Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The farnesyltransferase inhibitors (FTIs) have been shown in early clinical trials to elicit antitumor actions in a broad range of solid and hematologic malignancies. The mechanism of FTI action involves blockade of farnesyltransferase, an enzyme implicated in multiple cell-signaling pathways involved in proliferation, angiogenesis, or decreased apoptosis. Of the four main classes of FTIs, two orally bioavailable FTIs have advanced farthest in clinical development. ZARNESTRA (formerly R115777, Ortho Biotech Oncology, Raritan, NJ) and Sarasar (formerly SCH66336, Schering-Plough, Kenilworth, NJ) have demonstrated biologic and clinical activity in a range of solid tumors, and Zarnestra phase I trials have documented clinical responses in approximately 30% of patients with high-risk leukemias or myelodysplastic syndrome (MDS). The main across-class toxicities associated with the use of FTIs are myelosuppression and fatigue. Certain toxicities, such as the QTc abnormalities associated with L-778,123, do not appear to be class related. As results of phase II trials with FTIs in acute and chronic myeloid leukemias and in MDS become available, clinicians will learn more about the potential role of this class of targeted anticancer drugs-and possibly about the clinical distinctions among members of this class.
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PMID:Farnesyltransferase inhibitors: novel compounds in development for the treatment of myeloid malignancies. 1221 90

R115777 is a potent farnesyltransferase (FTase) inhibitor with substantial antitumor activity in preclinical models. We conducted a phase 1 study (3 + 3 design) of R115777 in patients with myelodysplastic syndrome (MDS). R115777 was administered twice daily (3-weeks-on/1-week-off schedule for 8 weeks) (starting dosage, 300 mg by mouth twice daily; total, 600 mg). Maintenance therapy at the dose/schedule tolerated during induction could be continued until toxicity or lack of benefit. Twenty-one patients with MDS were treated (median age, 66 years). Four (19%) patients had ras mutations (n-ras,3; k-ras, 1). Objective responses (hematologic improvement, 3; partial remission, 2; or complete remission, 1) were seen in 6 of 20 (30%) evaluable patients, only 2 of whom had ras mutations. Response sequences were unusual in some patients who had increases in platelet counts without intervening aplasia. Other responders demonstrated an initial, albeit modest, myelosuppressive effect. The maximum tolerated dose was 400 mg by mouth twice a day. The most frequent side effect was myelosuppression. Dose-limiting toxicities (fatigue and confusion) occurred at 900 mg by mouth total daily dose. R115777 inhibited HDJ-2 prenylation and suppressed the activity of FTase, but not of the related geranylgeranyltransferase I enzyme, in peripheral blood mononuclear cells. Modulation of Akt, Erk, and signal transducer and activator of transcription 3 (STAT3) phosphorylation was variable, and responses occurred even without their down-regulation. Reductions in serum tumor necrosis factor-alpha (TNF-alpha) levels by day 7 showed a trend toward correlation with response (P =.09). We conclude that, at doses that are well tolerated, R115777 markedly inhibits the FTase target and has antitumor activity in MDS.
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PMID:Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting. 1294 10

Patients with multiple myeloma (MM) with mutated RAS are less likely to respond to chemotherapy and have a shortened survival. Therefore, targeting RAS farnesylation may be a novel approach to treatment of MM. We evaluated the activity and tolerability of the farnesyltransferase (FTase) inhibitor tipifarnib (Zarnestra) in a phase 2 trial as well as its ability to inhibit protein farnesylation and oncogenic pathways in patients with relapsed MM. Forty-three patients (median age, 62 years [range, 33-82 years]) with a median of 4 (range, 1-6) chemotherapy regimens entered the study. Tipifarnib, 300 mg orally twice daily, was administered for 3 weeks every 4 weeks. The most common toxicity was fatigue occurring in 66% of patients. Other toxicities included diarrhea, nausea, neuropathy, anemia, and thrombocytopenia. Sixty-four percent of the patients had disease stabilization. Treatment with tipifarnib suppressed FTase (but not geranylgeranyltransferase I) in bone marrow and peripheral blood mononuclear cells and also inhibited the farnesylation of HDJ-2 in unfractionated mononuclear cells and purified myeloma cells. Inhibition of farnesylation did not correlate with disease stabilization. Finally, tipifarnib decreased the levels of phosphorylated Akt and STAT3 (signal transducer and activator of transcription 3) but not Erk1/2 (extracellular signal regulated kinase 1 and 2) in bone marrow cells. We conclude that tipifarnib is tolerable, can induce disease stabilization, and can inhibit farnesylation and oncogenic/tumor survival pathways.
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PMID:Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma. 1472 2

