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

Cancer Gene Therapy volume 14, pages 105–116 (2007)Cite this article

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.

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Abbreviations

NSCLC:

non-small cell lung cancer

IL-8:

interleukin-8

VEGF:

vascular endothelial growth factor

CAR:

coxsackie and adenovirus receptor

Ad5:

serotype 5 adenovirus

Ad3:

serotype 3 adenovirus

Ad5/3:

Ad5 containing a chimeric fiber protein possessing the Ad3 knob

CRAd:

conditionally replicative adenovirus

E1:

early region 1

E4:

early region 4

RT-PCR:

revers transcription-PCR

CMV:

cytomegalovirus

CsCl:

cesium chloride

VP:

viral particle

PFU:

plaque forming unit

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Acknowledgements

We thank Professor Semenza (John's Hopkins University) for providing us with the human VEGF promoter. We also thank Dirk M Nettelbeck, Joel N Glasgow, Akiko Harada and Nobuyuki Hara (Kyushu university, Fukuoka, Japan) for their excellent technical support and expert advice. This work was supported by National Cancer Institute Grant CA83821, The CapCURE Foundation, The Lustgarten Foundation, United States Department of Defense Grant 991018 and the American Cancer Society.

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Authors and Affiliations

  1. Departments of Medicine, Division of Human Gene Therapy, Pathology and Surgery, The University of Alabama at Birmingham, Birmingham, AL, USA

    K Takayama, P N Reynolds, Y Adachi, L Kaliberova & D T Curiel

  2. Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    K Takayama, J Uchino & Y Nakanishi

  3. Chest Clinic, Royal Adelaide Hospital, Adelaide, South Australia, Australia

    P N Reynolds

  4. Division of Gene Therapy Center, The University of Alabama at Birmingham, Birmingham, AL, USA

    D T Curiel

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  1. K Takayama
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Correspondence to K Takayama.

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Takayama, K., Reynolds, P., Adachi, Y. et al. Vascular endothelial growth factor promoter-based conditionally replicative adenoviruses for pan-carcinoma application. Cancer Gene Ther 14, 105–116 (2007). https://doi.org/10.1038/sj.cgt.7700991

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