Biomarkers of anticancer activity of R115777 (Tipifarnib, Zarnestra) in human breast cancer models in vitro.
BACKGROUND
Farnesyltransferase inhibitor R115777 (Tipifamib, Zarnestra) is active in breast cancer, but its efficacy in drug combinations has not been extensively investigated.


METHODS
The activity of R115777 and paclitaxel, alone and in combination, was studied in the human breast cancer cell lines, BT-474 (overexpressed HER2/neu) and MDA-MB-231 (low HER2/neu), with cell viability and biomarkers for farnesylation (HDJ-2, Rho B), tumor growth (Raf/MEK/ERK), survival (PI3K/Akt) and angiogenesis (VEGF, FGF-2, MMP-1, MMP-2, MMP-9) as the endpoints.


RESULTS
The drug combination resulted in additive cytotoxicity. R115777 +/- paclitaxel inhibited HDJ-2 farnesylation, up-regulated RhoB, transiently lowered (P)ERK/ERK and (P)Akt/Akt, reduced Raf-1 and MEK and inhibited secretion of VEGF and MMP-1.


CONCLUSIONS
The effect of R115777 on prenylation biomarkers is consistent with its mechanism of action. The drug interfered with tumor growth, survival and angiogenesis pathways in breast cancer models with low or overexpressed HER2/neu receptor. The combination of R115777 with paclitaxel might offer clinical advantage over monotherapies.
Izbicka
Elzbieta
E
Cancer Therapy and Research Center, The Institute for Drug Development, 14960 Omicron Drive, San Antonio, TX 78245, USA. eizbicka@idd.org
Campos
David
D
Carrizales
Gilbert
G
Patnaik
Amita
A
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D051231:Farnesyltranstransferase; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects; D015363:Quinolones / Q000008:administration & dosage / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D020743:rhoB GTP-Binding Protein / Q000378:metabolism
D019883:Alkyl and Aryl Transferases; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D017239:Paclitaxel; D015363:Quinolones; D018719:Erb-b2 Receptor Tyrosine Kinases; D020743:rhoB GTP-Binding Protein; C107481:DNAJA1 protein, human; C402769:tipifarnib