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Biomedical subjects

G Favre

Publications and source records attributed to G Favre.

At least 37 records · Page 2Linked to original sources
PubMed2000

The expression of CD70 and CD80 by gene-modified tumor cells induces an antitumor response depending on the MHC status.

The expression of costimulatory molecules such as CD70 or CD80 by gene-modified tumor cells has been shown to enhance the antitumor immune response based mainly on T lymphocytes. However, most human tumors show defects of major histocompatibility complex (MHC) expression, preventing them from being recognized by MHC-restricted T cells. To investigate if coexpression of CD70 and CD80 costimulatory molecules induces comparable antitumor responses in low and high MHC-expressing tumor cells, we used two low immunogenic murine tumor models, the B16.F10 melanoma and the TS/A mammary adenocarcinoma cell lines expressing, respectively, low and high levels of MHC class I molecules. Transfection of both CD70 and CD80 genes resulted in an increased capacity of gene-modified tumor cells to costimulate in vitro the proliferation and cytokine production of optimally activated lymphoid cells. Coexpression of CD70 and CD80 by the two tumor cell lines, TS/A and B16.F10, resulted in both cases in partial regression of subcutaneous tumors. Immunochemical analysis and studies in nude mice showed that, even in the B16.F10 model, T cells had a significant role in the antitumor response induced by combining CD70 and CD80. However, rejection of the CD70/CD80-transfected tumor cells appeared more effective in the MHC class I high TS/A model, leading to a protection against parental tumor cells. B16.F10 and TS/A transfectants were then tested with fibroblasts genetically modified to secrete interleukin-12 (IL-12) as a therapeutic vaccine in mice bearing parental tumors. In the two models tested, the injections of irradiated IL-12 and CD70/CD80 gene-modified cells generated an antitumor response to established tumors leading to the slowing down of the tumor growth rate. Although the mechanisms remain to be defined, these findings suggest that the combination of several immuno-modulatory molecules could provide additional strategies for cancer immuno-gene therapy, even for MHC expression-deficient tumors.

Animals↗
PubMed2000

Natural killer-type receptors for HLA class I antigens are clonally expressed in lymphoproliferative disorders of natural killer and T-cell type.

In recent years, natural killer (NK) cells, as well as subpopulations of T cells, have been found to express diverse NK receptors (NKRs) for HLA class I molecules. We have characterized NKR phenotypes in lymphoproliferative disorders of NK or T-cell type. Peripheral blood of patients with lymphoproliferative disorders (n = 9) was analysed by multiparametric immunofluorescence flow cytometry with eight different antibodies against NKRs. Abnormal neoplastic cell populations from different types of NK or T-cell lymphoproliferative disorders lacked diversity in their NKR repertoires, i.e. all or none of the abnormal cells expressed individual NKRs and this expression occurred at single levels of intensity. This pattern of expression was specific for lymphoproliferative disorders as these resticted NKR repertoires were not found either in healthy donors (n = 9) or in patients with viral or autoimmune disease (n = 5). We conclude that NKRs are clonally expressed in lymphoproliferative disorders of NK or T-cell origin. NKR repertoires may represent a novel tool in diagnosing clonal disorders of NK and T-cell type.

CD3 Complex↗
PubMed1999

Inhibition of human tumor cell growth in vitro and in vivo by a specific inhibitor of human farnesyltransferase: BIM-46068.

Oncogenic mutations of the ras gene leading to constitutive activation of downstream effectors have been detected in a large spectrum of human cancers (pancreas, thyroid, colon and NSCLC). Membrane anchorage of Ras required for functional activity in signal transduction is facilitated by post-translational modifications resulting in covalent attachment of a farnesyl group to the cysteine in the C-terminal CAAX motif. This attachment is mediated by farnesyltransferase (FTase). Here, we report a novel series of potent FTase inhibitors, where the tetrapeptide CAAX motif has been modified by incorporation of a thiazolidine carboxylic acid moiety followed by reduction of the 1st and 2nd peptide bonds to a secondary and tertiary amine, respectively. The C-terminal carboxylate was converted to esters for improved cellular penetration. These compounds showed specific inhibition of purified human FTase enzyme, inhibition of proliferation in vitro in a large spectrum of human tumor cell lines and inhibition of growth of human tumor xenografts in athymic nude mice. In addition, in regard to a panel of cell lines, using the Compare analysis to determine the Pearson coefficient correlation, the anti-proliferative spectrum of BIM-46068 has been shown to be distinct from the profile of typical chemotherapeutic agents.

