【摘要】：目的：采用前瞻性隨機(jī)對照臨床研究方法,以參桃軟肝方為基本方辨證加減與索拉非尼聯(lián)合應(yīng)用,觀察其對中晚期原發(fā)性肝癌的療效,同時采用國際公認(rèn)的生存質(zhì)量評分量表EORTC QLQ-C30對患者生存質(zhì)量進(jìn)行隨訪觀察評價其對患者生存質(zhì)量的影響,采用NCI不良反應(yīng)事件標(biāo)準(zhǔn)評價其安全性。通過動物實驗方法,構(gòu)建裸鼠肝癌移植瘤模型,探索參桃軟肝方聯(lián)合索拉非尼的抑瘤作用及其相關(guān)的作用機(jī)制,以為中醫(yī)藥聯(lián)合索拉非尼等靶向藥物治療原發(fā)性肝癌提供一定的實驗參考依據(jù)。方法：1.臨床研究部分：采用前瞻性隨機(jī)對照試驗研究方法,納入符合入組標(biāo)準(zhǔn)病例60例,其中中藥聯(lián)合組30例,對照組30例。中藥聯(lián)合組給予口服索拉非尼400mg,每日2次,同時給予參桃軟肝方為基本方的辨證中藥湯劑口服。對照組給予口服索拉非尼400mg,每日2次。每月對入組患者進(jìn)行隨訪,評價腫瘤控制情況,記錄患者疾病進(jìn)展時間及生存時間,同時隨訪監(jiān)測患者谷丙轉(zhuǎn)氨酶(ALT)、總膽紅素(TβIL)、白蛋白(ALB)等肝功能指標(biāo),評價患者肝功能分級情況。并采用國際公認(rèn)的生存質(zhì)量評分量表EORTC QLQ-C30對患者生存質(zhì)量進(jìn)行隨訪觀察評價患者生存質(zhì)量情況。采用NCI不良反應(yīng)事件評價標(biāo)準(zhǔn)記錄研究過程中發(fā)生的不良反應(yīng),以評價藥物安全性。2.實驗研究部分：構(gòu)建裸鼠HepG2肝癌移植瘤模型,造模成功后隨機(jī)分為對照組、參桃軟肝方組、索拉非尼組和參桃軟肝方聯(lián)合索拉非尼組,然后進(jìn)行灌胃給藥。給藥期間每3天測量瘤體體積和小鼠體重。給藥結(jié)束后,取瘤體測量瘤重,計算抑瘤率。應(yīng)用Western blot方法檢測瘤體組織PI3K、AKT及其磷酸化表達(dá)水平以及檢測血管內(nèi)皮生長因子(VEGF)和血小板源性生長因子(PDGF)表達(dá),以探索參桃軟肝方聯(lián)合索拉非尼的抑瘤機(jī)制。結(jié)果：1.臨床研究結(jié)果顯示,在索拉非尼聯(lián)合參桃軟肝方組中,患者的腫瘤客觀緩解率(ORR)與對照組無明顯無差異(13.3% VS 10.0%,P0.05)；而在腫瘤的疾病控制率(DCR)方面,聯(lián)合組的療效高于對照組(66.6% VS 46.6%,P0.05),提示索拉非尼聯(lián)合參桃軟肝方,不能提高對肝癌患者的客觀緩解率,但可提高其疾病控制率。兩組的生存率比較結(jié)果顯示,在索拉非尼聯(lián)合參桃軟肝方組中,患者的3個月生存率、6個月生存率與索拉非尼單藥組無明顯差異(51.0% VS 46.6%,43.7% VS 34.3%,均P0.05)；而對比兩組1年生存率發(fā)現(xiàn),中藥聯(lián)合組患者的1年生存率優(yōu)于對照組(38.3% VS 21.7%,P0.05),提示索拉非尼聯(lián)合參桃軟肝方,不能提高肝癌患者的的近期生存率,但可以提高患者遠(yuǎn)期的1年生存率。采用Kaplan-Meier方法對兩組的疾病進(jìn)展時間和生存時間進(jìn)行分析,結(jié)果顯示：索拉非尼聯(lián)合參桃軟肝方組肝癌患者的中位疾病進(jìn)展時間(mTTP)與索拉非尼單藥組相比無差異(4.3個月VS 3.6個月,Z=0.858,P=0.354),提示索拉非尼聯(lián)合參桃軟肝方組較索拉非尼單藥組,兩者在延長中晚期原發(fā)性肝癌患者的疾病進(jìn)展時間方面無明顯差別。患者生存曲線顯示,聯(lián)合組肝癌患者中位生存時間(mOS)為7.7個月,索拉非尼單藥組的中位生存時間為6.1個月,聯(lián)合組較對照組延長1.6個月,差異有統(tǒng)計學(xué)意義(Z=5.998,P=0.014),提示索拉非尼聯(lián)合參桃軟肝方組對比較索拉非尼單藥組可以提高中晚期原發(fā)性肝癌患者的中位生存時間。組內(nèi)治療前與治療后的血清AFP水平比較顯示,聯(lián)合組和對照組治療后的血清AFP水平均較治療前明顯下降,差異具有統(tǒng)計學(xué)(P0.01)；兩組間的血清AFP水平治療前后差值(AFP治療前后差值=治療前血清AFP-治療后血清AFP)比較顯示,聯(lián)合組血清AFP水平的下降程度較對照組更明顯(359.83ng/ml VS 266.23ng/ml, P0.05)。提示,經(jīng)治療后,兩組肝癌患者的血清AFP水平均出現(xiàn)明顯下降,且聯(lián)合組血清AFP水平的下降程度明顯高于對照組。組內(nèi)治療前與治療后血清ALT、TBIL及ALB水平統(tǒng)計學(xué)比較顯示,聯(lián)合組和對照組治療后的血清ALT和TBIL均較治療前明顯下降,差異具有統(tǒng)計學(xué)(P0.05)；而兩組治療后的血清ALB均較治療前提高,差異具有統(tǒng)計學(xué)(P0.05)；提示,治療后兩組的肝功能均有不程度的好轉(zhuǎn)。兩組間治療前后血清ALT、TBIL及ALB差值(治療前后差值=治療前數(shù)值-治療后數(shù)值的絕對值)比較顯示,聯(lián)合組患者ALT和ALB的差值均高于對照組,差異具有統(tǒng)計學(xué)(P0.05),而兩組患者的TBI治療前后差值無明顯差異(P0.05),提示聯(lián)合組對患者ALT和ALB等肝功能指標(biāo)的改善程度優(yōu)于對照組,而對TBIL的改善方面兩組無差異。治療后兩組肝功能分級的穩(wěn)定好轉(zhuǎn)率分別為76.7%和56.7%,聯(lián)合組肝功能分級的穩(wěn)定好轉(zhuǎn)率明顯高于對照組(P0.05),提示聯(lián)合組對肝功能的改善程度優(yōu)于對照組,參桃軟肝方聯(lián)合索拉非尼可增加對肝癌患者肝功能的保護(hù)作用。研究結(jié)果顯示,在索拉非尼聯(lián)合參桃軟肝方組中,患者在功能領(lǐng)域各項評分及總體健康狀況領(lǐng)域評分較治療前增加,差異具有統(tǒng)計學(xué)意義(均P0.05)；在癥狀領(lǐng)域的疲倦、惡心與嘔吐、氣促、失眠、食欲喪失、疼痛、便秘和腹瀉評分均較治療前減少,差異顯著(均P0.05),在經(jīng)濟(jì)困難領(lǐng)域評分較治療前升高(P0.05)(見表11)。