Disease relevance of Zarnestra

• We tested 52 pediatric acute myeloid leukemia (AML) and 36 pediatric acute lymphoblastic leukemia (ALL) samples for in vitro sensitivity to tipifarnib using a total cell-kill assay and compared these results to those obtained with normal bone marrow (N BM) samples (n = 25) [1].
• Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma [2].
• Farnesyltransferase inhibitor tipifarnib (R115777) preferentially inhibits in vitro autonomous erythropoiesis of polycythemia vera patient cells [3].
• CONCLUSION: The combination of gemcitabine and tipifarnib has an acceptable toxicity profile but does not prolong overall survival in advanced pancreatic cancer compared with single-agent gemcitabine [4].
• PATIENTS AND METHODS: Recurrent malignant glioma patients were treated with tipifarnib using an interpatient dose-escalation scheme [5].
• The MTD of tipifarnib administered was estimated as 125 mg/m(2)/dose b.i.d. When administered concurrently with radiation, the dose-limiting toxicities of tipifarnib are rash, infection with normal ANC, and neutropenia [6].
• Tipifarnib inhibits FTase activity in human breast tumors in vivo, is associated with down-regulation of p-STAT3, and enhances the breast pCR rate, thus meriting further evaluation [7].

High impact information on Zarnestra

• 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) [3].
• AML samples were significantly more sensitive to tipifarnib compared to B-cell precursor ALL (BCP ALL) or N BM samples [1].
• In vitro profiling of the sensitivity of pediatric leukemia cells to tipifarnib: identification of T-cell ALL and FAB M5 AML as the most sensitive subsets [1].
• Thus tipifarnib may specifically target PV stem cells and may be of clinical interest in the treatment of patients with PV [3].
• 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 [2].

Chemical compound and disease context of Zarnestra

• Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer [4].
• CONCLUSIONS: Tipifarnib (200 mg twice daily for 21 of 28 days) and tamoxifen (20 mg once daily) can be given safely with minimal toxicity [8].
• In this study, we investigated the activity of tipifarnib (Zarnestra, formerly R115777) combined with bortezomib (Velcade, formerly PS-341) in microenvironment models of multiple myeloma and AML [9].
• Diarrhea and palmar-plantar erythrodysesthesia were dose limiting at 300 mg tipifarnib/1125 mg/m(2) capecitabine b.i.d. When the capecitabine dose was fixed at 1000 mg/m(2) b.i.d., neutropenia was dose limiting at 400 and 500 mg b.i.d. of tipifarnib [10].
• The influence of farnesyl protein transferase inhibitor R115777 (Zarnestra) alone and in combination with purine nucleoside analogs on acute myeloid leukemia progenitors in vitro [11].

Biological context of Zarnestra

• We conclude that tipifarnib is tolerable, can induce disease stabilization, and can inhibit farnesylation and oncogenic/tumor survival pathways [2].
• This study compares the pharmacokinetics and pharmacodynamics of tipifarnib at MTD in patients on and off EIAEDs [5].
• PURPOSE: To determine the maximum-tolerated dose (MTD), toxicities, and clinical effect of tipifarnib, a farnesyltransferase (FTase) inhibitor, in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs (EIAEDs) [5].
• Proliferation and apoptosis assays after exposure to DNR in the presence or absence of tipifarnib demonstrated synergistic inhibition of cellular proliferation, and induction of apoptosis with the combination of tipifarnib and DNR [12].
• Budesonide (an anti-inflammatory glucocorticoid), R115777 (a farnesyl transferase inhibitor, Zarnestra, Tipifarnib) or combinations of them were evaluated for prevention of lung tumors and for modulation of DNA methylation in tumors [13].

Anatomical context of Zarnestra

• 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 [3].
• The farnesyl transferase inhibitor, tipifarnib, is a potent inhibitor of the MDR1 gene product, P-glycoprotein, and demonstrates significant cytotoxic synergism against human leukemia cell lines [12].
• The STOP trial objectives are to evaluate the effect of gefitinib and tipifarnib on histologic and biologic parameters in patients with evidence of sputum atypia, to evaluate various parameters as potential predictors of the effectiveness of these agents, and to evaluate the tolerability of these agents over a 6-month course of treatment [14].

Associations of Zarnestra with other chemical compounds

• R115777 (Zarnestra) is a farnesyl protein transferase inhibitor currently undergoing worldwide clinical trials [15].
• Tamoxifen does not have a significant effect on tipifarnib pharmacokinetics [8].
• Measurement of residual daunorubicin (DNR)-mediated fluorescence after incubation with DNR and tipifarnib demonstrated that tipifarnib significantly inhibited DNR efflux in CCRF-CEM with an IC(50) value less than 0.5 muM [12].
• Pharmacokinetics of tipifarnib, capecitabine and 5-fluorouracil (5-FU) were determined [10].
• Phase I and pharmacological study of the farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777) in combination with gemcitabine and cisplatin in patients with advanced solid tumours [16].
• Dose-limiting toxicity was rash, and the recommended phase II dose is sorafenib 400 mg p.o. qam/200 mg p.o. qpm and tipifarnib p.o. 100 mg bd [17].

Gene context of Zarnestra

• In primary human peripheral blood mononuclear cells, dose-dependent inhibition of LPS-induced tumor necrosis factor (TNF)-alpha, IL-6, MCP-1, and IL-1beta by tipifarnib was observed with no evidence of cytotoxicity [18].
• Overall, this study indicates that ABCB1 genotype might be correlated with tipifarnib pharmacokinetics, although considerable overlap in exposure measures between genotype groups was observed [19].
• Similar results were obtained in vivo in a murine model of LPS-induced inflammation, where pretreatment with tipifarnib resulted in significant inhibition of TNF-alpha, IL-6, MCP-1, IL-1beta, and MIP-1alpha production [18].
• Tipifarnib had no effect in vitro or in vivo on LPS-induced IL-8 [18].
• Computer simulations were undertaken to explore the CYP2D6 genotype effect on the tipifarnib pharmacokinetics [20].

Analytical, diagnostic and therapeutic context of Zarnestra

• The primary objective of this study was to identify intravenous regimens of tipifarnib that would mimic the systemic exposure obtained after the current twice-daily oral administration of tipifarnib [21].
• A total of 1083 subjects treated orally with a solution, capsule or tablet formulations of tipifarnib, given as a single dose or as multiple twice-daily doses (range 25-1300 mg) were combined with data from 1, 2 and 24 h intravenous infusions [22].
• It can be concluded that (123)I-Annexin V can be used to monitor Tipifarnib-induced apoptosis in LoVo xenograft tumours in athymic mice [23].
• Combination trials of tipifarnib with cytotoxic, hormonal or biological therapies are ongoing [24].
• Microarray analysis reveals genetic pathways modulated by tipifarnib in acute myeloid leukemia [25].

References