DDR SUBPRJ 3: BREAST CANCER TARGETED ANTICANCER AGENTS

DDR SUBPRJ 3：乳腺癌靶向抗癌药物

• 批准号: 7335963
• 负责人: John S Cooperwood
• 金额: $ 4.31万
• 依托单位: FLORIDA AGRICULTURAL AND MECHANICAL UNIV
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7335963
• 关键词: DDR; SUBPRJ; BREAST; CANCER; TARGETED

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.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一，该子项目和研究者 (PI) 可能已从其他 NIH 来源获得主要资助，因此可以在其他 CRISP 机构中得到体现。列出的是该中心，该中心不一定是研究者所在的机构。 化疗和放射治疗在乳腺肿瘤的治疗中发挥着不可或缺的作用。化疗药物已单独或联合使用，例如他莫昔芬、5-氟-2¿ -脱氧尿苷（5-FdUrd、氟尿苷）、阿霉素和甲羟孕酮是最常用的药物，然而，由于需要高剂量才能产生治疗效果且程度较高，因此它们的临床使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功效，我们决定采用前药方法，将抗雌激素与抗癌药结合起来。 5-氟-2¿ -脱氧尿苷或阿霉素化合物形成作为前药的甾族缀合物，预期前药将生物转化为其活性药物形式，从而通过释放释放两种具有不同作用机制的抗癌剂。两种具有不同作用机制的抗癌药物会产生协同效应，这种协同效应将导致与联合治疗类似的抗癌活性增强。如果前药被血浆酯酶在细胞外水解，则由于单个药物的细胞渗透有限，因此对细胞的作用将被最小化，这将导致这些药物的代谢降解和肾清除。通过将甾体缀合物设计为前药，我们认为，由于细胞渗透性增强（亲脂性增加）和协同效应，这将提高相关药物的功效。已经合成并评估了 Floxuridine 的一些类固醇缀合物，这些化合物表现出与母体药物针对 MCF-7 乳腺癌细胞系的抗癌活性（初步数据），在这些体外研究中，协同效应并不明显。出乎意料，因为类固醇成分没有t 具有抗癌活性。