered through a simple, manageable and efficient regimen.

Adolescent↗
PubMed1991

Cytotoxic potential despite impaired activation pathways in T lymphocytes infiltrating nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is an epithelial tumor consistently associated with EBV. The histological picture is characterized by a strikingly abundant lymphocytic infiltrate. Furthermore, the epithelial tumor cells present several immunological characteristics which suggest an important role for tumor-infiltrating lymphocytes (TIL) in the biology of this tumor. The present study reports the phenotypic and functional characterization of TIL from NPC obtained after enzymatic digestion of 15 NPC biopsies. Flow cytometric analysis of TIL suspensions indicated that most TIL were mature CD3+ T lymphocytes (mean = 60%) with a variable CD4/CD8 ratio. Most TIL were TCR alpha/beta-positive (mean = 55%) and only a few TCR gamma-delta-positive cells could be identified. A small percentage (mean = 9%) displayed an activated phenotype (CD25+, HLA class II+). Using limiting dilution analysis, we found that the average frequency of proliferative T-lymphocyte precursors (PTL-P) is lower among TIL (1/40) than in autologous (1/7) or normal PBL (1/1.4). Moreover, sorting experiments have shown that this defect is significantly more pronounced in the CD8+ than in the CD4+ TIL subset. Accordingly, the TCR and the CD2-mediated antigen-independent pathways of activation were impaired. Different types of cytotoxic precursor could be detected. These included lectin-dependent cell cytotoxicity (LDCC) and NK-like or lymphokine-activated killer (LAK) activity. Interestingly, some TIL from NPC were able to lyse an NPC tumor (C15) maintained in nude mice. Thus, despite impaired activation pathways, the cytolytic potential of proliferating TIL in NPC is preserved.

Adolescent↗
PubMed1991

CD77: an antigen of germinal center B cells entering apoptosis.

We have previously reported that a neutral glycolipid (globotriosylceramide; Gb3) was specifically expressed on Burkitt's lymphoma cells and on a subset of germinal center tonsillar B lymphocytes. Recently the Gb3 molecule was recognized as a new B cell differentiation antigen and now defines the CD77 cluster. Here we report an extensive phenotypic and functional characterization of the tonsillar CD77+ B lymphocytes. These cells have a low buoyant density and are thus purified using a Percoll gradient. They express various B cell antigens such as CD19, CD20, CD21, CD22 and CD40, as well as the adhesion molecules LFA-1, LFA-3 and CD44. They are positive for surface IgM and negative for surface IgD. Although these results suggest a phenotype of activated B cells, the CD77+ cells are negative for the classical activation antigens: CD23 (the low-affinity Fc receptor for IgE), CD25 [the interleukin (IL) 2 receptor alpha chain] and CD71 (the transferrin receptor). Proliferation and protein synthesis of CD77+ cells was measured after stimulation with a range of mitogens and IL. None of the agents tested are able to induce proliferation and protein synthesis with the exception of a combination of recombinant IL 4 plus anti-CD40 antibody. When examined by electron microscopy, CD77+ B lymphocytes present a morphology similar to that of cells undergoing programmed cell death, also called apoptosis (i.e. chromatin condensation, nuclear fragmentation, membrane blebbing). As shown by direct examination of DNA, these CD77+ cells are indeed in the process of apoptosis. Treatment of the CD77+ cells by recombinant IL 4 and anti-CD40 antibody prevents apoptosis. All these results suggest that the CD77 molecule defines a B lymphocyte maturation pathway, specific for germinal center, where the cells undergo programmed cell death.

Antibodies, Monoclonal↗
PubMed1991

Analysis of phenotypic and functional changes during ganglioside-induced inhibition of human T cell proliferation.

Glycosphingolipids added to the cell culture medium can be incorporated into the plasma membrane and interfere with the growth of certain cell types. In the past years, previous reports have shown that gangliosides, a class of glycosphingolipids bearing sialic acid can inhibit antigen or mitogen induced T cell proliferative responses in vitro. We report here that the inhibition of PHA induced proliferation by the trisialoganglioside GT1b was not reversed by addition of exogenous IL-1, IL-2, TPA and calcium ionophore. Furthermore, GT1b did not affect IL-2 production by activated T cells. In addition, GT1b ganglioside could also decrease strongly the expression of the T cell antigens CD3, CD2, CD4, CD8 and the alpha/beta T cell receptor antigenic complex whereas it did not affect HLA-class I antigens. By contrast, GT1b modulated only partially membrane expression of activation antigens such as CD25 (Tac) and transferrin receptor and increased the expression of HLA-class II antigens. Moreover CD25 messenger RNA induction was not affected by GT1b treatment of PHA-stimulated T cells. Our results demonstrate that gangliosides, in spite of their anti-proliferative capacity and their modulation effect on T cell antigen membrane expression, do not prevent the progression of T cells into early stages of the activation process.

Antigens, CD↗
PubMed1991

Sequential shifts in the three major glycosphingolipid series are associated with B cell differentiation.

Cell surface glycolipid expression as well as total glycolipid content of various B cell lines, representative of different B cell stages, and normal B lymphocytes were examined. Glycolipids, made up of a carbohydrate chain attached to a lipid called ceramide, are classified in four main 'series'. These series are defined according to the identity and chemical bonding of the sugars closest to the ceramide moiety. The pre-B cell lines contained lacto-series type II chain-based glycolipids and II3-alpha-N-acetyl-neuraminosyllactosylceramide (GM3) ganglioside. Upon differentiation, the lacto-series synthesis was shut down whereas compounds of the globo-series appeared: resting lymphocytes and lymphoblastoid cell lines (LCL) expressed GM3, globotriaosylceramide (Gb3), and globoside (Gb4). At a later stage of B cell differentiation, biosynthesis of the ganglio-series was extended and myeloma cells expressed II3-alpha-N-acetyl-neuraminosylgangliotriosylceramide (GM2). At the cell surface, in addition to Gb3, that we previously described as specifically expressed on Burkitt's lymphoma cells and on a subset of germinal centre tonsillar B cells, two glycolipids seemed specific of certain B cell lines: Gb4 was strongly positive on six out of eight LCLs and on the low buoyant density fraction of tonsillar B lymphocytes, whereas GM2 ganglioside was only detected on the two myeloma cell lines. These results, demonstrating the stage-dependent expression of certain glycolipids, suggest that these carbohydrate molecules could play functional roles during B cell differentiation.

Antibodies, Monoclonal↗
PubMed1991

Primary prostatic Wilms' tumor.

The first case of primary Wilms' tumor of the prostatic gland is described. It occurred in a 32-year-old man. Histologically, it consisted of a triphasic tumor; tubular and glomeruloid structures were identified, among prominent blastematous sheets and in an edematous stroma. No teratomatous components were encountered. We propose that this prostatic primary, nonteratomatous Wilms' tumor can arise from persistent, nephrogenic, blastematous rests in the prostate, in relation to the Wolffian duct system.

Adult↗