檢測奧沙利鉑對于結(jié)直腸癌有效性的試劑盒的制作方法
【專利說明】檢測奧沙利鉑對于結(jié)直腸癌有效性的試劑盒
[技術(shù)領(lǐng)域]
[0001] 本發(fā)明涉及檢測奧沙利鉑對于結(jié)直腸癌有效性的試劑盒。
[【背景技術(shù)】]
[0002] 結(jié)直腸癌（CRC)是世界第三大常見的惡性腫瘤，也是由癌癥引起死亡的第二大原 因，嚴重威脅人類健康（Jemal A，Bray F，Center MM，F(xiàn)erlay J，Ward E，F(xiàn)orman D. Global cancer statistics. CA:a cancer journal for clinicians. 2011 ;61 (2):69-90.)〇 近 幾十年來，結(jié)直腸癌的臨床結(jié)果已有顯著改善，不僅是由于外科技術(shù)的進步，還要歸因于 化療和革巴向藥物的介入療法（Moertel CG，F(xiàn)leming TR，Macdonald JS，et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. The New England journal of medicine. 1990 ；322(6):352-358 ；Andre T，Boni Cj Navarro M，et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. Journal of clinical oncology!official journal of the American Society of Clinical Oncology. 2009 ；27(19):3109-3116 ；Hurwitz HIjFehrenbacher LjHainsworth JDj et al.Bevacizumab in combination with fluorouracil and leucovorin:an active regimen for first-line metastatic colorectal cancer. Journal of clinical oncology:official journal of the American Society of Clinical Oncology. 2005 ； 23 (15) :3502-3508 ；Van Cutsem EjKohne CHjLang I, et al.Cetuximab plus irinotecan，fluorouracil，and leucovorin as first-line treatment for metastatic colorectal cancer:updated analysis of overall survival according to tumor KRAS and BRAF mutation status. Journal of clinical oncology:official journal of the American Society of Clinical 0ncology.2011;29(15):2011-2019·)。依據(jù)美 國國家綜合癌癥網(wǎng)絡指南，建議II期和III期結(jié)直腸癌高?；颊咴诮?jīng)根治性切除術(shù)后進行 輔助性化療。MOSAIC和NSABP C-07臨床試驗結(jié)果證明采用奧沙利鉑作為一線輔助化療 的方案得到認可（Andre Tj Boni Cj Navarro M，et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial.Journal of clinical oncology:official journal of the American Society of Clinical Oncology. 2009 ；27 (19):3109-3116 ； Kuebler JP，Wieand HS, O'Connell MJ，et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer:results from NSABP C-〇7. Journal of clinical oncology:official journal of the American Society of Clinical Oncology. 2007 ；25 (16):2198-2204.)〇 然而，在III期結(jié)直腸癌患者接受含有奧沙利鉑的輔助性化療法后的三年無病生存率依舊僅 有 65% (Uncu Dj Aksoy Sj Cetin Bj et al. Results of adjuvant F0LF0X regimens in stage III colorectal cancer patients:retrospective analysis of 667patients. Oncology. 2013 ;84 (4) : 240-245)。一個有效的治療策略就是區(qū)分奧沙利鉑輔助性化療法中 可能獲益較多或獲益較少的患者群體，對CRC患者進行個性化藥物治療，但目前仍缺少預 測標記奧沙利鉑敏感性和耐藥性的臨床驗證。為此，臨床研宄急需能夠簡便準確地進行預 后及療效預測的方法，為結(jié)直腸癌患者術(shù)后用藥提供重要參考。
[0003] 絲裂原激活蛋白激酶激酶激酶激酶I (MAP4K1)，系絲/蘇氨酸激酶亞家族STE20中 的一員，屬于絲裂原激活蛋白激酶（MAPK)信號傳導通路的一個上游激活因子，MAPK是一組 可以被多種細胞外信號（包括生長因子，激素，紫外線福射，DNA損傷劑，炎性細胞因子和環(huán) 境應激等）激活的絲/蘇氨酸激酶。MPK信號轉(zhuǎn)導通路在生物進化過程中高度保守，自膜 受
[0004] 體到MAPK激酶激酶（MAPKKK)再到MAPK激酶（MAPKK)然后到MAPK,呈瀑布 狀磷酸化下游激酶，在細胞信號轉(zhuǎn)導通路屮MPK處于細胞質(zhì)部分的終末位置，活化 后可以轉(zhuǎn)到核內(nèi)作用靶點，調(diào)芐基因的表達。這種激活模型存在于酵母至哺乳類動 物。它參與細胞的多種生物學行為，包括細胞凋亡（Kyosseva SV.Mitogen-Activated Protein Kinase Signaling. In:S. John, editor", editors^. International Review of Neurobiology, City ；Academic Press ；2004, p.201-20 ；ffiIIaime-Morawek S， et al. C-jun N-terminal kinases/c-Jun and p38pathways cooperate in ceramide-induced neuronal apoptosis.Neuroscience2003;119:387_97·)、分化和增殖（Aouadi M，et al.p38Mitogen-Activated Protein Kinase Activity Commits Embryonic Stem Cells to Either Neurogenesis or Cardiomyogenesis. STEM CELLS 2006 ;24:1399-406 ;Aouadi M, et al. Inhibition of p38MAPK Increases Adipogenesis From Embryonic to Adult Stages. Diabetes 2006 ；55:281-9 ；Roux PP and Blenis J. ERX and p38MAPK-Activated Protein Kin