Preclinical pharmacology and toxicology of intravenous MV-NIS, an oncolytic measles virus administered with or without cyclophosphamide
Preclinical pharmacology and toxicology of intravenous MV-NIS, an oncolytic measles virus administered with or without cyclophosphamide
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DOI：
10.1038/sj.clpt.6100409
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发表时间：
2007-12-01
影响因子：
6.7
通讯作者：
Russell, S. J.
中科院分区：
文献类型：
--
作者：
Myers, R. M.;Greiner, S. M.;Russell, S. J.
MV-NIS是一种溶瘤麻疹病毒，编码人甲状腺钠碘同向转运体（NIS）。在这里，我们报告了临床前药理学和毒理学研究的结果，这些研究是为了支持我们的临床方案“在复发性或难治性多发性骨髓瘤患者中全身给予Edmonston株麻疹病毒（经基因工程改造以表达NIS）（有或无环磷酰胺）的I期试验”。在KAS-6/1骨髓瘤异种移植模型中的剂量反应研究表明，最小有效剂量为4 × 10（6）TCID 50（组织培养感染剂量50）/kg。在首次接种麻疹的松鼠猴和麻疹易感转基因小鼠中进行的毒性研究中，静脉注射剂量分别高达10（8）和4 x 10（8）TCID 50/kg时，结果为阴性。丰富的病毒mRNA，最大的第8天，检测到在松鼠猴的脸颊拭子，更是如此，用环磷酰胺预处理后。基于这些数据，我们的临床方案中MV-NIS的安全起始剂量设定为1-2 x 10（4）TCID 50/kg（每例患者10（6）TCID 50）。
MV-NIS is an oncolytic measles virus encoding the human thyroidal sodium iodide symporter (NIS). Here, we report the results of preclinical pharmacology and toxicology studies conducted in support of our clinical protocol "Phase I Trial of Systemic Administration of Edmonston Strain of Measles Virus, Genetically Engineered to Express NIS, with or without Cyclophosphamide, in Patients with Recurrent or Refractory Multiple Myeloma.'' Dose-response studies in the KAS-6/1 myeloma xenograft model demonstrated a minimum effective dose of 4 x 10(6) TCID50 (tissue culture infectious dose 50)/kg. Toxicity studies in measles-naive squirrel monkeys and measles-susceptible transgenic mice were negative at intravenous doses up to 10(8) and 4 x 10(8) TCID50/kg, respectively. Abundant viral mRNA, maximal on day 8, was detected in cheek swabs of squirrel monkeys, more so after pretreatment with cyclophosphamide. On the basis of these data, the safe starting dose of MV-NIS for our clinical protocol was set at 1-2 x 10(4) TCID50/kg (10(6) TCID50 per patient).