Novel oncolytic adenovirus selectively targets tumor-associated polo-like kinase 1 and tumor cell viability.

Abstract

PURPOSE:

Polo-like kinase 1 (plk1) is a serine/threonine protein kinase essential for multiple mitotic processes. Previous observations have validated plk1 as a promising therapeutic target. Despite being conceptually attractive, the potency and specificity of current plk1-based therapies remain limited. We sought to develop a novel plk1-targeting strategy by constructing an oncolytic adenovirus to selectively silence plk1 in tumor cells.

EXPERIMENTAL DESIGN:

Two artificial features were engineered into one wild-type adenovirus type 5 (wt-Adv5) genome to generate a new oncolytic adenovirus (M1). First, M1 contains a 27-bp deletion in E1A region, which confers potent, oncolytic efficacy. Second, M1 is armed with a fragment of antisense plk1 cDNA that substitutes the E3 region encoding 6.7K and gp19K. In this design, tumor-selective replication of M1 would activate the native adenovirus E3 promoters to express the antisense plk1 cDNA preferentially in tumor cells and silence tumor-associated plk1 protein.

RESULTS:

By virtue of combining oncolysis with plk1 targeting, M1 exhibited potent antitumoral efficacy in vitro and in vivo. Systemic administration of M1 plus cisplatin induced complete tumor regression in 80% of orthotopic hepatic carcinoma model mice that were otherwise resistant to cisplatin and disseminated metastases.

CONCLUSIONS:

Coupling plk1 targeting with oncolysis had shown superior antitumor efficacy. Present findings would benefit the development of novel oncolytic adenoviruses generally applicable to a wide range of molecule-based therapeutics.

• Authors: Jianfeng Zhou, Qinglei Gao, Gang Chen, Xiaoyuan Huang, Yunping Lu, Kanyan Li, Daxing Xie, Liang Zhuang, Jingniu Deng, Ding Ma
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 23 Pg. 8431-40 (Dec 01 2005) ISSN: 1078-0432 [Print] United States
• PMID: 16322306 (Publication Type: Journal Article)

Chemical References

• Adenovirus E1A Proteins
• Adenovirus E3 Proteins
• Antineoplastic Agents
• Cell Cycle Proteins
• DNA, Antisense
• Proto-Oncogene Proteins
• Protein Serine-Threonine Kinases
• Cisplatin

Topics

• Adenoviridae (physiology)
• Adenovirus E1A Proteins (deficiency, genetics)
• Adenovirus E3 Proteins (genetics)
• Animals
• Antineoplastic Agents (therapeutic use)
• Carcinoma, Hepatocellular (enzymology, therapy, virology)
• Cell Cycle Proteins (antagonists & inhibitors, genetics, metabolism)
• Cell Survival
• Cisplatin (therapeutic use)
• Cytopathogenic Effect, Viral (physiology)
• DNA, Antisense (genetics)
• Female
• Genetic Vectors (genetics)
• Humans
• Liver Neoplasms (enzymology, therapy, virology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Promoter Regions, Genetic (genetics)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins (antagonists & inhibitors, genetics, metabolism)
• Tumor Cells, Cultured
• Virus Replication
• Xenograft Model Antitumor Assays
• Polo-Like Kinase 1