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Enhanced efficacy of combination therapy with adeno‑associated virus-delivered pigment epithelium-derived factor and cisplatin in a mouse model of Lewis lung carcinoma.

Abstract
Pigment epithelium-derived factor (PEDF) is a potent inhibitor of angiogenesis, and the antitumor effect of adeno-associated virus (AAV)-mediated PEDF expression has been demonstrated in a range of animal models. The combined treatment of low-dose chemotherapy and gene therapy inhibits the growth of solid tumors more effectively than current traditional therapies or gene therapy alone. In the present study, the effect of treatment with an AAV2 vector harboring the human PEDF (hPEDF) gene in combination with low-dose cisplatin on the growth of Lewis lung carcinoma (LLC) in mice was assessed. LLC cells were infected with AAV-enhanced green fluorescent protein (EGFP) in the presence or absence of cisplatin, and then the effect of cisplatin on AAV-mediated gene expression was evaluated by image and flow cytometric analysis. Tumor growth, survival time, vascular endothelial growth factor (VEGF) expression, microvessel density (MVD) and apoptotic index were analyzed in C57BL/6 mice treated with AAV-hPEDF, cisplatin or cisplatin plus AAV-hPEDF. The results of the present study provide evidence that cisplatin treatment is able to enhance AAV-mediated gene expression in LLC cells. In addition, the combined treatment of cisplatin plus AAV‑hPEDF markedly prolonged the survival time of the mice and inhibited tumor growth, resulting in significant suppression of tumor angiogenesis and induction of tumor apoptosis in vivo, and also protected against cisplatin-related toxicity. These findings suggest that combination of AAV-hPEDF and cisplatin has potential as a novel therapeutic strategy for lung cancer.
AuthorsSha-Sha He, Qin-Jie Wu, Chang Yang Gong, Shun-Tao Luo, Shuang Zhang, Meng Li, Lian Lu, Yu-Quan Wei, Li Yang
JournalMolecular medicine reports (Mol Med Rep) Vol. 9 Issue 6 Pg. 2069-76 (Jun 2014) ISSN: 1791-3004 [Electronic] Greece
PMID24714917 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Eye Proteins
  • Nerve Growth Factors
  • Serpins
  • pigment epithelium-derived factor
  • Cisplatin
Topics
  • Animals
  • Antineoplastic Agents (administration & dosage, pharmacology)
  • Apoptosis (drug effects)
  • Carcinoma, Lewis Lung (genetics, pathology, therapy)
  • Cell Line, Tumor
  • Cisplatin (administration & dosage, pharmacology)
  • Combined Modality Therapy
  • Dependovirus (genetics)
  • Disease Models, Animal
  • Eye Proteins (genetics, metabolism)
  • Gene Expression
  • Genetic Therapy
  • Genetic Vectors (administration & dosage, genetics)
  • Humans
  • Lung Neoplasms (genetics, pathology, therapy)
  • Male
  • Mice
  • Neovascularization, Pathologic (drug therapy, genetics)
  • Nerve Growth Factors (genetics, metabolism)
  • Serpins (genetics, metabolism)

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