Vascular endothelial growth factor promoter-based conditionally replicative adenoviruses for pan-carcinoma application

K. Takayama, P. N. Reynolds, Y. Adachi, L. Kaliberova, J. Uchino, Y. Nakanishi, D. T. Curiel

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Treatment of advanced lung cancer is one of the major challenges in current medicine because of the high morbidity and mortality of the disease. Advanced stage lung cancer is refractory to conventional therapies and has an extremely poor prognosis. Thus, new therapeutic approaches are needed. Lung tumor formation depends on angiogenesis in which the vascular endothelial growth factor (VEGF) produced by cancer cells plays a pivotal role. Neutralizing VEGF with a soluble VEGF receptor suppresses tumor growth; however, the anticancer effect with this therapy is weakened after the intratumoral vascular network is completed. In this study, we turned the expression of VEGF by tumors to therapeutic advantage using a conditionally replication-competent adenovirus (CRAd) in which the expression of E1 is controlled by the human VEGF promoter. This virus achieved good levels of viral replication in lung cancer cells and induced a substantial anticancer effect in vitro and in vivo. As a further enhancement, the cancer cell killing effect was improved with tropism modification of the virus to express the knob domain of Ad3, which improved infectivity for cancer cells. These VEGF promoter-based CRAds also showed a significant cell killing effect for various types of cancer lines other than lung cancer. Conversely, the VEGF promoter has low activity in normal tissues, and the CRAd caused no damage to normal bronchial epithelial cells. Since tumor-associated angiogenesis via VEGF signalling is common in many types of cancers, these CRAds may be applicable to a wide range of tumors. We concluded that VEGF promoter-based CRAds have the potential to be an effective strategy for cancer treatment.

Original languageEnglish
Pages (from-to)105-116
Number of pages12
JournalCancer gene therapy
Volume14
Issue number1
DOIs
StatePublished - Jan 22 2007
Externally publishedYes

Keywords

  • Angiogenesis
  • Chimeric vector
  • Replicative adenovirus
  • VEGF

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