Alkyl and Aryl Transferases↗
PubMed1999

Epidermal growth factor stimulates 3-hydroxy-3-methylglutaryl-coenzyme A reductase expression via the ErbB-2 pathway in human breast adenocarcinoma cells.

HMG-CoA reductase is the key enzyme for the biosynthesis of isoprenoid compounds essential for cell growth and differentiation. Its tyrosine kinase-dependent modulation has recently been suggested and described in the ErbB-2 overexpressing cell line SKBR-3 [Asslan et al. (1998) Biochem. J. 330, 241-246]. Epidermal growth factor (EGF) increased the HMG-CoA reductase activity, protein, and mRNA levels only in ErbB-2-expressing cells (SKBR-3 and MCF-7) but not in MDA-MB-468 cells that do not express ErbB-2 even though their EGF receptor was efficiently phosphorylated. Tyrphostin AG 879, a specific inhibitor of ErbB-2 tyrosine kinase activity, decreased HMG-CoA reductase activity only in cells that expressed ErbB-2. A functional EGF receptor appeared to be necessary since its inhibition by the specific tyrphostin AG 1478 abolished the EGF effects. Phosphatidylinositol 3-kinase (PI 3-kinase) might be a crucial enzyme in the signaling pathway since the specific inhibitor, LY 294002, was shown to inhibit HMG-CoA reductase activity and to completely abolish the stimulation by EGF in SKBR-3 cells.

Adenocarcinoma↗
PubMed1999

Graft-versus-myeloma after withdrawal of immunosuppression following allogeneic peripheral stem cell transplantation.

There is growing evidence for a graft-versus-myeloma effect following allogeneic stem cell transplantation. We add to this evidence by reporting complete remission achieved by withdrawal of immunosuppression in a patient with multiple myeloma progressing after HLA-identical sibling peripheral stem cell transplantation. De novo chronic graft-versus-host disease coincided with the anti-myeloma effect and responded to treatment. The patient remains in complete remission 3 years after transplant.

Adult↗
PubMed1999

Repeated peripheral stem cell mobilization in healthy donors: time-dependent changes in mobilization efficiency.

Mobilization of peripheral blood stem cells was analysed in 10 consecutive healthy donors undergoing repeated stem cell mobilization for allogeneic transplantation. Donors received recombinant G-CSF at a dose of 10 microg/kg/d for both mobilizations. Collection of stem cells was started on day 5 of G-CSF administration. To compare the efficiency of first and second mobilization, we determined the leucocyte and CD34+ cell counts in peripheral blood, and the yield of nucleated cells and CD34+ cell counts in the apheresis product. CD34+ cell numbers in peripheral blood were (median) 81.2 x 10(6)/l during the first and 50.4 x 10(6)/l during the second mobilization (P = 0.007). Likewise, CD34+ cells in the apheresis product decreased from 319.8 x 10(6) to 275.7 x 10(6) (P = 0.02). Decrease in CD34+ cell counts in peripheral blood and in the apheresis product was associated with the time interval between first and second mobilization. In a regression analysis there was a correlation between the ratios of CD34+ cell counts of first and second mobilization and the inverse of time interval between procedures (r2 = 0.51 peripheral blood; r2 = 0.74 apheresis product). Thus, stem cell yield is reduced when healthy donors receive repeated mobilization within a short time. Nevertheless, an adequate number of stem cells may repeatedly be mobilized within 2 months.

Antigens, CD34↗
PubMed1999

The farnesyltransferase inhibitor FTI-277 suppresses the 24-kDa FGF2-induced radioresistance in HeLa cells expressing wild-type RAS.

In this paper, we describe the effect of the inhibitor of farnesyltransferase (FTI-277) on radioresistance induced by the 24-kDa isoform of FGF2 in human cells expressing wild-type RAS. Treatment with FTI-277 (20 microM) for 48 h prior to irradiation led to a significant decrease in survival of radioresistant cells expressing the 24-kDa isoform (HeLa 3A) but had no effect on the survival of control cells (HeLa PINA). The radiosensitizing effect of FTI-277 is accompanied by a stimulation of postmitotic cell death in HeLa 3A cells and by a reduction in G(2)/M-phase arrest in both cell types. These results clearly demonstrate that at least one farnesylated protein is involved in the regulation of the radioresistance induced by the 24-kDa isoform of FGF2. Furthermore, the radiation-induced G(2)/M-phase arrest is also under the control of farnesylated protein. This work also demonstrates that FTase inhibitors may be effective radiosensitizers of certain human tumors with wild-type RAS.

Alkyl and Aryl Transferases↗
PubMed1998

Correction of spurious blood cell counts in a patient with cryoglobulinemia reversed by the use of citrate-anticoagulated blood.

