In vivo adenoviral-mediated gene transfer in the treatment of pancreatic cancer
In vivo adenoviral-mediated gene transfer in the treatment of pancreatic cancer
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DOI：
10.1006/jsre.1997.5051
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发表时间：
1997-04-01
影响因子：
2.2
通讯作者：
Lieberman, MD
中科院分区：
文献类型：
--
作者：
Evoy, D;Hirschowitz, EA;Lieberman, MD
基因治疗可能允许靶向递送杀肿瘤药物来治疗胰腺癌。胞嘧啶脱氨酶（CD）是一种细菌酶，可将无毒剂5-氟胞嘧啶（5 FC）转化为活性化疗剂5-氟尿嘧啶（5 FU）。用5 FC处理诱导表达CD基因的肿瘤细胞可产生局部高浓度的5 FU，同时使全身毒性最小化。本文研究了携带CD基因的复制缺陷型腺病毒载体（AdCMV.CD）对小鼠胰腺癌细胞株Pan 02的治疗作用。用AdCMV.CD和空载体（Ad. CD）体外感染Pan 02细胞，用北方印迹法检测CD信使RNA（mRNA）的表达，用分光光度法检测CD酶的活性。CD基因的mRNA转录水平在感染AdCMV. CD后呈剂量依赖性增加。在感染复数（MOI）为20时，孵育48小时后，5 FC转化为5 FU的转化率为51%。用MTT法和胸腺嘧啶核苷摄取法检测细胞生长抑制情况，AdCMV.CD和5 FC处理的Pan 02细胞的体外生长抑制率为80%，而AdCMV.CD和5 FC处理的Pan 02细胞的体外生长抑制率为80%。通过将2.5 × 10（5）个PAN 02细胞皮下注射到C57 BW 6小鼠的侧腹中来建立胰腺癌的体内模型。7天后，将AdCMV.CD注射到每个肿瘤中，并给予5 FC 10天。与仅接受AdCMV.CD或仅接受5 FC的小鼠相比，用AdCMV.CD和5 FG处理的小鼠抑制肿瘤生长。这些数据证明了酶前药策略在实验性胰腺癌中的治疗功效。(C)北京：科学出版社.
Gene therapy may allow targeted delivery of tumoricidal drugs to treat pancreatic cancer. Cytosine deaminase (CD) is a bacterial enzyme that converts the nontoxic agent 5-fluorocytosine (5FC) to the active chemotherapeutic agent 5-fluorouracil (5FU). Neoplastic cells induced to express the CD gene treated with 5FC may generate locally high concentrations of 5FU while minimizing systemic toxicity. Replication deficient adenovirus vector carrying the CD gene (AdCMV.CD) was tested for therapeutic efficacy against the murine pancreatic carcinoma cell line Pan02, Pan02 cells were infected in vitro with AdCMV.CD or null vector (Ad.Null) and were examined for expression of CD messenger RNA (mRNA) (Northern blot) and CD enzymatic function (spectrophotometry). mRNA transcripts of the CD gene increased in a dose-dependent manner after infection with AdCMV.CD. Conversion of 5FC to 5FU at a multiplicity of infection (MOI) of 20 was measured to be 51% after a 48-hr incubation. Growth inhibition was measured by MTT assay and thymidine uptake, Pan02 growth in vitro treated with AdCMV.CD and 5FC was inhibited by 80% as compared to cells treated with Ad.Null and 5FC. An in vivo model of pancreatic cancer was established by injecting 2.5 x 10(5) PAN02 cells subcutaneously into the flanks of C57BW 6 mice. Seven days later AdCMV.CD was injected into each tumor and 5FC was administered for 10 days. Treatment of mice with AdCMV.CD and 5FG inhibited tumor growth compared to mice mho received AdCMV.CD only or 5FC only. These data demonstrate the therapeutic efficacy of an enzyme prodrug strategy in experimental pancreatic cancer. (C) 1997 Academic Press.