Increasing 2-5A effectiveness through better chemistry

描述（由申请人提供）：核糖核蛋白复合物端粒酶与许多不同类型肿瘤的建立和发展有关。在大约80%的肿瘤细胞类型中检测到端粒酶活性，但在大多数正常细胞中没有。因此，端粒酶活性的破坏是治疗多种类型癌症的一种特别有吸引力的方法。Ridgeway生物系统公司正在开发一种用于反义治疗策略的新型嵌合寡核苷酸。这些2- 5a寡核苷酸由一个反义成分组成，它将化合物引导到互补的RNA序列，以及一个激活剂片段，2',5'-寡腺苷酸（2- 5a），它可以激活细胞酶，核糖核酸酶L (RNase L)，它可以切割目标RNA。

DESCRIPTION (provided by applicant): The ribonucleoprotein complex telomerase has been implicated in the establishment and progression of many different types of tumors. Telomerase activity is detected in roughly 80% of all tumor cell types, but is absent in most normal cells. Thus, the disruption of telomerase activity is a particularly attractive means of treating multiple types of cancer. Ridgeway Biosystems, Inc. is developing a novel class of chimeric oligonucleotides for use in antisense therapeutic strategies. These 2-5A oligonucleotides are comprised of an antisense component, which directs the compound to the complimentary RNA sequences, and an activator moiety, 2',5'-oligoadenylate (2-5A) that serve to activate a cellular enzyme, ribonuclease L (RNase L), which cleaves the targeted RNA. Preliminary studies have shown that a 2-5A antisense compound that targets telomerase RNA for degradation inhibits the growth and tumorigenicity of ovarian carcinoma cells in vitro. The goals of the proposed studies are to progress this compound toward commercialization by increasing its stability, affinity to RNase L, and anti-tumor potential through stabilizing the 2-5A moiety, in particular its 5'-phosphate. If successful, the 2-5A anti-telomerase compound will have widespread application to the treatment of many tumor types. It is anticipated that such a therapeutic would be incorporated into established chemotherapeutic regimens to increase their effectiveness. The proposed studies also offer the potential to dramatically improve the efficacy of the 2-5A oligonucleotide approach. Ridgeway Biosystems Inc. will apply successful chemical modifications to other therapeutics currently under development.