檢測folfox化療藥物對于結直腸癌有效性的試劑盒的制作方法
【專利說明】檢測FOLFOX化療藥物對于結直腸癌有效性的試劑盒
[技術領域]
[0001] 本發(fā)明涉及用于檢測FOLFOX化療藥物對于結直腸癌有效性的試劑盒。
[【背景技術】]
[0002] 結直腸癌(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,Ferlay J,Ward E,Forman D. Global cancer statistics. CA:a cancer journal for clinicians. 2011 ;61 (2):69-90.)〇 近 幾十年來,結直腸癌的臨床結果已有顯著改善,不僅是由于外科技術的進步,還要歸因于 引入化療和革巴向藥物療法(Moertel CG,Fleming 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 Oncology. 2011 ;29 (15) :2011_2019.)D 依據 美國國家綜合癌癥網絡指南(NCNN),建議III期結直腸癌患者在經根治性切除術后進行輔 助性化療。MOSAIC和NSABP C-07臨床試驗結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 測以奧沙利鉑為基礎的化療藥物的療效標志物。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,為結直腸癌患者術后用藥提供重要參考。
[0003] 絲裂原激活蛋白激酶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信號轉導通路在生物進化過程中高度保守,外界環(huán)境 改變刺激細胞膜受體發(fā)生磷酸化,進而刺激MAPK激酶MPKKK活化,繼而活化下游MPK激 酶MAPKK,然后活化MAPK,活化的MPK可以轉到核內作用靶點,促進基因的轉錄。這種 激活模式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.Neuroscience 2003 ;119:387_97·)、分化和增殖(Aouadi M,et al.p38Mitogen-Activated Prote