發(fā)布時(shí)間：2018-04-15 06:25

  本文選題：移植瘤 + 裸鼠��； 參考：《中國(guó)協(xié)和醫(yī)科大學(xué)》2010年博士論文

【摘要】： [背景]甲狀腺低分化癌和未分化癌是頭頸部腫瘤惡性程度最高的腫瘤,目前主要采用手術(shù)、放療和化療的綜合治療,由于病變發(fā)展迅速、遠(yuǎn)處轉(zhuǎn)移比例高,總體治療效果差,由于發(fā)病率較低,較難開展大樣本的隨機(jī)對(duì)照研究,目前尚缺乏統(tǒng)一的治療規(guī)范和化療方案。局部復(fù)發(fā)和遠(yuǎn)處轉(zhuǎn)移是主要致死原因,新的化療藥物尤其是分子靶向藥物的出現(xiàn),使研究者對(duì)化療在提高局部控制和降低遠(yuǎn)處轉(zhuǎn)移兩方面的作用冀以新的希望,國(guó)外多個(gè)Ⅰ／Ⅱ期臨床研究正在進(jìn)行,目前國(guó)內(nèi)尚無(wú)同類研究。 [目的]建立甲狀腺低分化和未分化癌的裸鼠移植瘤模型；評(píng)估脂質(zhì)體阿霉素、索拉非尼治療甲狀腺低分化癌移植瘤的療效；篩選對(duì)甲狀腺低分化和未分化癌細(xì)胞敏感的化療藥物,為臨床治療提供參考。 [方法]選取甲狀腺乳頭狀癌、低分化癌和未分化癌的手術(shù)標(biāo)本進(jìn)行裸鼠皮下接種,通過連續(xù)傳代建立穩(wěn)定的移植瘤模型；用脂質(zhì)體阿霉素(liposome doxorubicine)和索拉非尼(sorafenib, BAY 43-9006, Nexavar,多吉美)治療裸鼠甲狀腺低分化癌移植瘤,觀察腫瘤生長(zhǎng)情況,評(píng)估兩種藥物的療效；分別利用3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴鹽[3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide,MTT]及三磷酸腺苷腫瘤藥物敏感性檢測(cè)(adenosine triphosphate-tumor chemosensitivity assay, ATP-TCA)的方法對(duì)甲狀腺癌細(xì)胞進(jìn)行體外藥物敏感性檢測(cè),篩選敏感藥物。 [結(jié)果]3例甲狀腺低分化和未分化癌裸鼠移植瘤模型均成功建立并傳代,其中1例低分化癌模型連續(xù)傳代后生長(zhǎng)穩(wěn)定,成瘤率達(dá)100%,而且腫瘤生長(zhǎng)及信號(hào)傳導(dǎo)相關(guān)蛋白表達(dá)穩(wěn)定,適合進(jìn)一步的動(dòng)物實(shí)驗(yàn)；3例甲狀腺乳頭狀癌移植瘤均未生長(zhǎng)。利用脂質(zhì)體阿霉素和索拉非尼對(duì)甲狀腺低分化癌模型進(jìn)行化療,效果較明顯,空白對(duì)照組、溶劑對(duì)照組、單藥脂阿組、索拉非尼組、低量聯(lián)合組、中量聯(lián)合組、高量聯(lián)合組化療結(jié)束后移植瘤的最終平均體積分別為1274.13±393.76mm3、1060.00±469.05mm3、726.76±488.22mm3、451.54±97.75mm3、518.37±164.44mm3、310.51±210.53mm3和228.44±129.21mm3,瘤重分別為1.13±0.42g、0.91±0.39g、0.78±0.45g、0.55±0.17g、0.52±0.19g、0.34±0.21g和0.19±0.09g,單藥脂阿組、索拉非尼組、低量聯(lián)合組、中量聯(lián)合組、高量聯(lián)合組的抑瘤率分別為30.8%、40.8%、42.3%、62.9%和72.6%,高量聯(lián)合組抑瘤率除與中量聯(lián)合組無(wú)差異外(P=0.357)均高于其余各組,中量聯(lián)合組優(yōu)于單藥脂阿組(P=0.001),而與索拉非尼組無(wú)差異(P=0.192)。各治療組平均瘤重均明顯低于空白對(duì)照組(P0.05)。各治療組均無(wú)實(shí)驗(yàn)鼠死亡,高量聯(lián)合組實(shí)驗(yàn)鼠體重在治療過程中較其余各治療組有明顯減輕(P0.05)。利用MTT法發(fā)現(xiàn)索拉非尼對(duì)甲狀腺乳頭狀癌、低分化和未分化癌均不同程度的敏感,而ATP-TCA方法則顯示對(duì)3例甲狀腺低分化和未分化癌均敏感的藥物是長(zhǎng)春新堿(VCR)、吉西他濱(GEM)以及順鉑+紫杉醇(DDP+PTX)的聯(lián)合方案。 [結(jié)論]甲狀腺低分化癌和未分化癌較乳頭狀癌移植成瘤率高,移植瘤模型經(jīng)連續(xù)傳代后穩(wěn)定,適合動(dòng)物藥效學(xué)等研究；脂質(zhì)體阿霉素和索拉非尼無(wú)論單藥還是聯(lián)合應(yīng)用對(duì)本例甲狀腺低分化癌移植瘤模型均有明顯的抑瘤作用,中量聯(lián)合療效明顯且副作用小。甲狀腺低分化和未分化癌細(xì)胞藥物敏感性個(gè)體差異較大,臨床治療前建議進(jìn)行體外細(xì)胞藥敏檢測(cè)進(jìn)行個(gè)體化的選擇,ATP-TCA可能是一種比較理想的檢測(cè)方法。
[Abstract]:background of the invention thyroid low differentiation cancer and undifferentiated carcinoma are the most malignant tumors in the head and neck , and the present invention mainly adopts the comprehensive treatment of surgery , radiotherapy and chemotherapy , and has the advantages of rapid lesion development , high distant metastasis ratio and poor overall treatment effect .



