title: Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting.
abstract: 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.
authors.affiliation: Department of Bioimmunotherapy, Unit 422, 1515 Holcombe Blvd, Houston, TX 77030, USA. rkurzroc@mdanderson.org
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.forename: Neil
authors.initials: N
authors.lastname: Singhania
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Thomas
authors.forename: Edward F
authors.initials: EF
authors.lastname: Wilson
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: Emil J
authors.initials: EJ
authors.lastname: Freireich
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
authors.forename: Saïd M
authors.initials: SM
authors.lastname: Sebti
mesh_terms: D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D051231:Farnesyltranstransferase; D005260:Female; D011905:Genes, ras; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000201:enzymology; D017368:Protein Prenylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D015363:Quinolones / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D012074:Remission Induction; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D002352:Carrier Proteins; C107481:DNAJA1 protein, human; D004791:Enzyme Inhibitors; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D015363:Quinolones; D014409:Tumor Necrosis Factor-alpha; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); C402769:tipifarnib