Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

R115777 (Tipifarnib, Zarnestra)-farnesyl transferase inhibitor belongs to the new class of signal transduction inhibitors which seems to be yielding results in the treatment of patients with solid tumors. Recently it has also been considered as a drug of promise in hematologic malignancies such as acute myeloid leukemia (AML), especially in older patients, in chronic myelogenous leukemia (CML) as well as myelodysplastic syndromes (MDS). The aim of our study was to evaluate the influence of R115777 used alone or with purine nucleoside analogs (PNA): cladribine (2-CdA) and fludarabine (F-ara-A) on leukemic progenitors [colony-forming unit-leukemia (CFU)-L] from AML patients. Our studies were based on the methods of semisolid leukemic CFU-L and normal granulocyte-macrophage progenitor (CFU-GM) cultures in vitro. R115777 was added to the culture alone or in combinations with PNA. We showed that R115777 used alone or together with PNA at all combinations significantly inhibited the colony growth of AML CFU-L, when compared with normal CFU-GM (P < 0.01). In addition, the drugs used in combinations of two higher concentrations in significantly higher degree inhibited CFU-L colony growth, when compared either with R115777 or with any of PNA used alone (P < 0.04). IC(50) for R115777 were 67.1 and 121.9 nm for AML CFU-L and normal CFU-GM, respectively. Furthermore, in the case of AML the combination index was 0.89 and 1.16, respectively, for the combination of R115777 with 2-CdA and R115777 with F-ara-A. An additive effect on AML CFU-L cells and subadditive effect on normal CFU-GM were seen. To assess a proapoptotic effect, the drugs were added to the liquid cultures at the same concentrations as for clonogenic assays. A significant increase in the rate of apoptosis induced by combinations of drugs in comparison with single agents was observed. In conclusion, the combination of R115777 with both PNA could be more effective than the drugs used alone. However, further experimental studies on the usefulness of these combinations in the treatment of myeloid leukemia patients are warranted.
 ...
PMID:The influence of farnesyl protein transferase inhibitor R115777 (Zarnestra) alone and in combination with purine nucleoside analogs on acute myeloid leukemia progenitors in vitro. 1552 64

Farnesyltransferase inhibitors (FTIs) inhibit certain cellular signal transduction pathways, and are being evaluated for activity in hematologic malignancies. Tipifarnib and lonafarnib are orally available FTIs that are active against a variety of targets and inhibit several pathways involved in the pathogenesis of hematologic malignancies. FTIs have demonstrated activity in a variety of hematologic diseases, including acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia, and multiple myeloma. This article reviews the clinical experience with tipifarnib and lonafarnib in the treatment of hematologic malignancies.
 ...
PMID:Farnesyltransferase inihibitors in hematologic malignancies. 1729 17

Increased understanding of the cellular mechanisms associated with various malignancies has allowed researchers to develop agents that selectively target the cellular proteins and pathways implicated in the pathogenesis of malignancy. Tipifarnib is a specific and potent farnesyltransferase inhibitor that demonstrates in vivo and in vitro activity against a variety of human cancers. Although tipifarnib was initially thought to target the Ras protein, recent evidence suggests that the presence of ras mutations is not necessary for the antitumor effects of tipifarnib, and that tipifarnib may exert its effects downstream of Ras. The oral administration and favorable toxicity profile of tipifarnib, combined with its activity in a variety of intracellular pathways that have been implicated in the pathogenesis of hematologic malignancies, make it an especially attractive agent for use in patients with acute myeloid leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia (CML), and multiple myeloma. Because hematologic malignancies are likely driven by multiple genetic aberrations, the most effective treatment strategy will likely combine multiple agents with complementary mechanisms of action. Thus, additional studies of combination regimens that incorporate tipifarnib with other antineoplastic agents are crucial. Early results from studies combining tipifarnib with imatinib or etoposide in CML and AML have been promising and warrant further evaluation in larger clinical trials.
 ...
PMID:Farnesyltransferase inhibition in hematologic malignancies: the clinical experience with tipifarnib. 1849 98

Farnesyltransferase inhibitors (FTIs) represent a new class of signal transduction inhibitors that block the processing of cellular polypeptides that have cysteine terminal residues and, by so doing, interdict multiple pathways involved in proliferation and survival of diverse malignant cell types. Tipifarnib is an orally bioavailable, nonpeptidomimetic methylquinolone FTI that has exhibited clinical activity in patients with myeloid malignancies including elderly adults with acute myelogenous leukemia (AML) who are not candidates for traditional cytotoxic chemotherapy, patients with high-risk myelodysplasia, myeloproliferative disorders, and imatinib-resistant chronic myelogenous leukemia. Because of its relatively low toxicity profile, tipifarnib provides an important alternative to traditional cytotoxic approaches for elderly patients who are not likely to tolerate or even benefit from aggressive chemotherapy. In this review, we will focus on the clinical development of tipifarnib for treatment of newly diagnosed AML, both as induction therapy for elderly adults with poor-risk AML and as maintenance therapy following achievement of first complete remission following induction and consolidation therapies for poor-risk AML. As with all other malignancies, the optimal approach is likely to lie in rational combinations of tipifarnib with cytotoxic, biologic and/or immunomodulatory agents with non-cross-resistant mechanisms of action. Gene expression profiling has identified networks of differentially expressed genes and gene combinations capable of predicting response to single agent tipifarnib. The clinical and correlative laboratory trials in progress and under development will provide the critical foundations for defining the optimal roles of tipifarnib and in patients with AMl and other hematologic malignancies.
 ...
PMID:Tipifarnib in the treatment of newly diagnosed acute myelogenous leukemia. 1970 79