A study on overcoming drug resistance by antisense Bcl-2 for breast cancer

我们对使用反义（AS） Bcl-2磷酸化寡核苷酸（ODNs）增强实体肿瘤（包括乳腺癌、胃癌和甲状腺癌）的药物敏感性进行了临床前研究。研究结果如下：1。与对照细胞相比，1.0 μM AS Bcl-2以剂量依赖性方式处理后，Bcl-2蛋白的下调率约为60%。就odns的细胞毒作用而言，该浓度适合于对Bcl-2的最大抑制。asbcl -2联合用药对丝裂霉素（MMC）、紫杉醇（TXL）治疗乳腺癌，顺铂（CDDP）治疗胃癌，阿霉素（ADM）、CDDP、紫杉烷治疗甲状腺癌的药物敏感性增强。药物敏感性的增加与凋亡细胞死亡的诱导有关，凋亡细胞死亡是由Bax、细胞色素c、caspase-3和caspase-8在死亡受体依赖和非依赖途径中激活的。在裸鼠体内移植实验中，连续6天腹腔注射5 mg/kg AS Bcl-2，观察到对MMC、TXL和TXT的治疗效果有类似的增强作用。在AS治疗后第4天观察到Bcl-2下调，并持续到第14.4天。这些结果表明，AS - Bcl-2靶向治疗是一种有效的体外和体内增强药物敏感性的方法，可以调节实体瘤的凋亡途径。

We examined preclinical study for enhancement of drug sensitivity using antisense (AS) Bcl-2 phosphorothioated oligonucleotides (ODNs) in solid tumors including breast, gastric and thyroid cancer. The results are the followings :1. Downregulation of Bcl-2 protein was observed in approximately 60% by treatment with 1.0 μM AS Bcl-2 in a dose-dependent manner compared to control cells. This concentration was appropriate for maximal inhibition of Bcl-2 in terms of the cytotoxic effect of ODNs.2. Enhancement of drug sensitivity in combination with AS Bcl-2 was observed in mitomycin (MMC), paclitaxel (TXL) for breast cancer, cisplatin (CDDP) for gastric cancer, and adriamycin (ADM), CDDP, taxanes for thyroid cancer. The increased drug sensitivity was associated with induction of apoptotic cell death, which was activated by Bax, cytochrome c, caspase-3, and caspase-8 in the death receptor-dependent and -independent pathway.3. In vivo experiment with nude mice xenograft, similar enhancement of therapeutic effects to MMC, TXL, and TXT were observed with intraperitoneal administration of 5 mg/kg AS Bcl-2 for 6 consecutive days. Downreguiation of Bcl-2 was observed at day 4 after the treatment with AS Bcl-2 and it was continued for day 14.4. These results suggest that the targeting therapy with AS Bcl-2 is a useful method for enhancement of drug sensitivity in vitro and in vivo in the modulation of apoptotic pathway for solid tumors.