依據(jù)EORTC QLQ-C30(V3.0)中文版計分規(guī)則：功能領(lǐng)域和總體健康狀況領(lǐng)域得分越高,說明功能狀況和生命質(zhì)量越好；而癥狀領(lǐng)域得分越高,表明癥狀或問題越多(生命質(zhì)量越差),提示治療后聯(lián)合用藥組患者的生存質(zhì)量在經(jīng)濟(jì)困難領(lǐng)域出現(xiàn)惡化,而在其余各項領(lǐng)域均得到改善。在對照組中,患者功能領(lǐng)域各項評分及總體健康狀況領(lǐng)域評分均亦較治療前增加,差異具有統(tǒng)計學(xué)意義(均P0.05)；在癥狀領(lǐng)域的氣促、惡心與嘔吐、失眠、疼痛和便秘評分均較治療前減少,差異顯著(均P0.05),而在疲倦、食欲喪失、腹瀉和經(jīng)濟(jì)困難領(lǐng)域的評分均較治療前增加(均P0.05)(見表12)。依據(jù)EORTC QLQ-C30(V3.0)中文版計分規(guī)則：提示治療后索拉非尼單藥組的生存質(zhì)量總體上有一定提高,但在疲倦、食欲喪失、腹瀉和經(jīng)濟(jì)困難等領(lǐng)域出現(xiàn)惡化。比較兩組患者治療前后生存質(zhì)量評分差值(生存質(zhì)量評分差值=治療后生存質(zhì)量評分-治療前生存質(zhì)量評分)結(jié)果顯示,在功能領(lǐng)域方面,聯(lián)合組在軀體和情緒功能方面的評分優(yōu)于對照組(均P0.05),而在角色、認(rèn)知和社會功能方面的評分兩組無明顯差異(均P0.05)；在癥狀領(lǐng)域,聯(lián)合組在疲倦、惡心與嘔吐、氣促、食欲喪失和腹瀉方面的評分優(yōu)于對照組(均P0.05),在便秘、失眠、疼痛和經(jīng)濟(jì)困難領(lǐng)域等方面的評分兩組間無明顯差異(均P0.05)；在總體健康狀況領(lǐng)域,聯(lián)合用藥組的評分亦高于對照組(均P0.05)。提示治療后聯(lián)合用藥組的生存質(zhì)量總體上優(yōu)于索拉非尼單藥組,尤其在軀體、情緒功能領(lǐng)域以及在疲倦、惡心與嘔吐、氣促、食欲喪失和腹瀉等癥狀領(lǐng)域中,聯(lián)合組對生存質(zhì)量的改善程度優(yōu)于對照組。研究過程中,兩組患者發(fā)生的不良反應(yīng)情況如表,對比兩組不良反應(yīng)的發(fā)生情況,結(jié)果顯示,聯(lián)合用藥組的手足綜合征、腹瀉、疲勞、皮疹的發(fā)生率明顯低于對照組(均P0.05),而兩組患者骨髓抑制和高血壓不良反應(yīng)發(fā)生率無明顯差異(均P0.05)。提示索拉非尼與參桃軟肝方聯(lián)合應(yīng)用,可明顯降低索拉非尼的手足綜合征、腹瀉、疲勞、皮疹等不良反應(yīng)的發(fā)生,但對索拉非尼骨髓抑制和高血壓不良反應(yīng)的發(fā)生無明顯影響。2.實驗研究結(jié)果顯示：中藥組,索拉非尼組以及聯(lián)合組的瘤體體積均小于對照組(均P0.05),索拉非尼組的瘤體體積小于中藥組(P0.05),而聯(lián)合組的瘤體體積小于索拉非尼組(P0.05),提示參桃軟肝方對腫瘤的生長有一定抑制作用,但其對腫瘤的抑制作用不及索拉非尼,參桃軟肝方聯(lián)合索拉非尼應(yīng)用時,可增強(qiáng)索拉非尼的腫瘤抑制作用。各組瘤重的比較結(jié)果顯示,中藥組,索拉非尼組以及聯(lián)合組的瘤重均小于對照組(P0.05),索拉非尼組的抑瘤率優(yōu)于參桃軟肝方組(44.5% VS 31.9%,P0.05),而聯(lián)合組的抑瘤率高于索拉非尼組(68.7% VS 44.5%,P0.05),提示參桃軟肝方和索拉非尼體內(nèi)均對肝癌瘤體有一定抑制作用,其中索拉非尼對腫瘤的抑制作用高于參桃軟肝方,而兩者聯(lián)合應(yīng)用時,可進(jìn)一步增強(qiáng)對肝癌的抑制作用。Western blot結(jié)果顯示,正常的肝癌HepG2細(xì)胞瘤體組織中,其PI3K和AKT蛋白呈高表達(dá),而中藥組,索拉非尼組以及聯(lián)合組的PI3K和AKT蛋白表達(dá)及其磷酸化水平均出現(xiàn)不同程度下降(均P0.05),以索拉非尼聯(lián)合參桃軟肝方組的PI3K和AKT蛋白表達(dá)及其磷酸化水平下降最明顯(VS.中藥組和索拉非尼組,均P0.05),而索拉非尼組與中藥組的PI3K和AKT蛋白表達(dá)及其磷酸化水平無明顯差異(均P0.05),提示索拉非尼和參桃軟肝方均可抑制PI3K、AKT蛋白的活性,兩者對PI3K、AKT的抑制作用基本相同,而索拉非尼聯(lián)合參桃軟肝方應(yīng)用時,可增強(qiáng)對PI3K、AKT蛋白活性的抑制作用。Western blot結(jié)果還顯示,正常組的VEGF和PDGF蛋白呈高表達(dá),而中藥組,索拉非尼組以及聯(lián)合組的VEGF和PDGF蛋白表達(dá)均較正常組明顯下降(均P0.05),其中索拉非尼組中VEGF和PDGF的表達(dá)均低于中藥組(均P0.05),而索拉非尼聯(lián)合參桃軟肝方組的VEGF和PDGF蛋白表達(dá)下降最明顯(VS.中藥組和索拉非尼組,均P0.05),提示索拉非尼和參桃軟肝方均可抑制VEGF和PDGF蛋白的表達(dá),索拉非尼對VEGF和PDGF的抑制作用優(yōu)于參桃軟肝方,而兩者聯(lián)合應(yīng)用時,可進(jìn)一步增強(qiáng)對VEGF和PDGF蛋白表達(dá)的抑制作用。結(jié)論：1.參桃軟肝方聯(lián)合索拉非尼較單藥索拉非尼可提高中晚期原發(fā)性肝癌患者的疾病控制率,延長患者生存時間。2.參桃軟肝方聯(lián)合索拉非尼應(yīng)用可改善中晚期原發(fā)性肝癌患者生存質(zhì)量,其對肝癌患者生存質(zhì)量的改善程度優(yōu)于單藥索拉非尼。3.參桃軟肝方聯(lián)合索拉非尼治療中晚期原發(fā)性肝癌患者時,可改善患者肝功能情況,并可降低索拉非尼不良反應(yīng)的發(fā)生。4.參桃軟肝方聯(lián)合索拉非尼應(yīng)用,可增強(qiáng)對肝癌瘤體生長的抑制作用,其機(jī)制可能與其協(xié)同抑制PI3K/AKT信號通路以及抑制VEGF和PDGF等腫瘤新生血管生成因子的表達(dá)有關(guān)。
