In vivo bioavailability and pharmacokinetics of a c-MYC antisense phosphorodiamidate morpholino oligomer, AVI-4126, in solid tumors
In vivo bioavailability and pharmacokinetics of a c-MYC antisense phosphorodiamidate morpholino oligomer, AVI-4126, in solid tumors
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DOI：
10.1158/1078-0432.ccr-04-2091
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发表时间：
2005-05-15
影响因子：
11.5
通讯作者：
Iversen, PL
中科院分区：
文献类型：
--
作者：
Devi, GR;Beer, TM;Iversen, PL
磷酰二胺吗啉代寡聚物（PIVIO）通过阻止核糖体组装来抑制靶基因表达，从而阻止mRNA翻译。AVI-4126是一种靶向c-MYC的PIVIO，已在多种癌症和其他疾病模型中得到广泛表征，目前正在进行人体临床试验。进行I期临床研究以解决在静脉内施用单剂量90 mg AVI-4126 PMO后1天从患有前列腺和乳腺腺癌的患者手术切除的恶性肿瘤中PMO生物利用度的问题。研究目的是评价安全性，确定肿瘤组织样品中AVI-4126的浓度，并检查AVI-4126的分布（边缘与肿瘤核心）。在人前列腺和乳腺肿瘤组织中检测到与动物模型相似的显著浓度的完整PMO，其中血管性乳腺肿瘤的肿瘤核心中的分布增加。未报告严重不良事件（根据国家癌症研究所常见毒性标准分级）。在正常人类志愿者中进行另一项I期研究，以评估90 mg AVI-4126单次静脉内给药后AVI-4126的血浆药代动力学。两项人体研究的数据表明，血浆浓度-时间曲线相似。这些研究显示了PIVIO在肿瘤组织中的生物利用度，并确立了在人类癌症临床试验中使用PIVIO靶向特定基因的可行性。
Phosphorodiamiclate morpholino oligomers (PIVIO) inhibit targeted gene expression by preventing ribosomal assembly, thereby preventing m RNA translation. AVI-4126, a PIVIO targeted against c-MYC, has been extensively characterized in multiple cancer and other disease models and is currently in human clinical trials. A phase I clinical study was conducted to address the issue of PMO bioavailability in malignant tumors surgically excised from patients with adenocarcinoma of prostate and breast 1 day after i.v. administration of a single dose of 90 mg AVI-4126 PMO. The study objectives were to evaluate safety, to determine AVI-4126 concentration in tissue samples of the tumors, and to examine the distribution of AVI-4126 (margin versus tumor core). Significant concentrations of intact PMO similar to the animal models were detected in both human prostate and breast tumor tissues with increased distribution in the tumor core for the vascular breast tumors. No serious adverse events (graded according to National Cancer Institute Common Toxicity Criteria) were reported. Another phase I study was conducted in normal human volunteers to assess AVI-4126 plasma pharmacokinetics following single i.v. administration of 90 mg AVI-4126. Data from both human studies indicated similar plasma concentration-time profile. These studies show PIVIO bioavailability in tumor tissue and establish the feasibility of using PIVIO targeting specific genes in human cancer clinical trials.