DDR SUBPRJ 3: BREAST CANCER TARGETED ANTICANCER AGENTS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。乳腺癌是妇女死亡的主要原因之一。化疗和放疗在乳腺肿瘤的治疗中起着不可或缺的作用。多种化疗药物已被单独或联合使用。抗癌药物如他莫昔芬、5-氟-2¿-脱氧尿嘧啶（5-FdUrd，氟尿嘧啶）、阿霉素和甲羟孕酮是最常用的。然而，它们的临床使用受到非特异性生理和细胞杀伤作用的限制，因为必须高剂量才能产生治疗效果，并且由于疗效不足而发生高度耐药性。为了提高这些抗癌药物的疗效，我们决定采用前药方法。这种方法包括将抗雌激素与5-氟-2¿-脱氧尿苷或阿霉素化合物连接，形成作为前药的甾体偶联物。在体内和体外，预计前药将被生物转化为其活性药物形式，从而释放出两种具有不同作用机制的抗癌药物。通过释放两种不同作用机制的抗癌药物，产生协同效应。这种协同作用将导致增强的抗癌活性，类似于联合治疗。重要的是，这种协同效应将仅限于细胞内。如果前药通过血浆酯酶在细胞外水解，由于单个药物对细胞的渗透有限，对细胞的影响将最小，这将导致这些药物的代谢降解和肾脏清除。通过将甾体偶联物设计为前药，我们认为这将通过增强细胞渗透（增加亲脂性）和协同效应来提高药物的功效。作为一种方案，我们已经合成并评估了氟尿定的一些甾体缀合物，这些化合物对MCF-7乳腺癌细胞系的抗癌活性与母体药物相当（初步数据）。在这些体外研究中，由于甾体成分不具有抗癌活性，因此预计不会产生协同效应。

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. 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.