Cryoglobulins may interfere with automated cell counting when proteins precipitate or blood cells aggregate. This results in spurious platelet or leukocyte counts, false values for red blood cell parameters and abnormal scattergrams. Usually it can be reversed by warming blood specimens to 37 degrees C. We describe the case of a 63-year-old woman with autoimmune disease in whom the diagnosis of cryoglobulinemia was suspected due to typical changes in blood cell counts. Artifacts were resistant to warming of the sample to 37 degrees C in both EDTA- and heparin-anticoagulated blood specimens. In contrast, the use of citrate as anticoagulant allowed correct measurements. This case underlines the role of assessment of blood counts in the detection of cryoglobulinemia. Correct measurements of automated blood counts in cryoglobulinemia may depend on the use of alternative anticoagulants.

Anticoagulants↗
PubMed1998

[Optimizing plasma cell content in bone marrow aspirates].

Bone marrow samples used for flow cytometric analysis of plasma cells frequently provide a low plasma cell content. Regularly, samples used for flow cytometry are provided by second step aspiration while the first aspirate is used for cytologic examination. We investigated whether the use of secondary aspirates leads to a systematic underestimation of the bone marrow plasma cell content as a consequence of an increased blood contaminant. To test the hypothesis, plasma cell (CD38bright) percentages were established by flow cytometry in 13 pairs of primary/secondary aspirates. In all cases we found lower plasma cell contents in secondary as compared to primary aspirates (p = 0.0015). Median plasma cell counts in secondary aspirates were 57% lower compared to primary aspirates. We conclude that the use of secondary aspirates leads to systematic underestimation of the bone marrow plasma cell content.

Bone Marrow↗
PubMed1998

[Immunophenotype of blast crisis in chronic myeloid leukemia].

The blast crisis in chronic myeloid leukaemia (CML) is morphologically well defined. The aim of this report was to analyze whether immunophenotyping can divide CML blast crises into subtypes as is done in acute de novo leukaemia, and whether a specific CML pattern exists. Between 1991 and 1997 we reevaluated all the immunophenotypes of patients with CML blast crises with special regard to immunological subclassification, expression of CD34, presence of aberrant markers and number of immunological clusters. Twenty-nine CML blast crises were analyzed. Seventeen were myeloid, 11 lymphoid and one biphenotypic. The blast crises were divided into subtypes as de novo acute leukaemias: of the 17 myeloid blast crises 6 were undifferentiated, 5 differentiated and 6 had monocytic differentiation. In the lymphoid blast crises there were no pro-B, 8 common-B and 3 mature-B. No T-lymphoid blast crises were observed. In 26/29 analyses (90%) CD34 was expressed in the blasts. In 17/29 analyses (59%) one or two aberrant markers were found. In summary, immunophenotyping is important in distinguishing between myeloid and lymphoid blast crises. A subclassification, as in acute leukaemias, is possible. We found no specific immunophenotypic CML pattern. A study directly comparing immunophenotyping of CML blast crises with acute de novo leukaemia is planned.

Adolescent↗
PubMed1998

Competitive inhibition of choline phosphotransferase by geranylgeraniol and farnesol inhibits phosphatidylcholine synthesis and induces apoptosis in human lung adenocarcinoma A549 cells.

We have previously shown that, among various isoprenoids, farnesol and geranylgeraniol specifically induced actin fiber disorganization, growth inhibition, and apoptosis in human lung adenocarcinoma A549 cells (Miquel, K., Pradines, A., and Favre, G. (1996) Biochem. Biophys. Res. Commun. 225, 869-876). Here we demonstrate that isoprenoid-induced apoptosis was preceded by an arrest in G0/G1 phase. The isoprenoid effects were independent of protein prenylation and of mitogen-activated protein kinase activity. Moreover, geranylgeraniol and farnesol induced a rapid inhibition of phosphatidylcholine biosynthesis at the last step of the CDP-choline pathway controlled by choline phosphotransferase and not at the level of CTP:phosphocholine cytidylyltransferase, the key enzyme of the pathway. Inhibition of choline phosphotransferase was confirmed by in vitro assays on microsomal fractions, which clearly showed that the isoprenoids acted by competitive inhibition with the diacylglycerol binding. Exogenous phosphatidylcholine addition prevented all the biological effects of the isoprenoids, including actin fiber disorganization and apoptosis, suggesting that inhibition of phosphatidylcholine biosynthesis might be the primary event of the isoprenoid action. These data demonstrate the molecular mechanism of geranylgeraniol and farnesol effects and suggest that the mevalonate pathway, leading notably to prenylated proteins, might be linked to the control of cell proliferation through the regulation of phosphatidylcholine biosynthesis.

