Jhaveri Mona S, Rait Antonina S, Chung Koong-Nah, Trepel Jane B, Chang Esther H
Department of Oncology, Lombardi Cancer Center, Georgetown University Medical Center, Washington, District of Columbia 20007-2197, USA.
Mol Cancer Ther. 2004 Dec;3(12):1505-12.
Folates are essential for cell survival and are required for numerous biochemical processes. The human alpha isoform folate receptor (alphahFR) has a very high affinity for folic acid and is considered an essential component in the cellular accumulation of folates and folate analogues used in chemotherapy. The expression of alphahFR is not detected inmost normal tissues. In contrast, high levels of the expression of alphahFR have been reported in a variety of cancer cells. The significance of alphahFR overexpression in malignant tissues has not been elucidated, but it is possible that it promotes cell proliferation not only by mediating folate uptake but also by generating other regulatory signals. The purpose of the present study was to evaluate alphahFR as a potential target for the treatment of breast cancer. Initial studies were done in nasopharyngeal carcinoma (KB) cells, which express high levels of alphahFR. In KB cells, antisense oligodeoxyribonucleotides (ODN) complementary to the alphahFR gene sequences were found to reduce newly synthesized alphahFR protein up to 60%. To examine the effect of alphahFR antisense ODNs in a panel of cultured human breast cancer cell lines, we used a tumor cell-targeted, transferrin-liposome-mediated delivery system. The data show that alphahFR antisense ODNs induced a dose-dependent decrease in cell survival. Finally, we determined that alphahFR antisense ODNs sensitized MDA-MB-435 breast cancer cells by 5-fold to treatment with doxorubicin. The data support the application of alphahFR antisense ODNs as a potential anticancer agent in combination with doxorubicin.
叶酸对于细胞存活至关重要，并且是众多生化过程所必需的。人α亚型叶酸受体（alphahFR）对叶酸具有非常高的亲和力，被认为是细胞积累叶酸及化疗中使用的叶酸类似物的重要组成部分。在大多数正常组织中未检测到alphahFR的表达。相反，据报道在多种癌细胞中alphahFR表达水平很高。恶性组织中alphahFR过表达的意义尚未阐明，但有可能它不仅通过介导叶酸摄取而且通过产生其他调节信号来促进细胞增殖。本研究的目的是评估alphahFR作为乳腺癌治疗的潜在靶点。最初的研究是在表达高水平alphahFR的鼻咽癌（KB）细胞中进行的。在KB细胞中，发现与alphahFR基因序列互补的反义寡脱氧核苷酸（ODN）可使新合成的alphahFR蛋白减少多达60%。为了研究alphahFR反义ODN在一组培养的人乳腺癌细胞系中的作用，我们使用了一种肿瘤细胞靶向的、转铁蛋白 - 脂质体介导的递送系统。数据表明，alphahFR反义ODN诱导细胞存活呈剂量依赖性下降。最后，我们确定alphahFR反义ODN使MDA - MB - 435乳腺癌细胞对阿霉素治疗的敏感性提高了5倍。这些数据支持将alphahFR反义ODN作为一种潜在的抗癌剂与阿霉素联合应用。
