c-erbB-2与c-raf-1基因反义寡核苷酸对卵巢癌和宫颈癌放射敏感性影响的实验研究
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摘要
放射治疗在肿瘤治疗中占有重要地位。据统计，我国大约有70%的恶性肿瘤病人在病程的某一阶段需接受不同方式的放射治疗。在正常组织的耐受剂量范围内，肿瘤的平均治愈率仅为50%。
卵巢癌、宫颈癌是严重威胁妇女健康的恶性疾患，直接影响患者的寿命及生存质量，而肿瘤细胞对放射治疗具有一定的放射抵抗性以及由于放疗副反应限制了有效治疗剂量的增加是疗效不佳的重要原因，所以如何降低肿瘤细胞的辐射抗性，增加辐射敏感性一直是放射肿瘤学者研究和关注的课题。
第一部分
目的：探讨c-erbB-2、c-raf-1基因反义寡核苷酸对受照后人卵巢癌SKOV3细胞增殖的抑制作用及其分子机制。方法：实验分为四组：正常对照组（空白对照组）、Lipofectin组（仅加入等量的脂质体）、正义寡核苷酸治疗组、反义寡核苷酸治疗组。卵巢癌细胞在寡核苷酸处理前后c-raf-1、c-erbB-2表达水平和细胞周期的变化用RT-PCR和FCM检测；接受60Coγ射线不同剂量照射前后肿瘤细胞的存活分数、集落形成率、凋亡情况分别用MTT试验、平板克隆形成试验、电镜、荧光显微镜观察。结果：c-raf-1与c-erbB-2反义寡核苷酸能明显抑制c-raf-1和c-erbB2癌基因的表达，但两者引起的细胞周期阻滞并不一
致；反义寡核苷酸作用的卵巢癌细胞经60Coγ射线照射后其细胞存活分数、集落形成率和转染正义寡核苷酸+照射组及单纯照射组比较明显下降、凋亡率明显增加（p<0.01），而转染正义寡核苷酸+照射组与单纯照射组相比无明显差异（p>0.05）。结论：c-raf-1、c-erbB-2 反义寡核苷酸通过下调c-raf-1和c-erbB-2的表达抑制了人卵巢癌细胞株SKOV3的增殖，降低了辐射抗性。该作用可能与c-raf-1、c-erbB-2反义寡核苷酸抑制了引起细胞辐射抵抗的信号转导途径有关，而与改变受照前细胞周期分布关系不明确。
第二部分
目的：由于Ki-67反映肿瘤细胞的增殖能力，Bcl-2具有抗凋亡的作用，它们的表达程度可用于预测肿瘤细胞的放射疗效（即表达越高，辐射抗性越强），为此第二部分用免疫组织化学法检测与放射敏感性相关的Ki-67、Bcl-2蛋白，观察它们在c-erbB-2/ c-raf-1反义寡核苷酸作用后受照人卵巢癌SKOV3细胞的表达情况。结果：c-erbB-2反义寡核苷酸+照射组Ki-67、Bcl-2免疫组化阳性率分别为19.8%和20.7%（与照射组比较，p﹤0.01）；c-raf-1反义寡核苷酸+照射组两者的免疫组化阳性率分别为19.8%和21.7%（与照射组比较，p﹤0.01）。转染c-erbB-2/ c-raf-1正义寡核苷酸+照射组和照射组比较无明显差异(p>0.05)。结论：，脂质体介导的c-erbB-2/c-raf-1反义寡核苷酸能显著下调经60Coγ射线照射后卵巢癌细胞Ki-67、Bcl-2蛋白的表达。这可能是c-raf-1、c-erbB-2反义寡核苷酸对人卵巢癌细胞株SKOV3放射增敏的分子机制之一。
第三部分
目的：体外测定实际上细胞脱离了其生长存在的体内微环境，许多决定其放射生物效应的因素将被改变，如氧合状态、周期分布、相关损伤修复的物理化学条件以及相关于增殖的细胞间接触效应等。临床一个肿瘤病灶的放疗疗效除取决于其本身固有的放射敏感性外，尚受到细胞内外，宿主情况等多种因素的影响，为此建立宫颈癌的皮下移植瘤动物模型，来研究c-erbB-2/c-raf-1基因反义寡核苷酸对小鼠宫颈癌皮下移植瘤放射治疗效应的影响。方法：将Balb/C小鼠随机分为六组：一组：对照组（腹腔注射等量脂质体），二组：腹腔注射正义寡核苷酸，三组：腹腔注射反义寡核苷酸，四组：照射组（腹腔注射等量脂质体），五组：腹腔注射正义寡核苷酸+照射，六组：腹腔注射反义寡核苷酸+照射。用原位杂交检测寡核苷酸作用前后的靶基因表达；通过观察肿瘤受60Coγ射线照射后肿瘤组织体积随时间的变化、肿瘤倍增时间、小鼠存活时间来研究c-erbB-2、c-raf-1基因反义寡核苷酸对小鼠宫颈癌皮下移植瘤放射治疗效应的影响。结果：c-erbB-2/c-raf-1基因反义寡核苷酸能明显抑制相应基因的表达。c-erbB-2/ c-raf-1反义寡核苷酸+照射组的抑瘤率、肿瘤的倍增时间、小鼠的存活时间比照射组明显增加(p﹤0.01)，而转染c-erbB-2/ c-raf-1正义寡核苷酸+照射组和照射组比较无明显差异(p>0.05)。结论：c-erbB-2/c-raf-1反义寡核苷酸作用后能使小鼠宫颈癌皮下移植瘤的生长明显受到抑制，小鼠生存期明显延长，提高了放疗疗效。
第四部分
目的：由于PCNA表达一定程度上可以反映放疗后肿瘤的增殖情况，而c-Jun、c-Fos能被包括辐射在内的外界刺激激活，导致辐射抗性增加，因此本部分探讨c-erbB-2/c-raf-1反义寡核苷酸对小鼠宫颈癌皮下移植瘤照射前后c-Jun、c-Fos、PCNA表达的影响及其意义。方法：实验分为照射前和照射后各四组。采用免疫组化SABC法检测c-Jun、c-Fos、PCNA表达情况。结果：转染c-erbB-2反义寡核苷酸后受照小鼠宫颈癌皮下移植瘤c-Jun、c-Fos、PCNA的阳性表达率分别为19.76 %、19.47 %、16.49 %（与单纯照射组比较，P<0.01），而转染c-raf-1反义寡核苷酸组的阳性率分别为20.06 %、20.23 %、14.89 %（与单纯照射组比较，P<0.01）。转染c-erbB-2/c-raf-1正义寡核苷酸+照射组各指标与照射组无统计学显著性差异。结论：c-erbB-2、c-raf-1?
Radiotherapy plays an important role in the treatment of malignant tumors. About 70 percent tumor patients would receive radiotherapy in the progress of disease. The average cure rate is only 50 percent when adopting the bearable dosage of normal tissue。