[Abstract]:Objective: To observe the curative effect of Shentao Ruangan Prescription combined with sorafenib on advanced primary hepatocellular carcinoma by prospective randomized controlled clinical research method, and to evaluate the quality of life of patients with EORTC QLQ-C30. To explore the anti-tumor effect of Shentao Ruangan Prescription combined with sorafenib and its related mechanism, and to provide a certain experiment for targeting Chinese medicine combined with sorafenib in the treatment of primary liver cancer. Methods: 1. Clinical study: Prospective randomized controlled trial was used to study 60 cases, including 30 cases of Chinese medicine combined group and 30 cases of control group. Patients in group A were given oral sorafenib 400 mg twice a day. The patients were followed up monthly to evaluate tumor control, to record disease progression time and survival time, and to monitor liver function indexes such as glutamic-alanine aminotransferase (ALT), total bilirubin (Tbet-IL), albumin (ALB). Recognized Quality of Life Scale EORTC QLQ-C30 was used to follow up the patients'quality of life and evaluate their quality of life. The adverse reactions during the study were recorded by NCI adverse event evaluation criteria to evaluate the drug safety. 2. Experimental study: HepG2 liver cancer xenograft model was constructed in nude mice. Randomly divided into control group, Shentao Ruangan Fang group, Sorafenib group and Shentao Ruangan Fang combined with Sorafenib group, and then given intragastric administration. Tumor volume and weight of mice were measured every three days during the administration period. Tumor weight was measured after administration, and tumor inhibition rate was calculated. The level of vascular endothelial growth factor (VEGF) and the expression of platelet-derived growth factor (PDGF) were measured to explore the mechanism of anti-tumor effect of Shentao Ruangan Prescription combined with sorafenib. VS 10.0%, P 0.05), and the tumor disease control rate (DCR) in the combined group was higher than that in the control group (66.6% VS 46.6%, P 0.05), suggesting that sorafenib combined with Shentao Ruangan Fang can not improve the objective remission rate of liver cancer patients, but can improve the disease control rate. The 3-month survival rate and 6-month survival rate of patients in Ruangan Fang group were no significant difference from those in Sorafenib alone group (51.0% VS 46.6%, 43.7% VS 34.3%, all P 0.05). Compared with the 1-year survival rate of the two groups, the 1-year survival rate of the Chinese medicine combined group was better than that of the control group (38.3% VS 21.7%, P 0.05), suggesting that Sorafenib combined with Shentao Ruangan Fang could not be extracted. The Kaplan-Meier method was used to analyze the disease progression time and survival time of the two groups. The results showed that the median disease progression time (mTTP) of the sorafenib combined with Shentao Ruangan Recipe group was no different from that of the sorafenib alone group. 