Induced Phenotype Targeted Therapy: Radiation-Induced Apoptosis-Targeted Chemotherapy
Induced Phenotype Targeted Therapy: Radiation-Induced Apoptosis-Targeted Chemotherapy
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DOI：
10.1093/jnci/dju403
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发表时间：
2015-02-01
影响因子：
10.3
通讯作者：
Kim, Sang Yoon
中科院分区：
文献类型：
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作者：
Lee, Beom Suk;Cho, Yong Woo;Kim, Sang Yoon
背景：肿瘤的异质性和进化的复杂性可能是治疗失败的基础，尽管许多靶向药物的发展。我们提出了一种新的策略，称为诱导表型靶向治疗（IPTT），以简化复杂的靶点，因为肿瘤的异质性和克服肿瘤的进化复杂性。方法：我们设计了一种caspase-3特异性激活的前药DEVD- s - dox，它含有阿霉素，与caspase-3在细胞凋亡时可切割的肽段（DEVD）相连。为了在肿瘤中诱导局部细胞凋亡，我们使用了伽玛刀，它可以照射一个非常小的，确定的目标区域。在C3H/HeN荷瘤小鼠（每组5只）体内研究caspase-3特异性活化前药联合放疗的抗肿瘤活性，并采用Student’st检验或Mann-Whitney U检验进行分析。所有统计检验均为双侧检验。我们使用caspase敏感纳米探针（Apo-NP）证实了基本原理。结果：单次辐射照射能够在肿瘤的小范围内诱导细胞凋亡，导致caspase-3的表达。Caspase-3切割DEVD并激活前药。释放的游离DOX通过对邻近肿瘤或支持细胞施加细胞毒作用，进一步激活DEVD-S-DOX，反复诱导caspase-3的表达和DEVD-S-DOX的激活。这一连续重复的过程促进了细胞凋亡的诱导。这种新的治疗策略不仅对肿瘤生长有很高的抑制作用（14天肿瘤体积[mm(3)]比单独放疗：848.21 +/- 143.24比2511.50 +/- 441.89,P < 0.01），而且对正常细胞和组织的毒性也很低。结论：这种表型诱导策略代表了一种概念上的新方法，可以克服肿瘤的异质性和复杂性，并大大改善目前的常规放化疗，减少后遗症和副作用。
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(3)] 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.