DDR SUBPRJ 3: BREAST CANCER TARGETED ANTICANCER AGENTS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，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。 已经单独或组合使用了一系列化学治疗剂。最常用的抗癌药物有他莫昔芬、5-氟-2-脱氧尿苷（5-FdUrd，氟尿苷）、阿霉素和甲羟孕酮。 然而，由于需要高剂量才能引起治疗效果，以及由于疗效不足而发生高度耐药，因此其临床应用受到非特异性生理和杀细胞作用的限制。 为了提高这些抗癌药物的疗效，我们决定应用前药方法。 该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以形成作为前药的甾体缀合物。 在体内以及体外，预期前药将被生物转化成其活性药物形式，从而释放具有不同作用机制的两种抗癌剂。 通过释放具有不同作用机制的两种抗癌剂，将产生协同效应。这种协同效应将导致与联合治疗类似的增强的抗癌活性。 重要的是，这种协同效应将仅限于细胞内。如果前药在细胞外被血浆酯酶水解，由于单个药物的细胞渗透有限，对细胞的影响将最小化，这将导致这些药物的代谢降解和肾清除。通过设计类固醇缀合物作为前药，我们概念化这将由于增强的细胞渗透（增加的亲脂性）和协同效应而改善所讨论的药物的功效。作为一种方案，我们合成并评价了氟尿苷的一些甾体缀合物，这些化合物显示出与母体药物相当的抗癌活性，对MCF-7乳腺癌细胞系（初步数据）。 在这些体外研究中，预期不会产生协同效应，因为甾体成分没有抗癌活性。

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.