Combination of RET siRNA and irinotecan inhibited the growth of medullary thyroid carcinoma TT cells and xenografts via apoptosis
Combination of RET siRNA and irinotecan inhibited the growth of medullary thyroid carcinoma TT cells and xenografts via apoptosis
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DOI：
10.1111/j.1349-7006.2009.01484.x
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发表时间：
2010-04-01
期刊：
影响因子：
5.7
通讯作者：
Maitani, Yoshie
中科院分区：
文献类型：
--
作者：
Koga, Kimiko;Hattori, Yoshiyuki;Maitani, Yoshie
甲状腺髓样癌(MTC)是一种罕见的内分泌肿瘤，易发生转移，伊立替康(CPT-11)的治疗因其副作用而受到限制。原癌基因重排(RET)的突变被认为是MTC的致病事件。本研究的目的是检测小干扰RNA(SiRNA)及其与CPT-11联合作用是否能在体内外抑制MTC细胞的生长。RET siRNA通过下调Bcl2的表达，抑制RET的表达，抑制细胞增殖，增强caspase-3/7的活性。与RET siRNA、CPT-11或SN-38单独处理相比，CPT-11或SN-38联合处理显著提高caspase3/7活性。重要的是，瘤内注射RET siRNA和静脉注射CPT-11显著地抑制了MTC移植瘤的生长，这是通过增加凋亡效应来实现的。RET siRNA增强了对CPT-11的敏感性，这些发现将为RET突变的MTC的治疗提供新的策略。(《癌症科学》2010；101：941-947)
Medullary thyroid carcinoma (MTC) is a rare endocrine tumor that frequently metastasizes, and treatment with irinotecan (CPT-11) is limited because of side effects. Mutations in the Rearranged during transfection (RET) proto-oncogene are considered the causative event of MTC. The objective of this study was to examine whether small interfering RNA (siRNA) and its combined treatment with CPT-11 could inhibit MTC cell growth in vitro and in vivo. The transfection of RET siRNA suppressed RET expression, reduced proliferation, and increased caspase-3/7 activity via the down-regulation of Bcl-2 expression. Combined treatments with CPT-11 or SN-38 significantly increased caspase 3/7 activity compared with RET siRNA, CPT-11 or SN-38 treatment alone. Importantly, intratumoral injection of RET siRNA along with intravenous injection of CPT-11 significantly inhibited the tumor growth of MTC xenografts via an increased apoptotic effect. These findings that RET siRNA enhanced sensitivity for CPT-11 will provide a novel strategy for the treatment of MTC with RET mutation. (Cancer Sci 2010; 101: 941-947)