Combining the farnesyltransferase inhibitor lonafarnib with paclitaxel results in enhanced growth inhibitory effects on human ovarian cancer models in vitro and in vivo.
OBJECTIVE
To determine the effects of combining lonafarnib with paclitaxel on the growth of human ovarian cancer cells and tumor xenografts as well as to monitor a pharmacodynamic marker of farnesyltransferase inhibition (HDJ-2) in peripheral blood mononuclear cells (PBMCs) isolated from tumor-bearing animals after treatment with this combination.


METHODS
Proliferation of A2780, PA-1, IGROV-1, and TOV-112D cells was assessed after treatment with lonafarnib and paclitaxel. Cell cycle progression was determined by flow cytometry, and apoptosis was evaluated by assaying for caspase-3 and cleaved PARP. The effects of lonafarnib and paclitaxel on the tumor growth of each model were determined in immunocompromised mice. Proteins extracted from cells, tumors, and PBMCs were assayed for HDJ-2 mobility shifts by Western blotting as well as for farnesyl protein transferase (FTase) enzyme activity by biochemical analyses.


RESULTS
In A2780, PA-1, IGROV-1, and TOV-112D cells lonafarnib potentiated the growth inhibitory effects of paclitaxel. In each of the models lonafarnib enhanced paclitaxel-induced mitotic arrest and apoptosis. The combination of lonafarnib plus paclitaxel resulted in marked tumor regressions in A2780, TOV-112D, PA-1, and IGROV-1 tumor xenografts. Western blotting demonstrated that in PBMCs isolated from the animals, paclitaxel treatment suppressed lonafarnib-induced HDJ-2 mobility shifts. Paclitaxel did not affect lonafarnib inhibition of FTase enzyme activity levels in these PBMCs.


CONCLUSIONS
Lonafarnib enhances the antiproliferative effects of paclitaxel on ovarian cancer cells in vitro and ovarian tumor xenografts in vivo. Measuring FTase enzyme activity levels rather than HDJ-2 shifts in PBMCs may be a more accurate biomarker to predict levels of farnesyltransferase inhibition in patients who are also receiving paclitaxel chemotherapy.
Taylor
Stacey A
SA
Schering-Plough Research Institute, Biological Research-Oncology, 2015 Galloping Hill Road, K15-2-2700, Kenilworth, NJ 07033, USA.
Marrinan
Cindy H
CH
Liu
Gongjie
G
Nale
Lissette
L
Bishop
W Robert
WR
Kirschmeier
Paul
P
Liu
Ming
M
Long
Brian J
BJ
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000097:blood; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D005260:Female; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D003986:Dibenzocycloheptenes
D014408:Biomarkers, Tumor; D051231:Farnesyltranstransferase; D050956:HSP40 Heat-Shock Proteins; D017239:Paclitaxel; D010880:Piperidines; D011725:Pyridines; C107481:DNAJA1 protein, human; C115354:lonafarnib; D003986:Dibenzocycloheptenes