4.3 months VS 3.6 months, Z = 0.858, P = 0.354), suggesting that the combination of Sorafenib and Shentao Ruangan Recipe group than Sorafenib alone group, the two groups in prolonging the progression of disease in patients with advanced primary liver cancer in no significant difference. The median survival time was 6.1 months, and the combined group was 1.6 months longer than the control group. The difference was statistically significant (Z = 5.998, P = 0.014). Compared with the control group, AFP levels in the combined group and the control group were significantly decreased after treatment, the difference was statistically significant (P 0.01). The difference of AFP levels between the two groups before and after treatment (AFP difference before and after treatment = AFP before and after treatment) showed that the level of AFP in the combined group decreased more significantly than that in the control group (35. 9.83ng/ml VS 266.23ng/ml, P 0.05). It was suggested that after treatment, the serum AFP levels in both groups were significantly decreased, and the level of AFP in the combined group was significantly higher than that in the control group. The serum ALB levels in both groups were significantly higher than those before treatment (P 0.05). The difference was statistically significant (P 0.05). It was suggested that the liver function in both groups was improved to some extent after treatment. Compared with the control group, the difference of ALT and ALB in the combined group was higher than that in the control group, the difference was statistically significant (P 0.05), but there was no significant difference between the two groups before and after TBI treatment (P 0.05), suggesting that the improvement of ALT and ALB in the combined group was better than that in the control group, but there was no difference in the improvement of TBIL between the two groups. The stabilization and improvement rates of liver function grading were 76.7% and 56.7% respectively in the latter two groups. The stabilization and improvement rates of liver function grading in the combined group were significantly higher than those in the control group (P 0.05), suggesting that the improvement of liver function in the combined group was better than that in the control group. Sorafenib combined with Shentao Ruangan Recipe group, patients in the functional areas of the score and the overall health score increased, the difference was statistically significant (all P 0.05); in the symptomatic areas of fatigue, nausea and vomiting, shortness of breath, insomnia, loss of appetite, pain, constipation and diarrhea scores were significantly lower than before treatment (all P 0.05). According to the Chinese version of EORTC QLQ-C30 (V3.0), the higher the scores in functional areas and general health, the better the functional