Biomedical subjects

C Chomienne

Publications and source records attributed to C Chomienne.

131 records · Page 8Linked to original sources

PubMedDate not supplied

Differential expression of c-myc and c-fos oncogenes during the differentiation of human leukemic cells by Ara-C.

1-B-D-arabinofuranosyl cytosine (Ara-C) is, at very low concentrations, an inducer of monocytic differentiation of human leukemic cells. By what mechanisms this differentiation is obtained and how the monocytic pathway is determined, is not yet understood. We studied the effect of Ara-C on the RNA transcript levels of two c-oncogenes often associated to cell proliferation and differentiation. In the monoblastic U-937 cell line, where Ara-C has a maximum (100%) monocytic differentiation, RNA transcript level of c-myc is not detectable, whereas c-fos levels are rapidly increased. On the other hand, in the bipotential promyelocytic HL-60 cells, Ara-C induces only 40% monocytic differentiation after 7 days; this is associated to a weaker decrement of c-myc expression; c-fos is however greatly induced 3 log after 2 days treatment, but before monocytic phenotype is observed. Ara-C, at low concentrations, may, by arresting cell proliferation, restore the leukemic's cell proliferation/differentiation equilibrium. The rapid inducement of c-fos expression may allow to foresee a rapid prescreening of Ara-C sensitive-blasts.

Cell Division↗

PubMedDate not supplied

Discrepancy between in vitro and in vivo passaged U-937 human leukemic cells: tumorigenicity and sensitivity to differentiating drugs.

The treatment of nude mice bearing tumors of transplanted human leukemic cells with drugs known to induce differentiation of the same leukemic cells in vitro does not always affect tumor yield, tumor cell differentiation or nude mice survival. We have transplanted human monoblastic leukemic cells of the U-937 cell line into newborn Swiss nu/nu mice. Priming with cyclophosphamide, followed by subcutaneous injections of at least 10 x 10(6) cells allowed us to obtain solid tumors. The cytology, HLA phenotype and in vitro proliferation characteristics of the U-937 tumor cells were conserved. However, these tumor cells were more tumorigenic when reinjected into nude mice and showed a modified response to differentiation induction. A decreased capacity to differentiate with retinoic acid (RA) and a resistance to 1-beta-D arabinofuranosyl cytosine (Ara-C) and 1-25 dihydroxy vitamin D3 (1-25 (OH)2 D3) were noted in three tumor cell lines tested. With regard to the latter, the resistance was not due to a modification of the number of cell receptors. The study shows that though in vivo transplantation of human leukemic cells in nude mice may lead to a selection of resistant cells, systematic checking of in vitro differentiation characteristics of the tumor cells permits the nude mouse model to be maintained for the in vivo screening of new differentiating agents.

Animals↗

PubMedDate not supplied

Granulocytic differentiation induced by retinoic acid in HL-60 cells is associated with changes in adenylate cyclase activity.

The effect of all-trans Retinoic Acid (RA) on the activity of membrane bound adenylate cyclase (AC) of human malignant cell lines (HL-60 and U-937) was studied. Granulocytic terminal differentiation of the HL-60 cells was correlated to an increase of AC activity and to a potentiation of guanosine 5' triphosphate (GTP) inhibitory effects on the enzyme activity. No direct in vitro effect of RA on HL-60 membranes was found. Monocytic terminal differentiation obtained on 1 B-D arabinofuranosyl cytosine (Ara-C) treated HL-60 cells, or on RA treated U-937 cells, did not modify AC activity. The results here reported suggest relations between the modification of GTP binding protein activity and RA induced granulocytic differentiation of malignant cells.

Adenylyl Cyclases↗

PubMedDate not supplied

Changes in the patterns of protein phosphorylation associated with granulocytic and monocytic-induced differentiation of HL-60 cells.

Using two-dimensional gel electrophoresis we have analyzed the pattern of phosphorylated proteins in HL-60 leukemia cells and changes associated with their differentiation into granulocyte and monocyte-like cells. In undifferentiated cells 18 spots with MW ranging from 110 to 17, kDa were individualized with high resolution and reproducibility. Myelocytic differentiation induced by dimethyl sulfoxide (DMSO) and retinoic acid (RA) resulted in a decrease of the overall phosphorylation, the disappearance of two proteins of 42 and 17 kDa, and the appearance of one new acidic protein of 46-48 kDa. These changes seem to be specifically related to this differentiation pathway since they are not found in two HL-60 subclones resistant to DMSO or RA-induced differentiation. Monocytic differentiation induced by 1,25-dihydroxyvitamin D3 [1,25 (OH)2D3] and the combination of RA + 1-B-D-arabinofuranosyl cytosine (Ara-C) was associated with the appearance of 2 proteins of 68 kDa and 2 proteins of 80 kDa located in the acidic region of the gel. The protein of 17 kDa, when disappeared completely in granulocytic-like cells was present in monocytic cells, this suggesting that its phosphorylation state may be involved in the control of the differentiation pathway of HL-60 cells. Data concerning the effect of phorbol myristate acetate (PMA) and histamine on the level of phosphorylation of various proteins in HL-60 cells have also been obtained and discussed. Our results show that the myelocytic and monocytic phenotypes are characterized by a specific pattern of phosphoproteins involving both phosphorylation and dephosphorylation reactions.

Calcitriol↗

PubMedDate not supplied

Retinoids and differentiation treatment: a strategy for treatment in cancer.

The retinoids are a large group of compounds structurally related to vitamin A. Retinoids elicit specific biological responses by binding to and activating nuclear receptors. Information about the metabolism and storage of vitamin A and retinoids, their plasma transport and uptake and the retinoid dose efficient on target cell had to be established because retinoic acid (RA), the natural acidic derivative of vitamin A (retinol), is likely to be a key factor during specific phases of embryonic development and maintenance of normal differentiated phenotypes in adult, so vitamin A is involved in the normal morphological differentiation of the visual system. RA appears an important agent since it induces in vitro leukemic cells from acute promyelocytic leukemia (APL) to differentiate into mature functional granulocytes which lose their self-renewal ability and die spontaneously. In vivo, APL patients treated with oral all-trans retinoic acid (all-trans RA) alone achieve complete remission in 80% of the cases. APL results from a malignant process that leads to the accumulation in the blood and in the bone marrow of myeloid precursor cells characterized by an abnormal behavior and a differentiation arrest. APL is characterized cytogenetically by a t(15;17) translocation which involves both the PML gene on chromosome 15 and the RARa gene on chromosome 17 and gives rise to the PML/RARa fusion protein. The high sensitivity of the promyelocytic blasts to all-trans RA should be related to the presence in APL blast of an abnormal protein, the PML/RAR alpha. The antineoplastic effects of retinoids suggest that these drugs could be used therapeutically for the chemoprevention of cancer.

Animals↗