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Promoter-controlled infectivity-enhanced conditionally replicative adenoviral vectors for the treatment of gastric cancer

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Abstract

Background

Gastric cancer is the fourth most common malignancy worldwide. Adenoviral vectors (Ads) have been applied for gene therapy of various cancers because of their high transduction efficiency. However, the infectivity of gastrointestinal cancer cells is poor due to the limited expression of the Coxsackie-adenovirus receptor (CAR). In addition, few tumor-specific promoters (TSPs) have been characterized for this type of cancer. To overcome these problems, we proposed TSP-driven conditionally replicating adenoviruses (CRAds) with fiber modification for virotherapy of gastric cancer.

Methods

We assessed the expression profile of eight TSPs in gastric cancer cell lines and evaluated promising candidates in the context of CRAd cytocidal effect. Next, infectivity enhancement by fiber modifications was analyzed in the gastric cancer cell lines. Finally, we combined the TSP-driven CRAds of choice with the fiber modifications to augment the killing effect.

Results

Out of the eight TSPs, the midkine (MK) and cyclooxygenase-2 (Cox-2M and Cox-2L) promoters showed high transcriptional activity in gastric cancer cells. When these promoters were used in a CRAd context, Cox-2 CRAds elicited the strongest cytocidal effect. The greatest infectivity enhancement was observed with adenoviral vectors displaying 5/3 chimeric fibers. Likewise, Cox-2 CRAds with 5/3 chimeric fibers showed the strongest cytocidal effect in gastric cancer cell lines. Therefore, Cox-2 CRAds with 5/3 chimeric fiber modification showed good selectivity and infectivity in gastric cancer cells to yield enhanced oncolysis.

Conclusions

Cox-2 CRAds with 5/3 chimeric fiber modification are promising for virotherapy of gastric cancer.

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Authors and Affiliations

  1. Division of Human Gene Therapy, Department of Medicine, Pathology and Surgery, and the Gene Therapy Center at UAB, University of Alabama at Birmingham BMR2-410, 901 19th Street South, Birmingham, AL, 35294-2172, USA

    Hidetaka A. Ono, Julia G. Davydova, Yasuo Adachi, Koichi Takayama, Shannon D. Barker, Paul N. Reynolds, David T. Curiel & Masato Yamamoto

  2. Second Department of Surgery, Yokohama City University School of Medicine, Yokohama, Japan

    Hidetaka A. Ono, Chikara Kunisaki & Hiroshi Shimada

  3. Department of Experimental Diagnostic Imaging, MD Anderson Cancer Center, University of Texas, Houston, TX, USA

    Victor N. Krasnykh

Authors
  1. Hidetaka A. Ono
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  2. Julia G. Davydova
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  3. Yasuo Adachi
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  4. Koichi Takayama
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  5. Shannon D. Barker
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  6. Paul N. Reynolds
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  7. Victor N. Krasnykh
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  8. Chikara Kunisaki
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  9. Hiroshi Shimada
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  10. David T. Curiel
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  11. Masato Yamamoto
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Ono, H., Davydova, J., Adachi, Y. et al. Promoter-controlled infectivity-enhanced conditionally replicative adenoviral vectors for the treatment of gastric cancer. J Gastroenterol 40, 31–42 (2005). https://doi.org/10.1007/s00535-004-1490-y

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  • DOI: https://doi.org/10.1007/s00535-004-1490-y

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