Biological activities of a recombinant adenovirus p53 (SCH 58500) administered by hepatic arterial infusion in a Phase 1 colorectal cancer trial
Biological activities of a recombinant adenovirus p53 (SCH 58500) administered by hepatic arterial infusion in a Phase 1 colorectal cancer trial
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DOI：
10.1038/sj.cgt.7700870
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发表时间：
2006-02-01
影响因子：
6.4
通讯作者：
Warren, R
中科院分区：
文献类型：
--
作者：
Atencio, IA;Grace, M;Warren, R
肝内动脉给药腺病毒(Ad)的主要焦点是安全性。目前，关于通过这一途径给药时对Ad的生物学反应的公开数据很少。作为一项第一阶段研究的一部分，我们评估了编码p53转基因的复制缺陷型腺病毒(SCH 58500)通过肝动脉灌注治疗主要转移到肝脏的结直肠癌患者的生物学反应。在分析对Ad载体的生物学反应时，我们发现在注射SCH 58500几周后，总的和中和的Ad抗体都增加了。抗体滴度的成倍增加不依赖于SCH 58500剂量。促炎细胞因子白介素6(IL-6)在给药后6h内短暂达到峰值。细胞因子sTFR2在治疗后24 h开始升高，并与SCH 58500剂量直接相关。细胞因子TNF-α、IL-1β和sTNF-R1在24小时内没有升高。剂量前抗体水平似乎不能预测转导，血清Ad中和因子(SNF)也不能预测转导。尽管我们发现SCH 58500主要分布在肝组织中，而不是肿瘤组织中，但还是发生了SCH 58500向肿瘤组织的传递。逆转录聚合酶链式反应显示肝组织中腺病毒2型和5型受体(CAR)的表达水平显著升高(P<；0.0001，ANOVA)，提示与转导有关。激光扫描细胞术提供了肿瘤特异性凋亡活性的证据，它确定了患者组织中核P53蛋白表达升高与细胞凋亡的一致性。IHA注射复制缺陷型腺病毒是一种可行的递送方式，允许外源性将p53基因转移到靶组织，并证明有功能的p53。对药物的有限和短暂的炎症反应发生，但对Ad的预先存在的免疫并不排除SCH 58500的传递。
The major focus of intrahepatic arterial (IHA) administration of adenoviruses (Ad) has been on safety. Currently, there is little published data on the biological responses to Ad when administered via this route. As part of a Phase I study, we evaluated biological responses to a replication-defective adenovirus encoding the p53 transgene (SCH 58500) when administered by hepatic arterial infusion to patients with primarily colorectal cancer metastatic to the liver. In analyzing biological responses to the Ad vector, we found that both total and neutralizing Ad antibodies increased weeks after SCH 58500 infusion. The fold increase in antibody titers was not dependent on SCH 58500 dosage. The proinflammatory cytokine interleukin-6 (IL-6) transiently peaked within 6 h of dosing. The cytokine sTNF-R2 showed elevation by 24 h post-treatment, and fold increases were directly related to SCH 58500 doses. Cytokines TNF-alpha, IL-1 beta, and sTNF-R1 showed no increased levels over 24 h. Predose antibody levels did not appear to predict transduction, nor did serum Ad neutralizing factor (SNF). Delivery of SCH 58500 to tumor tissue occurred, though we found distribution more predominantly in liver tissues, as opposed to tumors. RT-PCR showed significantly higher expression levels (P < 0.0001, ANOVA) for adenovirus type 2 and 5 receptor (CAR) in liver tissues, suggesting a correlation with transduction. Evidence of tumor-specific apoptotic activity was provided by laser scanning cytometry, which determined a coincidence of elevated nuclear p53 protein expression with apoptosis in patient tissue. IHA administration of a replication defective adenovirus is a feasible mode of delivery, allowing for exogenous transfer of the p53 gene into target tissues, with evidence of functional p53. Limited and transient inflammatory responses to the drug occurred, but pre-existing immunity to Ad did not preclude SCH 58500 delivery.