status and quality of life; the higher the score in symptom areas, the more symptoms or problems (the worse the quality of life), suggesting treatment. After treatment, the quality of life in the combined medication group deteriorated in the areas of economic difficulties, and improved in the other areas. In the control group, the scores of functional areas and the overall health status were also increased, the difference was statistically significant (all P 0.05); in the symptomatic areas of shortness of breath, nausea and nausea. The scores of vomiting, insomnia, pain and constipation decreased significantly (all P 0.05), while those of fatigue, loss of appetite, diarrhea and economic difficulties increased (all P 0.05) (see Table 12). The difference of QOL score between the two groups before and after treatment (QOL score difference = QOL score after treatment - QOL score before treatment) showed that the combined group scored better in terms of physical and emotional function in functional areas. The scores of fatigue, nausea and vomiting, shortness of breath, loss of appetite and diarrhea in the combined group were superior to those in the control group (all P 0.05), and the scores of constipation, insomnia, pain and economic difficulties were not significantly different between the two groups (all P 0.05). There was no significant difference between the two groups (all P 0.05), and the scores of the combined group were higher than those of the control group (all P 0.05). In the course of the study, the adverse reactions of the two groups were as follows. Comparing the adverse reactions of the two groups, the results showed that the incidence of hand-foot syndrome, diarrhea, fatigue, skin rash in the combined group was significantly lower than that in the control group (all P 0.05), while the incidence of bone marrow depression in the two groups was significantly lower. There was no significant difference in the incidence of adverse reactions to hypertension (all P 0.05). It was suggested that the combination of sorafenib and Shentao Ruangan Prescription could significantly reduce the incidence of hand-foot syndrome, diarrhea, fatigue, rash and other adverse reactions of sorafenib, but had no significant effect on the incidence of marrow suppression and adverse reactions to hypertension. The results showed that the tumor volume of traditional Chinese medicine group, sorafenib group and combined group was smaller than that of control group (all P 0.05). The tumor volume of sorafenib group was smaller than that of traditional Chinese medicine group (P 0.05). The tumor volume of combined group was smaller than that of sorafenib group (P 0.05), suggesting that Shentao Ruangan Fang had certain inhibitory effect on tumor growth, but its inhibitory effect on tumor was not obvious. The results showed that the tumor weight of traditional