The farnesyltransferase inhibitor R115777 (tipifarnib) in combination with tamoxifen acts synergistically to inhibit MCF-7 breast cancer cell proliferation and cell cycle progression in vitro and in vivo.
Cross-talk between receptor tyrosine kinases and estrogen receptor is at least partly responsible for the development of acquired resistance to endocrine therapies. Hence, targeting receptor tyrosine kinases and their downstream partners with inhibitors/antagonists may reverse this resistance. Although ras mutations are rare in breast cancer (2%), aberrant function of Ras signal transduction pathways is common. We therefore investigated the efficacy of the farnesyltransferase inhibitor (FTI) R115777 (tipifarnib) in combination with tamoxifen in MCF-7 human breast cancer models both in vitro and in vivo. There was a synergistic antiproliferative interaction between R115777 and 4-hydroxy-tamoxifen in vitro as calculated by median effect analysis. The combination resulted in a significantly greater G(1) arrest than either drug alone and this was associated with marked inhibition of cyclin D1 and induction of the cell cycle inhibitor p27(kip1). Combining R115777 with either tamoxifen or estrogen withdrawal in vivo produced a significantly greater inhibition of tumor growth and lower xenograft cell proliferation than either therapy alone. These results suggest that the combination of this FTI with endocrine therapy may be of therapeutic benefit in the treatment of breast cancer. Enhanced G1 arrest due to modulation of cell cycle regulatory proteins may be the underlying mechanism for the positive interaction between FTIs and tamoxifen.
Martin
Lesley-Ann
LA
Breakthrough Breast Cancer Centre, Institute of Cancer Research, Fulham Road, London, SW3 6JB United Kingdom. lesley-ann.martin@icr.ac.uk
Head
Julia E
JE
Pancholi
Sunil
S
Salter
Janine
J
Quinn
Emma
E
Detre
Simone
S
Kaye
Stan
S
Howes
Angela
A
Dowsett
Mitch
M
Johnston
Stephen R D
SR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004359:Drug Therapy, Combination; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D015363:Quinolones / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D015363:Quinolones; D011960:Receptors, Estrogen; D013629:Tamoxifen; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C016601:afimoxifene; D051231:Farnesyltranstransferase; C402769:tipifarnib