DDR SUBPRJ 3: BREAST CANCER TARGETED ANTICANCER AGENTS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 乳腺癌是女性死亡的主要原因之一。化疗和放射治疗在乳腺肿瘤的治疗中发挥了不可或缺的作用。化疗药物的武器库已经单独或联合使用。最常用的抗癌药物有他莫昔芬、5-氟-2-脱氧尿苷(5-FdUrd)、阿霉素和甲孕酮。然而，它们的临床应用受到非特异性生理和细胞杀灭作用的限制，原因是需要大剂量才能产生治疗效果，并且由于疗效不足而出现高度耐药。为了努力提高这些抗癌药物的疗效，我们决定应用前药方法。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起来，形成类固醇偶合物作为前药。在体内和体外，前药有望被生物转化为其活性药物形式，从而释放出两种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，将产生协同效应。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。如果前体药物被血浆酯酶在细胞外降解，由于单个药物对细胞的渗透有限，对细胞的影响将降至最低，这将导致这些药物的代谢降解和肾脏清除。通过设计类固醇结合物作为前体药物，我们设想这将由于增强细胞穿透性(增加亲脂性)和协同作用而提高所述药物的疗效。作为一种方案，我们合成并评价了一些氟尿苷的甾体偶联化合物，这些化合物表现出与母药对MCF-7乳腺癌细胞株的抗癌活性相当(初步数据)。在这些体外研究中，由于类固醇成分没有抗癌活性，所以没有预期的协同作用。

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.