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E10A, an adenovirus-carrying endostatin gene, dramatically increased the tumor drug concentration of metronomic chemotherapy with low-dose cisplatin in a xenograft mouse model for head and neck squamous-cell carcinoma

Cancer Gene Therapy volume 19, pages 144–152 (2012)Cite this article

Abstract

Most cancer chemotherapeutic agents are administered at the maximum-tolerated dose (MTD) in short cycles with treatment breaks. However, MTD-based chemotherapies are often associated with significant toxicity and treatment breaks allow the opportunity for tumor regrowth and acquisition of chemoresistance. To minimize these drawbacks, a metronomic strategy, in which chemotherapeutics are administered at doses significantly below the MTD without treatment breaks, has been suggested by many investigators. The antitumor effect of metronomic chemotherapy may be partially due to inhibition of tumor angiogenesis, and it could be enhanced by a combination therapy, including antiangiogenic agents. In this study, we evaluated the synergistic effect of E10A, an adenovirus carrying the endostatin gene, the most potent inhibitors of tumor angiogenesis, in combination with weekly low-dose cisplatin in a xenograft mouse model for head and neck squamous-cell carcinoma. The E10A induced mRNA and protein expressions of endostatin in H891 cells in vitro. E10A significantly enhanced the in vivo tumor growth inhibitory effect of cisplatin. Immunohistochemical analysis with a TUNEL (terminal deoxynucleotidyl transferase-mediated nick-end labeling) assay and anti-CD31 antibodies revealed that the combination of E10A and cisplatin induced high levels of cell apoptosis and inhibited tumor angiogenesis. Importantly, E10A increased the platinum concentrations in tumors to fivefold higher than that induced by cisplatin alone.

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Acknowledgements

This research was supported by Japanese Research Project, Grant-in-aid for Scientific Research (B); project number 21390462 (TS), in part by Grants-in-Aid for Scientific Research; project number 20251283 and 21390462 (K-iN) and the Society for Promotion of International Oto-Rhino-Laryngology (SPIO), Japan (ZA).

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Authors and Affiliations

  1. Division of Otolaryngology-Head and Neck Surgery, Kobe University Graduate School of Medicine, Kobe, Japan

    Z Adhim, N Otsuki & K Nibu

  2. Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe, Japan

    Z Adhim, N Morishita & T Shirakawa

  3. Department of Otolaryngology-Head and Neck Surgery, Fatmawati General Hospital/Syarif Hidayatullah State Islamic University (UIN), Jakarta, Indonesia

    Z Adhim

  4. Cancer Center, Sun Yat-sen University, Guangzhou, China

    X Lin & W Huang

  5. Department of Pharmacology, Himeji Dokkyo University, Himeji, Japan

    T Nakamura

  6. Kyoto Pharmaceutical University, Kyoto, Japan

    H Yasui & T Shirakawa

  7. Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan

    K Shigemura & M Fujisawa

  8. Division of Translational Research for Biologics, Kobe University Graduate School of Medicine, Kobe, Japan

    T Shirakawa

  9. Department of International Health, Kobe University Graduate School of Health Sciences, Kobe, Japan

    T Shirakawa

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  1. Z Adhim
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  2. X Lin
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Correspondence to T Shirakawa.

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Adhim, Z., Lin, X., Huang, W. et al. E10A, an adenovirus-carrying endostatin gene, dramatically increased the tumor drug concentration of metronomic chemotherapy with low-dose cisplatin in a xenograft mouse model for head and neck squamous-cell carcinoma. Cancer Gene Ther 19, 144–152 (2012). https://doi.org/10.1038/cgt.2011.79

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  • DOI: https://doi.org/10.1038/cgt.2011.79

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