The farnesyltransferase inhibitors (FTIs) are in active clinical development in a variety of human malignancies. The most promising activity to date has been demonstrated in patients with hematological malignancies, in particular acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). In patients with MDS, two non-peptidomimetic agents, tipifarnib (Zarnestra, Johnson & Johnson, New Brunswick, NJ) and lonafarnib (Sarasar, Schering-Plough, Kenilworth, NJ) have been the most extensively studied. In both phase I and phase II trials, tipifarnib has demonstrated significant efficacy with overall response rates of 30%, with complete remissions in about 15%. Dose-limiting side effects have been primarily myelosuppression, although fatigue, neurotoxicity, and occasional renal dysfunction have required dose reductions. Lonafarnib in patients with MDS has also resulted in clinical responses in approximately 30%, including significant improvements in platelet counts. Lonafarnib has been associated with primarily diarrhea and other gastrointestinal toxicity, anorexia, and nausea, which has limited its efficacy. Clinical response correlation with documentation of inhibition of farnesyltransferase and/or evidence of decreased farnesylation of downstream protein targets has not been demonstrated with either agent. In addition, the presence of an activating Ras mutation has not predicted response to therapy with FTIs in MDS and AML. Despite this, significant clinical efficacy of the FTIs in MDS, on par with that of currently available chemotherapeutic agents, has been observed, leading to further development of this new class of drugs in MDS and AML.
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PMID:Farnesyltransferase inhibitors in myelodysplastic syndrome. 1586 70

Patients with primary myelofibrosis (PMF) or post-polycythemia vera or post-essential thrombocythemia myelofibrosis (post-PV/ET MF) have limited therapeutic options. The farnesyltransferase-inhibitor tipifarnib inhibits in vitro proliferation of myeloid progenitors from such patients. In the current phase II clinical trial, single-agent oral tipifarnib (300 mg twice daily x 21 of 28 days) was given to 34 symptomatic patients with either PMF (n=28) or post-PV/ET MF (n=6). Median time to discontinuation of protocol therapy was 4.6 months; reasons for early termination (n=19; 56%) included disease progression (21%) and adverse drug effects (18%). Toxicities (>/=grade 3) included myelosuppression (n=16), neuropathy (n=2), fatigue (n=1), rash (n=1) and hyponatremia (n=1). Response rate was 33% for hepatosplenomegaly and 38% for transfusion-requiring anemia. No favorable changes occurred in bone marrow fibrosis, angiogenesis or cytogenetic status. Pre- and post-treatment patient sample analysis for in vitro myeloid colony growth revealed substantial reduction in the latter. Clinical response did not correlate with either degree of colony growth, measurable decrease in quantitative JAK2(V617F) levels or tipifarnib IC(50) values (median 11.8 nM) seen in pretreatment samples. The current study indicates both in vitro and in vivo tipifarnib activity in PMF and post-PV/ET MF.
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PMID:A phase II trial of tipifarnib in myelofibrosis: primary, post-polycythemia vera and post-essential thrombocythemia. 1758 8

The farnesyltransferase inhibitors (FTIs) are in active clinical development in a variety of human malignancies. The most promising activity to date has been demonstrated in patients with hematologic malignancies, in particular acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). In patients with MDS, two nonpeptidomimetic agents, tipifarnib (Zarnestra, Johnson & Johnson, New Brunswick, NJ) and lonafarnib (Sarasar, Schering-Plough, Kenilworth, NJ) have been the most extensively studied. In both phase I and phase II trials, tipifarnib has demonstrated significant efficacy, with overall response rates of 30% and complete remissions in about 15%. Dose-limiting adverse effects have been primarily myelosuppression, although fatigue, neurotoxicity, and occasional renal dysfunction have required dose reductions. Lonafarnib in patients with MDS has also resulted in clinical responses in approximately 30%, including significant improvements in platelet counts. Lonafarnib has been associated primarily with diarrhea and other gastrointestinal toxicity, anorexia, and nausea, which has limited its efficacy. Clinical response correlation with documentation of inhibition of farnesyltransferase and/or evidence of decreased farnesylation of downstream protein targets has not been demonstrated with either agent. In addition, the presence of an activating Ras mutation has not predicted response to therapy with FTIs in MDS and AML. Despite this lack of evidence, significant clinical efficacy of the FTIs has been observed in MDS, on a par with the efficacy of currently available chemotherapeutic agents, leading to further development of this new class of drugs in MDS and AML.
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PMID:Farnesyltransferase inhibitors in myelodysplastic syndrome. 2042 27

A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib was conducted in 93 adult patients with relapsed or refractory lymphoma. Patients received tipifarnib 300 mg twice daily on days 1-21 of each 28-day cycle. The median number of prior therapies was 5 (range, 1-17). For the aggressive B-cell, indolent B-cell, and T-cell and Hodgkin lymphoma (HL/T) groups, the response rates were 17% (7/42), 7% (1/15), and 31% (11/36), respectively. Of the 19 responders, 7 were diffuse large B-cell non-Hodgkin lymphoma (NHL), 7 T-cell NHL, 1 follicular grade 2, and 4 HL. The median response duration for the 19 responders was 7.2 months (mean, 15.8 months; range, 1.8-62), and 5 patients in the HL/T group are still receiving treatment at 29-64+ months. The grade 3/4 toxicities observed were fatigue and reversible myelosuppression. Correlative studies suggest that Bim and Bcl-2 should be examined as potential predictors of response in future studies. These results indicate that tipifarnib has activity in lymphoma, particularly in heavily pretreated HL/T types, with little activity in follicular NHL. In view of its excellent toxicity profile and novel mechanism of action, further studies in combination with other agents appear warranted. This trial is registered at www.clinicaltrials.gov as #NCT00082888.
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PMID:Multi-institutional phase 2 study of the farnesyltransferase inhibitor tipifarnib (R115777) in patients with relapsed and refractory lymphomas. 2172 56