Actins↗
PubMed1998

Tyrosine kinase-dependent modulation of 3-hydroxy-3-methylglutaryl-CoA reductase in human breast adenocarcinoma SKBR-3 cells.

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase is the major rate-limiting enzyme in sterol and non-sterol isoprenoid synthesis. Isoprenoids are involved in the mechanisms of cell proliferation and transformation leading notably to crucial post-translational maturation of small G-proteins of the Ras superfamily. HMG-CoA reductase is among the most highly regulated enzymes. It is controlled by several feedback regulation mechanisms induced by sterol and non-sterol metabolites. The present results show that tyrosine kinase activity is also involved in the regulation of HMG-CoA reductase activity in the human breast cancer cell line SKBR-3. Incubation of SKBR-3 cells with the tyrosine kinase inhibitor, herbimycin A, induces a concentration-dependent reduction of HMG-CoA reductase activity with an IC50 of 80nM. The inhibition of HMG-CoA reductase activity by herbimycin A is also time-dependent. A similar effect of herbimycin A was obtained on the steady-state level of the HMG-CoA reductase protein. The effect of herbimycin A is probably specific as it abolished the stimulation of reductase activity by epidermal growth factor. To elucidate the molecular basis of the inhibition of HMG-CoA reductase activity and protein level by herbimycin A, we performed experiments to study the metabolic turnover of this enzyme using [35S]methionine and [35]cysteine. Herbimycin A (1 microM) did not have any significant effect on the rate of HMG-CoA reductase protein degradation but did affect its rate of synthesis and mRNA levels. The decrease in protein synthesis rate correlates with the lower reductase protein level but is more pronounced than the decrease in mRNA levels. Taken together, the results reveal a novel pathway of regulation of HMG-CoA reductase expression and activity by cellular tyrosine kinase activities.

Adenocarcinoma↗
PubMed1998

SupraMolecular BioVectors (SMBV) improve antisense inhibition of erbB-2 expression.

New therapeutic strategies are now being developed against adenocarcinoma associated with erbB-2 amplification, particularly by inhibiting p185erbB-2 expression. Antisense oligodeoxynucleotides seem promising for this purpose as long as they are efficiently protected against degradation and targeted into the cells. We present antisense oligonucleotide carriers, the supramolecular biovectors (SMBVs), for which we have already demonstrated the ability to improve both cellular uptake and protection of oligodeoxynucleotide. The present work demonstrates that SMBVs elicit a specific and non-toxic action of antisense compounds in a cell model, irrespective of their sensitivity to nucleases. This is a major point, considering the specificity problems associated with the use of nuclease-resistant phosphorothioate oligodeoxynucleotide. SMBVs improve antisense efficiency of oligodeoxynucleotide designed against p185erbB-2, with a complete growth arrest of SK-Br-3, human adenocarcinoma mammary cells that overexpress p185erbB-2 and no effect on MCF-7 cells that normally express p185erbB-2. The comparison of SMBVs with DOTAP reveals the statistically higher efficiency of SMBVs, which allows the antisense inhibition of p185erbB-2 expression in 65-75% of SK-Br-3 cells (P < 0.05). The efficiency and controlled synthesis of SMBVs underline their potentialities as oligodeoxynucleotide carriers for in vivo experiments.

Cell Division↗
PubMed1998

Double allogeneic peripheral stem cell transplants for patients at high risk of relapse.

Patients with chronic myeloid leukemia (CML) relapsing in blast crisis after HLA-identical sibling bone marrow transplantation (BMT) are difficult to treat. Infusion of donor lymphocytes or retransplantation are unlikely to result in long-term disease-free survival. Treatment intensification with allogeneic double-BMT, made possible by using repeatedly mobilized peripheral blood stem cells, offers a new treatment option. We report two patients with Philadelphia chromosome positive CML transplanted in chronic phase, relapsing with CML in myeloid blast crisis. Both received intensive induction chemotherapy (ICE) followed by a first, T cell-depleted peripheral stem cell transplant from the initial donor. Both patients engrafted rapidly (day 15). Upon hematologic recovery, a second G-CSF mobilized non-T cell-depleted peripheral stem cell transplant from the same donor was given after pretransplant conditioning with busulphan and cyclophosphamide. Again, engraftment was rapid (days 18 and 16) and both patients are alive and disease-free 18 and 21 months after allogeneic double-BMT. G-CSF mobilized peripheral stem cells allow new ways of treatment intensification with double-BMT in refractory leukemias relapsing post-transplant. This approach warrants further study.

Adult↗