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.Breast cancer is one of the major causes of death among women. Chemotherapy and radiation therapy have played integral roles in the treatment of breast tumors. An arsenal of chemotherapeutic agents have been used alone or in combinations. Anti-cancer agents such as tamoxifen, 5-fluoro-2 -deoxyuridine (5-FdUrd, Floxuridine), adriamycin and medroxyprogesterone have been the most frequently used. Nevertheless, their clinical use has been limited by non-specific physiological and cytocidal effects due to the necessity of high doses to elicit therapeutic effect and high degree of resistance occurrences because of insufficient efficacy. In an effort to improve the efficacy of these anti-cancer agents, we decided to apply the prodrug approach. This approach consists of linking an antiestrogens with 5-fluoro-2 -deoxyuridine or adriamycin compounds to form steroidal conjugates as prodrugs. In vivo as well as in vitro, it is expected that the prodrugs will be bioconverted to their active drug forms, thus releasing two anti-cancer agents with different mechanism of action. By releasing two anti-cancer agents with different mechanisms of action, a synergistic effect will be produced. This synergistic effect will lead to an enhanced anti-cancer activity similar to that of combination therapy. Importantly, this synergistic effect will be limited to within the cells. If the prodrug is hydrolyzed extracellularly by plasma esterases, there will be a minimized effect upon cells due to limited cell penetration by the individual drugs, which will lead to metabolic degradation and renal clearance of those drugs. By designing steroidal conjugates as prodrugs, we conceptualize that this will improve the efficacy of the drugs in question due to enhanced cell penetration (increased lipophilicity) and synergistic effect. As a protocol, we have synthesized and evaluated some steroidal conjugates of Floxuridine, and these compounds have exhibited anti-cancer activity comparable to that of the parent drug against MCF-7 breast cancer cell line (Preliminary Data). In these in vitro studies, a synergistic effect wasn t expected because the steroidal component didn t have anti-cancer activity.
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