losartan-potassium and tipifarnib

The pathogenetic mechanisms underlying the clonal myeloproliferation and reactive marrow fibrosis that characterize myelofibrosis with myeloid metaplasia (MMM) are poorly understood. Recent advances into the pathophysiology of the disease have not yet translated into effective therapeutic options for patients. There is no standard treatment, and no therapies identified yet, besides allogeneic stem cell transplantation, that will significantly change the natural history of MMM. Treatment is therefore palliative and is geared towards alleviating symptoms of the disease and improving blood counts. Conventional therapies for anemia include androgens and corticosteroids. Cytoreductive agents such as hydroxyurea are indicated for symptomatic organomegaly and the control of leucocytosis or thrombocytosis. Several novel agents have been investigated in the recent past, and include antiangiogenic agents and signal transduction inhibitors that target the angiogenic and fibrogenic cytokines that have been implicated in the pathogenesis of the detrimental bone marrow stromal reaction. Ultimately, an improved understanding of the biological factors that cause the clonal myeloproliferation in MMM will lead to the development of effective therapeutic interventions.

Topics: Androgens; Angiogenesis Inhibitors; Antineoplastic Agents; Azacitidine; Benzamides; Chronic Disease; Decitabine; Erythropoietin; Humans; Imatinib Mesylate; Piperazines; Primary Myelofibrosis; Pyrimidines; Quinolones; Recombinant Proteins

In the postgenome era, development of novel targeted therapeutics is anticipated to accelerate, with the promise of specifically tailored strategies to treat specific molecularly characterized disease entities. Greater understanding of disease pathophysiology and pharmacologic actions at the molecular, cellular, and tissue levels have provided the basis for expanding the clinical application of available therapies such as recombinant human erythropoietin (r-HuEPO, epoetin alfa). The role of epoetin alfa in anemic cancer patients receiving chemotherapy has grown as our understanding of the relationship between anemia and quality of life in this patient population has evolved. With anemia and tumor hypoxia associated with poorer outcomes in various solid tumors, the potential impact of epoetin alfa on outcomes, as well as quality of life, in patients undergoing radiation or chemoradiation is of considerable interest. Anemia occurs almost universally in critically ill patients, resulting in substantial transfusion requirements. In this setting, the anemia appears to be consistent with anemia of chronic inflammatory disease and is potentially treatable by epoetin alfa. Recent preclinical studies indicate that erythropoietin exhibits neuroprotective effects in models of central nervous system injury, suggesting additional potential novel clinical applications for epoetin alfa worthy of careful investigation. Advances in the understanding of the ras genes and their functional proteins in signaling pathways involved in the development of cancer, particularly hematologic malignancies, over the last decade have prompted development of a new class of agents, farnesyl protein transferase inhibitors (FTIs), designed specifically to inhibit the initial step in Ras protein activation. Initial clinical evaluation of FTIs is ongoing, and preliminary results demonstrate antitumor activity in hematologic malignancies. Further identification and understanding of the function and complex interactions of proteins involved in diseases holds the promise of targeted therapies and improved patient outcomes.

Topics: Alkyl and Aryl Transferases; Anemia; Enzyme Inhibitors; Erythropoietin; Farnesyltranstransferase; Humans; Neoplasms; Quinolones; Recombinant Proteins

Polycythemia vera (PV) is an acquired myeloproliferative disorder with primary expansion of the red cell mass leading to an increased risk of thrombosis and less frequently to myelofibrosis and secondary acute leukemia. Standard therapies include cytoreduction with either phlebotomy or chemotherapeutic agents and antithrombotic drugs. Because long-term exposure to cytotoxic chemotherapy may increase the risk of acute transformation, new therapeutic options are needed. Tipifarnib is a nonpeptidomimetic inhibitor of farnesyl transferase that was developed as a potential inhibitor of RAS signaling. In the present study we report that tipifarnib used at pharmacologically achievable concentrations strongly inhibits the erythroid burst-forming unit (BFU-E) autonomous growth that characterizes patients with PV. Moreover, at low tipifarnib concentrations (0.15 muM), the inhibitory effect was preferentially observed in PV BFU-E progenitors and not in normal BFU-E progenitors and was not rescued by erythropoietin (EPO). Thus tipifarnib may specifically target PV stem cells and may be of clinical interest in the treatment of patients with PV.

Topics: Alkyl and Aryl Transferases; Case-Control Studies; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Farnesyltranstransferase; Humans; Polycythemia Vera; Quinolones