Bioavailability and efficacy of antisense morpholino oligomers targeted to c-myc and cytochrome P-450 3A2 following oral administration in rats
Bioavailability and efficacy of antisense morpholino oligomers targeted to c-myc and cytochrome P-450 3A2 following oral administration in rats
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DOI：
10.1002/jps.10088
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发表时间：
2002-04-01
影响因子：
3.8
通讯作者：
Iversen, PL
中科院分区：
文献类型：
--
作者：
Arora, V;Knapp, DC;Iversen, PL
反义磷酸二酰胺吗啉代寡聚物 (PMO) 能够抵抗细胞水解酶、DNA 酶、RNA 酶和磷酸二酯酶的降解，但对长时间暴露于低 pH 下仍然敏感。目前的研究评估了两种针对 c-myc 和细胞色素 P-450 (CYP) 3A2 的不同 PMO 序列的口服分数生物利用度、稳定性和功效。 c-myc 反义 20 聚体 AVI-4126 (5'-ACGTTTGAGGGGCATCGTCGC-3') 可减缓 70% 部分肝切除 (PH) 后大鼠肝脏的再生过程。 PH后立即通过静脉推注向大鼠施用3.0 mg/kg AVI-4126在0.1 mL盐水中的溶液或通过强饲法在0.5 mL无菌磷酸盐缓冲盐水中的溶液。血浆浓度与时间曲线下的面积显示，10 分钟至 24 小时内的口服利用率为 78.8%。对口服 AVI-4126 的大鼠肝组织进行的免疫印迹分析表明，靶蛋白 c-Myc 以及次级增殖标志物：增殖细胞核抗原 (PCNA)、细胞周期蛋白 D1 和 p53 出现序列特异性减少。 CYP3A2 反义 22 聚体 AVI-4472 (5'-GAGCTGAAAGCAGGTCCATCCC-3') 在以 2 mg/kg 剂量口服给药后 24 小时内，引起大鼠肝脏 CYP3A2 蛋白水平和红霉素去甲基化活性的序列依赖性降低约五倍。结论是口服PMOs可以通过基于反义的作用机制抑制大鼠肝脏中c-myc和CYP3A2基因的表达。这些研究强调了 PMO 作为口服治疗剂的开发潜力。 (C) 2002 Wiley-Liss, Inc.
Antisense phosphorodiamidate Morpholino oligomers (PMO) are resistant to degradation by cellular hydrolases, DNases, RNases, and phosphodiesterases, but remain sensitive to prolonged exposure to low pH. The present studies evaluate the oral fractional bioavailability, stability, and efficacy of two distinct PMO sequences targeted to c-myc and cytochrome P-450 (CYP) 3A2. The c-myc antisense 20-mer, AVI-4126 (5'-ACGTTGAGGGGCATCGTCGC-3'), slowed the regenerative process in the rat liver after a 70% partial hepatectomy (PH). Rats were administered 3.0 mg/kg AVI-4126 in 0.1 mL saline via a bolus intravenous injection or in 0.5 mL sterile phosphate-buffered saline via gavage immediately following PH. The areas under the plasma concentration versus time curves revealed a fractional oral availability of 78.8% over a period of 10 min through 24 h. Immunoblot analysis of liver tissue from rats treated orally with AVI-4126 demonstrated a sequence-specific reduction in the target protein c-Myc, as well as secondary proliferation markers: proliferating cell nuclear antigen (PCNA), cyclin D1, and p53. The CYP3A2 antisense 22-mer AVI-4472 (5'-GAGCTGAAAGCAGGTCCATCCC-3') caused a sequence-dependent reduction of approximately five-fold in the rat liver CYP3A2 protein levels and erythromycin demethylation activity in 24 h following oral administration at a dose of 2 mg/kg. It is concluded that oral administration of PMOs can inhibit c-myc and CYP3A2 gene expression in rat liver by an antisense-based mechanism of action. These studies highlight the potential for development of PMOs as orally administered therapeutic agents. (C) 2002 Wiley-Liss, Inc.