Induced phenotype targeted therapy: Radiation-induced apoptosis-targeted chemotherapy

Beom Suk Lee, Yong Woo Cho, Gui Chul Kim, Do Hee Lee, Chang Jin Kim, Hee Seup Kil, Dae Yoon Chi, Youngro Byun, Soon Hong Yuk, Kwang Meyung Kim, In-San Kim, Ick Chan Kwon, Sang Yoon Kim

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35 Citations (Scopus)

Abstract

Background: Tumor heterogeneity and evolutionary complexity may underlie treatment failure in spite of the development of many targeted agents. We suggest a novel strategy termed induced phenotype targeted therapy (IPTT) to simplify complicated targets because of tumor heterogeneity and overcome tumor evolutionary complexity. Methods: We designed a caspase-3 specific activatable prodrug, DEVD-S-DOX, containing doxorubicin linked to a peptide moiety (DEVD) cleavable by caspase-3 upon apoptosis. To induce apoptosis locally in the tumor, we used a gamma knife, which can irradiate a very small, defined target area. The in vivo antitumor activity of the caspase-3-specific activatable prodrug combined with radiation was investigated in C3H/HeN tumor-bearing mice (n = 5 per group) and analyzed with the Student's t test or Mann-Whitney U test. All statistical tests were two-sided. We confirmed the basic principle using a caspase-sensitive nanoprobe (Apo-NP). Results: A single exposure of radiation was able to induce apoptosis in a small, defined region of the tumor, resulting in expression of caspase-3. Caspase-3 cleaved DEVD and activated the prodrug. The released free DOX further activated DEVD-S-DOX by exerting cytotoxic effects on neighboring tumor or supporting cells, which repetitively induced the expression of caspase-3 and the activation of DEVD-S-DOX. This sequential and repetitive process propagated the induction of apoptosis. This novel therapeutic strategy showed not only high efficacy in inhibiting tumor growth (14-day tumor volume [mm<sup>3</sup>] vs radiation alone: 848.21±143.24 vs 2511.50±441.89, P <. 01) but also low toxicity to normal cells and tissues. Conclusion: Such a phenotype induction strategy represents a conceptually novel approach to overcome tumor heterogeneity and complexity as well as to substantially improve current conventional chemoradiotherapy with fewer sequelae and side effects.

Original languageEnglish
Article numberdju403
JournalJournal of the National Cancer Institute
Volume107
Issue number2
DOIs
Publication statusPublished - 2015 Feb 1

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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    Lee, B. S., Cho, Y. W., Kim, G. C., Lee, D. H., Kim, C. J., Kil, H. S., Chi, D. Y., Byun, Y., Yuk, S. H., Kim, K. M., Kim, I-S., Kwon, I. C., & Kim, S. Y. (2015). Induced phenotype targeted therapy: Radiation-induced apoptosis-targeted chemotherapy. Journal of the National Cancer Institute, 107(2), [dju403]. https://doi.org/10.1093/jnci/dju403