Yong Kwon Joong, Milenic Diane E, Baidoo Kwamena E, Brechbiel Martin W
Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda MD, United States of America.
PLoS One. 2016 Jul 28;11(7):e0159904. doi: 10.1371/journal.pone.0159904. eCollection 2016.
In pre-clinical studies, combination therapy with gemcitabine and targeted radioimmunotherapy (RIT) using 212Pb-trastuzumab showed tremendous therapeutic potential in the LS-174T tumor xenograft model of disseminated intraperitoneal disease. To better understand the underlying molecular basis for the observed cell killing efficacy, gene expression profiling was performed after a 24 h exposure to 212Pb-trastuzumab upon gemcitabine (Gem) pre-treatment in this model. DNA damage response genes in tumors were quantified using a real time quantitative PCR array (qRT-PCR array) covering 84 genes. The combination of Gem with α-radiation resulted in the differential expression of apoptotic genes (BRCA1, CIDEA, GADD45α, GADD45γ, IP6K3, PCBP4, RAD21, and p73), cell cycle regulatory genes (BRCA1, CHK1, CHK2, FANCG, GADD45α, GTSE1, PCBP4, MAP2K6, NBN, PCBP4, and SESN1), and damaged DNA binding and repair genes (BRCA1, BTG2, DMC1, ERCC1, EXO1, FANCG, FEN1, MSH2, MSH3, NBN, NTHL1, OGG1, PRKDC, RAD18, RAD21, RAD51B, SEMA4G, p73, UNG, XPC, and XRCC2). Of these genes, the expression of CHK1, GTSE1, EXO1, FANCG, RAD18, UNG and XRCC2 were specific to Gem/212Pb-trastuzumab administration. In addition, the present study demonstrates that increased stressful growth arrest conditions induced by Gem/212Pb-trastuzumab could suppress cell proliferation possibly by up-regulating genes involved in apoptosis such as p73, by down-regulating genes involved in cell cycle check point such as CHK1, and in damaged DNA repair such as RAD51 paralogs. These events may be mediated by genes such as BRCA1/MSH2, a member of BARC (BRCA-associated genome surveillance complex). The data suggest that up-regulation of genes involved in apoptosis, perturbation of checkpoint genes, and a failure to correctly perform HR-mediated DSB repair and mismatch-mediated SSB repair may correlate with the previously observed inability to maintain the G2/M arrest, leading to cell death.
在临床前研究中，吉西他滨与使用212Pb-曲妥珠单抗的靶向放射免疫疗法（RIT）联合治疗在弥漫性腹膜内疾病的LS-174T肿瘤异种移植模型中显示出巨大的治疗潜力。为了更好地理解观察到的细胞杀伤效果的潜在分子基础，在该模型中，先用吉西他滨（Gem）预处理，再暴露于212Pb-曲妥珠单抗24小时后进行基因表达谱分析。使用覆盖84个基因的实时定量PCR阵列（qRT-PCR阵列）对肿瘤中的DNA损伤反应基因进行定量。吉西他滨与α辐射的联合导致凋亡基因（BRCA1、CIDEA、GADD45α、GADD45γ、IP6K3、PCBP4、RAD21和p73）、细胞周期调节基因（BRCA1、CHK1、CHK2、FANCG、GADD45α、GTSE1、PCBP4、MAP2K6、NBN、PCBP4和SESN1）以及受损DNA结合和修复基因（BRCA1、BTG2、DMC1、ERCC1、EXO1、FANCG、FEN1、MSH2、MSH3、NBN、NTHL1、OGG1、PRKDC、RAD18、RAD21、RAD51B、SEMA4G、p73、UNG、XPC和XRCC2）的差异表达。在这些基因中，CHK1、GTSE1、EXO1、FANCG、RAD18、UNG和XRCC2的表达是吉西他滨/212Pb-曲妥珠单抗给药所特有的。此外，本研究表明，吉西他滨/212Pb-曲妥珠单抗诱导的应激性生长停滞条件增加可能通过上调参与凋亡的基因（如p73）、下调参与细胞周期检查点的基因（如CHK1）以及下调参与受损DNA修复的基因（如RAD51旁系同源物）来抑制细胞增殖。这些事件可能由BARC（BRCA相关基因组监测复合体）成员如BRCA1/MSH2等基因介导。数据表明，参与凋亡的基因上调、检查点基因的扰动以及未能正确进行HR介导的DSB修复和错配介导的SSB修复可能与先前观察到的无法维持G2/M期停滞并导致细胞死亡相关。
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