Intratumoral adenovirus-mediated suicide gene transfer for hepatic metastases from colorectal adenocarcinoma: results of a phase I clinical trial.
Intratumoral adenovirus-mediated suicide gene transfer for hepatic metastases from colorectal adenocarcinoma: results of a phase I clinical trial.
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DOI：
10.1006/mthe.2001.0444
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发表时间：
2001-09
期刊：
影响因子：
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通讯作者：
M. Sung;H. Yeh;S. Thung;M. Schwartz;J. Mandeli;Shu-Hsia Chen;S. Woo
中科院分区：
文献类型：
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作者：
M. Sung;H. Yeh;S. Thung;M. Schwartz;J. Mandeli;Shu-Hsia Chen;S. Woo
动物研究表明，将表达疱疹胸苷激酶基因的腺病毒载体（Adv.RSV-tk）直接注射到已建立的肝脏肿瘤中，然后全身给药更昔洛韦，可有效诱导肿瘤坏死。在治疗有效的载体剂量下毒性最小，尽管在高得多的超治疗剂量下观察到严重的肝坏死炎症。我们在肝脏转移性结直肠癌患者中进行了一项临床I期试验，以评估肿瘤内注射Adv.RSV-tk（递增剂量）然后静脉注射更昔洛韦（固定剂量）的安全性。将载体在局部麻醉下经皮置针注射到肝脏转移瘤中，同时超声监测，防止注射或渗漏到邻近的正常肝脏结构。我们在5个剂量水平的Adv.RSV-tk队列中治疗了16例患者，每个患者的病毒颗粒从1.0x10（10）到1.0x10（13）不等。肝毒性较低，16例患者中有3例血清转氨酶水平短暂升高1级。其他毒性也是短暂的：16例患者中有5例出现2-3级发热，16例患者中有1例出现3级血小板减少，16例患者中有3例出现2级白细胞减少。这些结果表明，Adv.RSV-tk可以安全地经皮瘤内注射给肝转移患者，剂量可达每例患者1.0x10（13）个病毒颗粒，为未来瘤内腺病毒载体注射的临床试验提供基础。
Animal studies have shown that direct injection of an adenoviral vector (Adv.RSV-tk) expressing the herpes thymidine kinase gene into established tumors in the liver, followed by systemic ganciclovir administration, was effective in inducing tumor necrosis. Toxicities were minimal at therapeutically effective vector doses, although severe hepatic necroinflammation was seen at much higher supratherapeutic doses. We conducted a clinical phase I trial in patients with metastatic colorectal adenocarcinoma in the liver to assess the safety of intratumoral Adv.RSV-tk injection (escalating doses) followed by intravenous ganciclovir (fixed dose). The vector was injected into a metastatic tumor in the liver under local anesthesia by percutaneous needle placement with concurrent ultrasonographic monitoring to prevent injection or leakage into adjacent normal liver structures. We treated 16 patients in five dose level cohorts of Adv.RSV-tk, from 1.0x10(10) to 1.0x10(13) virus particles per patient. Hepatic toxicities were low, with transient grade 1 elevations in serum aminotransferase levels in 3 of 16 patients. Other toxicities were also transient: grade 2-3 fevers in 5 of 16 patients, grade 3 thrombocytopenia in 1 of 16 patients, and grade 2 leucopenia in 3 of 16 patients. These results indicate that Adv.RSV-tk can be safely administered by percutaneous intratumoral injection in patients with hepatic metastases at doses up to 1.0x10(13) virus particles per patient, and can provide the basis for future clinical trials involving intratumoral adenoviral vector injection.