Effect of farnesyl transferase inhibitor R115777 on the growth of fresh and cloned myeloma cells in vitro.
Ras gene mutations occur in 30% to 40% of patients with multiple myeloma (MM), and farnesylation is the first and most important step in the posttranslational modification of Ras proteins. R115777 is a newly synthesized potent farnesyl transferase inhibitor (FTI) and has recently demonstrated significant antitumor activities in vitro and in vivo. Therefore, we examined the effect of R115777 on the growth of fresh and cloned myeloma cells in vitro. R115777 inhibited the growth of fresh and cloned myeloma cells dose dependently, and effects were not dependent on the status of N-Ras mutation in fresh myeloma cells. Flow cytometric analysis using annexin V and 7-aminoactinomycin D (7AAD) showed that R115777 induced apoptosis of 2 of 3 myeloma cell lines at a concentration of 1.0 x 10(-8) M. R115777 appears to be a potent inducer of apoptosis, and its effects depend on the status of Ras mutation in cloned myeloma cells but not on the status of N-Ras mutation in fresh myeloma cells. This is the first report that demonstrates the relationship between the N-Ras mutation in fresh myeloma cells and the effect of R115777. R115777 might have some benefit in the treatment of myeloma patients.
Ochiai
Naoya
N
Department of Medicine, Division of Hematology and Oncology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. naoya@koto.kpu-m.ac.jp
Uchida
Ryo
R
Fuchida
Shin-ichi
S
Okano
Akira
A
Okamoto
Masashi
M
Ashihara
Eishi
E
Inaba
Tohru
T
Fujita
Naohisa
N
Matsubara
Hiroaki
H
Shimazaki
Chihiro
C
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002455:Cell Division; D045744:Cell Line, Tumor; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D051231:Farnesyltranstransferase; D006801:Humans; D009101:Multiple Myeloma / Q000473:pathology*; D009154:Mutation; D015363:Quinolones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics / Q000502:physiology
D000970:Antineoplastic Agents; D015363:Quinolones; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018631:ras Proteins; C402769:tipifarnib