Chinese medicine group, sorafenib group and combined group were less than that of control group (P 0.05). The tumor inhibition rate of sorafenib group was better than that of Shentao Ruangan Fang group (44.5% VS 31.9%, P 0.05), while that of combined group was better than that of Shentao Ruangan Fang group (44.5% VS 31.9%, P 0.05). The inhibition rate of Shentao Ruangan Recipe and Sorafenib on hepatoma was higher than that of Shentao Ruangan Recipe (68.7% VS 44.5%, P 0.05), suggesting that both Shentao Ruangan Recipe and Sorafenib had certain inhibitory effect on hepatoma in vivo. The inhibitory effect of Sorafenib on hepatoma was higher than that of Shentao Ruangan Recipe, and the combination of them could further enhance the inhibitory effect on hepatoma. The expression and phosphorylation of PI3K and AKT protein in normal hepatoma HepG2 cells were significantly decreased (all P 0.05). The expression and phosphorylation of PI3K and AKT protein in Sorafenib group, Sorafenib group and Shentao Ruangan Fang group were significantly decreased (all P 0.05). VS. Chinese medicine group and sorafenib group, both P 0.05, while sorafenib group and Chinese medicine group PI3K and AKT protein expression and phosphorylation levels were not significantly different (all P 0.05), suggesting that sorafenib and Shentao Ruangan Formula can inhibit PI3K, AKT protein activity, both of them have the same inhibitory effect on PI3K, AKT, but sorafenib combined with Shentao Ruangan Formula should be used. Western blot also showed that the expression of VEGF and P DGF protein in normal group was high, while the expression of VEGF and P DGF protein in traditional Chinese medicine group, sorafenib group and combined group was significantly lower than that in normal group (all P 0.05). The expression of VEGF and P DGF protein in sorafenib group was lower than that in traditional Chinese medicine group (all P Sorafenib combined with Shentao Ruangan Recipe showed the most significant decrease in the expression of VEGF and PDGF protein (VS. Chinese medicine group and Sorafenib group, both P 0.05), suggesting that both Sorafenib and Shentao Ruangan Recipe could inhibit the expression of VEGF and PDGF protein, and the inhibitory effect of Sorafenib on VEGF and PDGF was better than that of Shentao Ruangan Recipe. Conclusion: 1. Shentao Ruangan Prescription combined with sorafenib can improve the disease control rate and prolong the survival time of patients with advanced primary liver cancer. 2. Shentao Ruangan Prescription combined with sorafenib can improve the quality of life of patients with advanced primary liver cancer. 3. Shentao Ruangan Decoction combined with sorafenib in the treatment of middle and advanced primary stage
【學(xué)位授予單位】：廣州中醫(yī)藥大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R735.7

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