This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. While taxanes, including both paclitaxel and docetaxel, have been shown to be very active drugs in the treatment of patients with metastatic breast cancer, most women will eventually die of their disease. Docetaxel has been shown to be one of the most active agents in the treatment of advanced breast cancer both as second and first-line therapy. Docetaxel was initially found to be an active agent in the treatment of patients with metastatic breast cancer. Subsequent phase III trials confirmed docetaxel was a highly active second-line agent. Results from phase III clinical trials, comparing taxane monotherapy with a control regimen, have revealed that docetaxel is also a highly active first-line agent in the treatment of advance breast cancer. Lovastatin, the other drug of interest, impairs the proliferation of a wide variety of cell types and preclinical studies have revealed a synergistic interaction between lovastatin and paclitaxel in human leukemia cell lines. The mechanism(s) of action underlying lovastatin's cytotoxic effects are largely unknown and continue to be the focus of active investigation. One potential mechanism of action is the interference of lovastatin with an early step of farnesyl pyrophosphate biosynthesis due to the depletion of mevalonate and susequent combined inhibition of both farnesylation and geranylgeranylation. This results in the inhibition of prenylation of proteins of the RAS superfamily, including Ras, RhoB, and Rap1A, which are highly dependent upon farnesylation and geranylgeranylation for membrane location and biological activity. The rationale for combining lovastatin and docetaxel is based on preclinical data that revealed a synergistic action between lovastatin and paclitaxel in human leukemia cell lines. Given that there is such synergistic interaction in vitro, and given the high activity of docetaxel in breast cancer, it is reasonable to determine whether such synergy exists in vivo when combining lovastatin and docetaxel in the treatment of patients with various cancers as in the Phase I part of this study and in the treatment of patients with breast cancer as in the Phase II part of this study. No clinical trials have been completed that examine the combined effect of lovastatin and docetaxel for the treatment of solid tumors and breast cancer. It is therefore of great interest to determine whether the combination of lovastatin and docetaxel will induce additive or supra-additive effects in patients with metastatic or recurrent breast canc
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