Cancer screening by systemic administration of a gene delivery vector encoding tumor-selective secretable biomarker expression.
Cancer screening by systemic administration of a gene delivery vector encoding tumor-selective secretable biomarker expression.
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DOI：
10.1371/journal.pone.0019530
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发表时间：
2011-05-11
期刊：
影响因子：
3.7
通讯作者：
Cripe TP
中科院分区：
文献类型：
--
作者：
Browne AW;Leddon JL;Currier MA;Williams JP;Frischer JS;Collins MH;Ahn CH;Cripe TP
癌症生物标志物有助于筛查和早期检测，但已知仅用于少数癌症类型。我们证明了诱导肿瘤分泌血清生物标志物的原理，其使用靶向肿瘤以选择性表达工程化盒的全身施用的基因递送载体。我们利用了条件复制型单纯疱疹病毒（HSV）与复制依赖性晚期病毒启动子组合的肿瘤选择性复制，以实现肿瘤选择性生物标志物表达作为示例基因递送载体。病毒复制，细胞毒性和生物标志物的生产在静止的正常人包皮角质形成细胞低，在体外癌细胞高。在静脉内注射病毒后，>90%的荷瘤小鼠表现出比非荷瘤小鼠更高水平的生物标志物，并且在尸检时，我们仅在肿瘤中检测到病毒。我们迫使肿瘤分泌血清生物标志物的策略可能有助于高风险患者的癌症筛查，并可能用于监测对治疗的反应。此外，因为用于肿瘤特异性基因递送的溶瘤载体是细胞毒性的，所以它们可以作为“治疗不确定性”剂补充我们的筛选策略。在这项工作中提出的癌症筛查方法引入了基因递送效用的范式转变，我们预见通过靶向基因递送和表达到肿瘤的替代载体来改进。完善这种方法将迎来一个新的时代，临床癌症筛查，可能在发达国家和不发达国家实施。
Cancer biomarkers facilitate screening and early detection but are known for only a few cancer types. We demonstrated the principle of inducing tumors to secrete a serum biomarker using a systemically administered gene delivery vector that targets tumors for selective expression of an engineered cassette. We exploited tumor-selective replication of a conditionally replicative Herpes simplex virus (HSV) combined with a replication-dependent late viral promoter to achieve tumor-selective biomarker expression as an example gene delivery vector. Virus replication, cytotoxicity and biomarker production were low in quiescent normal human foreskin keratinocytes and high in cancer cells in vitro. Following intravenous injection of virus >90% of tumor-bearing mice exhibited higher levels of biomarker than non-tumor-bearing mice and upon necropsy, we detected virus exclusively in tumors. Our strategy of forcing tumors to secrete a serum biomarker could be useful for cancer screening in high-risk patients, and possibly for monitoring response to therapy. In addition, because oncolytic vectors for tumor specific gene delivery are cytotoxic, they may supplement our screening strategy as a “theragnostic” agent. The cancer screening approach presented in this work introduces a paradigm shift in the utility of gene delivery which we foresee being improved by alternative vectors targeting gene delivery and expression to tumors. Refining this approach will usher a new era for clinical cancer screening that may be implemented in the developed and undeveloped world.
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影响因子：
8
作者：
Aghi M;Visted T;Depinho RA;Chiocca EA
通讯作者：
Chiocca EA
影响因子：
10.8
作者：
Kocbek, Petra;Obermajer, Natasa;Kristl, Julijana
通讯作者：
Kristl, Julijana
影响因子：
1.2
作者：
Bharatan, NS;Currier, MA;Cripe, TP
通讯作者：
Cripe, TP
DOI：
10.1073/pnas.77.7.4030
发表时间：
1980-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
HWANG, KJ;LUK, KFS;BEAUMIER, PL
通讯作者：
BEAUMIER, PL
影响因子：
5.1
作者：
Kanerva, A;Zinn, KR;Hemminki, A
通讯作者：
Hemminki, A