Objective To establish a model of nude mice transplantation tumor with low thyroid and undifferentiated carcinoma .
To evaluate the efficacy of liposomal doxorubicin and sorbiani in the treatment of low - differentiated thyroid carcinoma ;
Screening of chemotherapeutics sensitive to low thyroid and undifferentiated cancer cells provides a reference for clinical treatment .



Methods : The operation specimens of thyroid papillary carcinoma , low differentiation carcinoma and undifferentiated carcinoma were subcutaneously inoculated in nude mice , and stable transplanted tumor model was established by continuous passage .
To evaluate the effects of liposome doxorubescens and soralea , BAY 43 - 9006 , Nexavar , Dogius in the treatment of low - differentiated thyroid carcinoma in nude mice and to observe the growth of tumor and evaluate the efficacy of the two drugs .
The sensitivity of 3 - ( 4,5 - dimethylthiazol - 2 ) -2,5 - diphenyltetrazol - 3 - ( 4,5 - dimethylimidazol - 2 - yl ) -2,5 - diphenyltetrazol bromide ( MTT ) and adenosine triphosphate ( ATP - TCA ) was used to detect the drug sensitivity of thyroid cancer cells in vitro and to screen sensitive drugs .



Results Three cases of low differentiation and undifferentiated carcinoma of nude mice were successfully established and passaged . Among them , 1 case of low differentiation cancer model was stable after continuous passage , the rate of tumor formation reached 100 % , and tumor growth and signal transduction related protein expression was stable , which was suitable for further animal experiments ;
There was no difference between the two groups ( P = 0 . 05 ) . The tumor weight was significantly lower than that in the control group ( P = 0 . 05 ) . The tumor weight was 1 . 13 鹵 393.76 mm3 , 0 . 78 鹵 0 . 21 g , 0 . 91 鹵 0 . 19 g , 0 . 34 鹵 0 . 21 g and 0 . 19 鹵 0 . 09 g .



Conclusion Low differentiation and undifferentiated carcinoma of the thyroid gland have higher tumor rate than papillary carcinoma , and the transplanted tumor model is stable after continuous passage and is suitable for animal pharmacodynamics and other studies .
In the present case , the tumor model of low differentiation and undifferentiated carcinoma of the thyroid has obvious tumor inhibiting effect , and the combined effect of the liposome doxorubicin and sorbiani is obvious and the side effect is small . The sensitivity of the thyroid low differentiation and the undifferentiated cancer cell is small . The sensitivity of the thyroid low differentiation and the undifferentiated cancer cell is large , and the individual selection of the in vitro cell drug sensitivity detection is recommended before clinical treatment , and the ATP - TCA may be a comparatively ideal detection method .

【學(xué)位授予單位】：中國(guó)協(xié)和醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2010
【分類號(hào)】：R-332;R736.1

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本文編號(hào)：1752930