Faculty Collaboration Database

Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting. Blood 2003 Dec 15;102(13):4527-34

Date

08/30/2003

Pubmed ID

12947010

DOI

10.1182/blood-2002-11-3359

Scopus ID

2-s2.0-10744227474 (requires institutional sign-in at Scopus site)   129 Citations

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.

Author List

Kurzrock R, Kantarjian HM, Cortes JE, Singhania N, Thomas DA, Wilson EF, Wright JJ, Freireich EJ, Talpaz M, Sebti SM

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged
Alkyl and Aryl Transferases
Carrier Proteins
Dose-Response Relationship, Drug
Enzyme Activation
Enzyme Inhibitors
Farnesyltranstransferase
Female
Genes, ras
HSP40 Heat-Shock Proteins
Heat-Shock Proteins
Humans
Male
Maximum Tolerated Dose
Middle Aged
Myelodysplastic Syndromes
Protein Prenylation
Protein Processing, Post-Translational
Proto-Oncogene Proteins p21(ras)
Quinolones
Remission Induction
Signal Transduction
Treatment Outcome
Tumor Necrosis Factor-alpha