Luo Xunyi, Gong Xiaoqi, Tang Careen K
Lombardi Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC 20007, USA.
Int J Cancer. 2003 May 10;104(6):716-21. doi: 10.1002/ijc.11007.
EGFRvIII is a tumor specific, ligand-independent, constitutively active variant of the epidermal growth factor receptor. Its expression has been detected in many human malignancies including breast cancer. No detectable level of EGFRvIII has, however, been observed in adult tissues, including normal breast tissues. These unique features of the EGFRvIII make it an excellent target for biologically based therapies. We have designed and generated a tumor specific ribozyme targeted to EGFRvIII. This specific EGFRvIII ribozyme is able to effectively cleave EGFRvIII mRNA under physiological conditions in a cell-free system, but does not cleave wild-type EGFR and other EGF-family receptors. While expressing this EGFRvIII-ribozyme in breast cancer cells, EGFRvIII-ribozyme is capable of downregulating endogenous EGFRvIII expression at the mRNA and protein levels. Inhibition of proliferation was observed in EGFRvIII-ribozyme transfectants. In addition, downregulation of EGFRvIII in breast cancer cells significantly inhibited tumor growth in athymic nude mice. Furthermore, this ribozyme has no effect on EGF-family receptor expression or the proliferation of breast cancer cells, which do not express EGFRvIII but express wild-type EGFR and other EGF-family receptors. These results suggest that we have generated a tumor-specific, biologically functional ribozyme and further demonstrate that EGFRvIII plays a significant role in breast cancer cell proliferation. The ultimate goal of this approach is to provide a potential treatment for breast cancer by specifically targeting this receptor.
EGFRvIII是表皮生长因子受体的一种肿瘤特异性、不依赖配体、组成型激活的变体。在包括乳腺癌在内的许多人类恶性肿瘤中都检测到了它的表达。然而，在包括正常乳腺组织在内的成年组织中未观察到可检测水平的EGFRvIII。EGFRvIII的这些独特特征使其成为基于生物学的治疗的理想靶点。我们设计并构建了一种靶向EGFRvIII的肿瘤特异性核酶。这种特异性的EGFRvIII核酶能够在无细胞系统的生理条件下有效切割EGFRvIII mRNA，但不切割野生型EGFR和其他EGF家族受体。在乳腺癌细胞中表达这种EGFRvIII核酶时，EGFRvIII核酶能够在mRNA和蛋白质水平下调内源性EGFRvIII的表达。在EGFRvIII核酶转染细胞中观察到增殖受到抑制。此外，乳腺癌细胞中EGFRvIII的下调显著抑制了无胸腺裸鼠的肿瘤生长。此外，这种核酶对不表达EGFRvIII但表达野生型EGFR和其他EGF家族受体的乳腺癌细胞的EGF家族受体表达或增殖没有影响。这些结果表明我们构建了一种肿瘤特异性、具有生物学功能的核酶，并进一步证明EGFRvIII在乳腺癌细胞增殖中起重要作用。这种方法的最终目标是通过特异性靶向该受体为乳腺癌提供一种潜在的治疗方法。
