Synergism of aminobisphosphonates and farnesyl transferase inhibitors on tumor metastasis.
Aminobisphosphonates have shown significant antitumor activity in vitro and in vivo with selective pharmacodistribution to bone, and an established role in the treatment of malignant bone disease. Given that the mode of action of aminobisphosphonates involves decreasing the prenylation of the Rho family of proteins, through decreasing the availability of prenyl groups (farnesyl and geranylgeranyl isoprenoids), the authors sought the inhibition of Rho protein prenylation at two points, by using an aminobiphosphonate (alendronate) in conjunction with a prenyl transferase inhibitor (R115777, a specific farnesyl transferase inhibitor with limited effects in geranylgeranyl transferase). The authors show synergistic inhibition of the prenylation dependent membrane association and migratory function of Rho proteins, translating into a suppressive effect on in vitro tumor cell invasiveness and in vivo metastasis. The findings support the use of aminobisphosphonates in conjunction with farnesyl transferase inhibitors in the prevention of metastatic progression and suggest that metastatic progression is a valid end point in assessing the antitumor activity of farnesyl transferase inhibitors.
Andela
Valentine B
VB
Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA.
Rosenblatt
Joseph D
JD
Schwarz
Edward M
EM
Puzas
Edward J
EJ
O'Keefe
Regis J
RJ
Rosier
Randy N
RN
D019386:Alendronate / Q000627:therapeutic use*; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D051231:Farnesyltranstransferase; D005260:Female; D005434:Flow Cytometry; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D015363:Quinolones / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D015363:Quinolones; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C402769:tipifarnib; D019386:Alendronate