This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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 cancer.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
General Clinical Research Centers Program (M01)
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National Center for Research Resources Initial Review Group (RIRG)
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University of Iowa
Internal Medicine/Medicine
Schools of Medicine
Iowa City
United States
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Lorenz, Douglas J; Levy, Steven; Datta, Somnath (2018) Inferring marginal association with paired and unpaired clustered data. Stat Methods Med Res 27:1806-1817
Oweis, Reem Reda; Levy, Steven M; Eichenberger-Gilmore, Julie M et al. (2018) Fluoride intake and cortical and trabecular bone characteristics in adolescents at age 17: A prospective cohort study. Community Dent Oral Epidemiol 46:527-534
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Choo-Wosoba, Hyoyoung; Gaskins, Jeremy; Levy, Steven et al. (2018) A Bayesian approach for analyzing zero-inflated clustered count data with dispersion. Stat Med 37:801-812
Levy, Steven M; Eichenberger-Gilmore, Julie M; Warren, John J et al. (2018) Associations of fluoride intake with children's cortical bone mineral and strength measures at age 11. J Public Health Dent 78:352-359
Rao, Satish S C; Valestin, Jessica A; Xiang, Xuelian et al. (2018) Home-based versus office-based biofeedback therapy for constipation with dyssynergic defecation: a randomised controlled trial. Lancet Gastroenterol Hepatol 3:768-777
Curtis, Alexandra M; VanBuren, John; Cavanaugh, Joseph E et al. (2018) Longitudinal associations between dental caries increment and risk factors in late childhood and adolescence. J Public Health Dent 78:321-328
Kwon, Soyang; Janz, Kathleen F; Letuchy, Elena M et al. (2017) Association between body mass index percentile trajectories in infancy and adiposity in childhood and early adulthood. Obesity (Silver Spring) 25:166-171
Warren, John J; Van Buren, John M; Levy, Steven M et al. (2017) Dental caries clusters among adolescents. Community Dent Oral Epidemiol 45:538-544

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