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1.
Mol Cancer Ther ; 6(9): 2458-67, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17876043

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/pathology , Cell Proliferation/drug effects , Farnesyltranstransferase/antagonists & inhibitors , G1 Phase/drug effects , Quinolones/pharmacology , Tamoxifen/analogs & derivatives , Animals , Blotting, Western , Breast Neoplasms/drug therapy , Cell Line, Tumor/drug effects , Cell Line, Tumor/metabolism , Cell Line, Tumor/pathology , Cyclin D1/metabolism , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Drug Therapy, Combination , Female , Flow Cytometry , Fluorescent Antibody Technique , Humans , In Situ Nick-End Labeling , Mice , Mice, Nude , Receptors, Estrogen/metabolism , Tamoxifen/pharmacology , Transcription, Genetic/drug effects , Transplantation, Heterologous
2.
Expert Opin Emerg Drugs ; 8(1): 163-78, 2003 May.
Article in English | MEDLINE | ID: mdl-14610919

ABSTRACT

Current systemic cytotoxic therapies for cancer are limited by their nonspecific mechanism of action, unwanted toxicities on normal tissues and short-term efficacy due to the emergence of drug resistance. However, identification of the molecular abnormalities in cancer, in particular the key proteins involved in abnormal cell growth, has resulted in various signal transduction inhibitor drugs being developed as new treatment strategies against the disease. Protein farnesyltransferase inhibitors (FTIs) were originally designed to target the Ras signal transduction pathway, although it is now clear that several other intracellular proteins are dependent on post-translational farnesylation (addition of a 15-carbon farnesyl moiety) for their function. Preclinical data revealed that although FTIs inhibit the growth of ras-transformed cells, they are also potent inhibitors of a wide range of cancer cell lines, many of which contain wild type ras. While understanding the mechanism of action of FTIs remains an important research goal, three different FTIs have entered clinical development. Several Phase I trials with each drug have explored different schedules for prolonged administration, and dose-limiting toxicities (DLTs) have varied from myelosuppression, gastrointestinal toxicity and neuropathy. Evidence for anticancer efficacy has come from a number of Phase II studies, not necessarily in tumour types containing ras mutations, which were the initial target for these drugs. Perhaps the most promising use for FTIs will be in combination with conventional cytotoxic drugs, based on preclinical data suggesting synergy, particularly with the taxanes. Clinical combination studies are in progress, and larger Phase II/III clinical trials are planned to see if FTIs can add to the efficacy of conventional therapies.


Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/therapeutic use , Alkyl and Aryl Transferases/metabolism , Animals , Clinical Trials as Topic/statistics & numerical data , Humans , Neoplasms/drug therapy , Neoplasms/enzymology
3.
Breast Cancer Res ; 5(2): 109-12, 2003.
Article in English | MEDLINE | ID: mdl-12631391

ABSTRACT

The Annual San Antonio Breast Cancer Symposium is one of the largest regular conferences devoted to breast cancer research and treatment. In particular, it provides a forum in which to discuss the more translational aspects of current basic research, and the 2002 meeting was no exception. Growth factor pathways and endocrine resistance, cancer genomics and the clinical applications of proteomics were three of the major topics for discussion. Presentations on genetic susceptibility and the development of prognostic and predictive markers also created much interest.


Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/metabolism , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/therapy , Female , Genomics , Growth Substances/metabolism , Humans , Proteome , Signal Transduction
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