Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

R115777 is a nonpeptidomimetic enzyme-specific inhibitor of farnesyl protein transferase (FT) that was developed as a potential inhibitor of Ras protein signaling, with antitumor activity in preclinical models. This study was a phase 1 trial of orally administered R115777 in 35 adults with poor-risk acute leukemias. Cohorts of patients received R115777 at doses ranging from 100 mg twice daily (bid) to 1200 mg bid for up to 21 days. Dose-limiting toxicity occurred at 1200 mg bid, with central neurotoxicity evidenced by ataxia, confusion, and dysarthria. Non-dose-limiting toxicities included reversible nausea, renal insufficiency, polydipsia, paresthesias, and myelosuppression. R115777 inhibited FT activity at 300 mg bid and farnesylation of FT substrates lamin A and HDJ-2 at 600 mg bid. Extracellular signal-regulated kinase (ERK), an effector enzyme of Ras-mediated signaling, was detected in its phosphorylated (activated) form in 8 (36.4%) of 22 pretreatment marrows and became undetectable in 4 of those 8 after one cycle of treatment. Pharmacokinetics revealed a linear relationship between dose and maximum plasma concentration or area under the curve over 12 hours at all dose levels. Weekly marrow samples demonstrated that R115777 accumulated in bone marrow in a dose-dependent fashion, with large increases in marrow drug levels beginning at 600 mg bid and with sustained levels throughout drug administration. Clinical responses occurred in 10 (29%) of the 34 evaluable patients, including 2 complete remissions. Genomic analyses failed to detect N-ras gene mutations in any of the 35 leukemias. The results of this first clinical trial of a signal transduction inhibitor in patients with acute leukemias suggest that inhibitors of FT may have important clinical antileukemic activity. (Blood. 2001;97:3361-3369)
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PMID:Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. 1136 25

Ras oncogenes (K-, H- and N-ras) are known to be involved in signal transduction pathways regulating cell growth and differentiation in many human cancers. These proteins are synthesized as a cytosolic precursor that ultimately localizes to the inner plasma membrane. This process is initiated by the attachment of a farnesyl moiety to the protein and is catalysed by the farnesyl transferase. Since activated (mutated) ras oncogenes have been shown to be essential for the malignant phenotype in many tumors, farnesyl transferase inhibitors (FTIs) have emerged as a novel class of antineoplastic agents. Four FTIs are currently in clinical trials. Two of these agents, R-115777 and SCH-66336, are orally active heterocyclic compounds and already in phase II/III studies. Preliminary results of R-115777 or SCH-66336 in combination with gemcitabine or 5-FU/FA in patients with advanced pancreatic carcinomas have been reported. The dose-limiting toxicity was neutropenia, nausea, diarrhea and fatigue. The recommended doses for phase II studies were 200 mg R-115777 or 2 x 200 mg SCH-66336. Durable objective partial responses were noted in several patients. Furthermore, the FTIs were found to be well tolerated. Ongoing phase III studies in patients with advanced pancreatic cancers will determine the extent of clinical activity and whether these agents can be used as single agents for the treatment of pancreatic carcinomas or have to be used in combination with other cytostatic drugs. In addition, it remains to be clarified whether FTIs may sensitize drug-resistant cancers following conventional chemotherapy.
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PMID:Farnesyltransferase inhibitors--a novel approach in the treatment of advanced pancreatic carcinomas. 1282 Mar 5