tretinoin and 4-phenylbutyric-acid

Successful treatment of acute promyelocytic leukemia (APL) has identified several novel approaches to induce leukemic cell differentiation and selective apoptosis by overcoming the site-specific transcriptional repression by dominant fusion leukemogenic proteins characteristic of APL and other forms of acute myelogenous leukemia (AML). These therapeutic approaches include the use of site-specific ligands, receptors and cytokines, disruption of dominant fusion leukemogenic proteins, chromatin remodeling and combining the above with cytotoxic chemotherapy. With the exception of cytotoxic chemotherapy, the above therapeutic strategies do not significantly affect normal hematopoiesis and their combinations have been shown to be synergistic in inducing myeloid differentiation and apoptosis in several AML cell lines and in patients with APL. These approaches are, in general, non-cross resistant and should be well tolerated particularly in elderly patients with AML. Clinical studies which include biologic end points for differentiation induction, histone acetylation and selective apoptosis are presently in development to evaluate these strategies in the treatment of AML.

Topics: Acute Disease; Adult; Aged; Animals; Antineoplastic Agents; Apoptosis; Butyrates; Cell Differentiation; Cholecalciferol; Chromatin; Drug Design; Drug Synergism; Gene Expression Regulation, Leukemic; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid; Ligands; Mice; Middle Aged; Oncogene Proteins, Fusion; Phenylbutyrates; Transcription, Genetic; Translocation, Genetic; Tretinoin

Topics: Acetylation; Adult; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Child; China; Chromatin; Drug Evaluation; Drug Resistance, Neoplasm; Enzyme Inhibitors; Gastrointestinal Diseases; Histone Deacetylase Inhibitors; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Melarsoprol; Neoplasm Proteins; Neoplasms; Nervous System Diseases; Oxides; Phenylbutyrates; Protein Processing, Post-Translational; Salvage Therapy; Tretinoin

Overexpression of Her2/neu is implicated in the development of resistance to the antiestrogen tamoxifen (TAM) that exerts its inhibitory effect through interaction with estrogen receptor (ER). Whereas Her2/neu and ER are believed to be important cell survival/death factors in human breast cancer cells, if and how they interact to confer resistance to hormone therapy is not known. This prompted us to investigate whether modulation of the effect of TAM occurs via the Her2/neu pathway and whether targeting the interaction between the Her2/neu pathway and the ER pathway is beneficial. There are 2 forms of ER that are localized to the cell membrane and to the nucleus. For the first time, we found that Her2/neu directly interacts with ER at the cell membrane. We then investigated the role of Her2/neu overexpression in the regulation of the cell membrane ER pathway in TAM-resistant breast cancer cells and the nature of this interaction in apoptotic signaling. Relief of TAM resistance was associated with Her2/neu downregulation and ER upregulation. TAM-induced apoptosis occurred immediately after dissociation of Her2/neu from cell membrane ER. These results demonstrate a novel mechanism by which Her2/neu regulates the cell membrane ER-coupled apoptosis and the possible involvement of the Her2/neu in TAM resistance of breast cancer cells. Moreover, the antiproliferative activity of TAM should rely on the integration between the signal transduction from the cell membrane ER and the gene regulation by the nuclear ER. Coordinated modulation on the cell membrane ER/Her2/neu pathway and the nuclear ER/RAR pathway may provide a new approach for treatment of ER-positive, Her2/neu overexpressing breast cancer.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Breast Neoplasms; Caspase 3; Caspases; Cell Membrane; Cell Nucleus; Cell Separation; Cytosol; DNA Fragmentation; Down-Regulation; Drug Resistance, Neoplasm; Flow Cytometry; Humans; Immunohistochemistry; Microscopy, Confocal; Microscopy, Fluorescence; Mitochondria; Phenylbutyrates; Precipitin Tests; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Retinoic Acid; Subcellular Fractions; Tamoxifen; Time Factors; Tretinoin; Tumor Cells, Cultured

Acetylation of DNA-associated histones is linked to activation of gene transcription, whereas histone deacetylation is associated with transcriptional repression. Recent studies have shown that inhibitors of histone deacetylases can relieve transcriptional repression caused by the products of certain oncogenes. We tested whether these findings could be applied clinically to a patient with highly resistant acute promyelocytic leukemia.. A patient who had experienced multiple relapses was treated with all-trans-retinoic acid alone and in combination with sodium phenylbutyrate, an inhibitor of histone deacetylases. Immunohistochemistry and western blot analysis were used to assay for histone hyperacetylation in mononuclear cells from the patient's blood and bone marrow. Marrow mononuclear cells and reverse transcription-polymerase chain reaction (RT-PCR) analysis of messenger RNA encoded by the PML/RAR-alpha oncogene were used to assess minimal residual disease.. The patient proved clinically resistant to treatment with all-trans-retinoic acid alone. However, 23 days after sodium phenylbutyrate was added to the treatment regimen, visible leukemic cells had been eliminated from her bone marrow, and she achieved a complete clinical and cytogenetic remission shortly thereafter. With a second treatment course, analysis for minimal residual disease by RT-PCR proved negative. Immunofluorescence and western blot analysis showed that phenylbutyrate caused a time-dependent increase in histone acetylation in blood and bone marrow mononuclear cells.. Clinical treatment with an inhibitor of histone deacetylase induces histone hyperacetylation in target cells and may restore sensitivity to the anti-leukemic effects of all-trans-retinoic acid in acute promyelocytic leukemia. Similar therapy may prove useful in other neoplastic diseases that are associated with oncogenic repression of gene transcription due to recruitment of histone deacetylases.

Topics: Acetylation; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; Drug Administration Schedule; Female; Fluorescent Antibody Technique; Histone Deacetylases; Humans; Leukemia, Promyelocytic, Acute; Phenylbutyrates; Reverse Transcriptase Polymerase Chain Reaction; Transcription, Genetic; Tretinoin