Ovarian cancer and cervical cancer are the most common malignant gynecological tumors, seriously threatening women’ lives. Owing to high frequency of abdominal cavity metastasis and the existence of side complications, the life span, quality and survival of patients have been affected directly, while the radioresistance of these diseases has a bad effect on the radiotherapy. So how to increase the radiosensitivity has attracted significant interest to radiobiological research in recent years.
Part One
Objective: To explore the effect and the mechanism of lipofectin-c-erbB2 or c-raf-1 antisense oligodeoxynucleotides on radiosensitivity in human ovarian cancer cell line SKOV3. Methods: There were four groups in the study: normal control group,
Lipofectin control group, c-erbB-2 SODN (sense oligodeoxynucleotides) or c-raf-1 SODN experimental group, c-erbB-2 ASODN (antisense oligodeoxynucleotides) or c-raf-1 ASODN experimental group. The expression of c-erbB2 or c-raf-1 was detected by means of RT-PCR; cellular response to irradiation was evaluated by the colony forming test and MTT assay; Apoptosis and cell cycle were observed by flow cytometry, electronic microscope, fluorescent microscope. Results: Lipofectin- c-erbB2 or c-raf-1 ASODN could suppress the expression of c-erbB2 or c-raf-1, leading to different cell cycle arrests. They significantly decreased the proliferation rate and statistically increased the apoptosis rate of human ovarian cancer cells after ionizing irradiation (vs control group, p<0.01), while non-treament and the SODNs groups did not decrease the radio-resistance level of SKOV3 cell line (vs control group, p>0.05). Conclusions: c-erbB2 or c-raf-1 antisense oligodeoxynucleotides sensitized the SKOV3 to ionizing irradiation through decreasing the expression of c-erbB2 or c-raf-1, which might be the result of the fact that antisense oligodeoxynucleotides inhibit the celluar signal transduction pathway relating to the radiation-resistant phenotype, but there was no clear relationship between cell cycle distribution led by c-erbB2 or c-raf-1ASODNs and the radiosensitivity.
Part Two
Objective: It was reported that the expressions of Ki-67 and Bcl-2 protein are associated with the resistance of radiotherapy, that is to say, the higher overexpression of Ki-67 or Bcl-2, the more resistant tumor cells might be. In the second part of the study, we investigated the effect of c-erbB-2 or c-raf-1 antisense oligodeoxynucleotides on expression of Ki-67,Bcl-2 protein in irradiated human ovarian cancer cell line SKOV3. Methods: Immunohistochemical method was performed to analysis expression of Ki-67, Bcl-2 protein in pre-or post-irradiated human ovarian cancer cells. There were four groups in the study, normal control group, Lipofectin control group, c-erbB-2 or c-raf-1 SODN experimental group, c-erbB-2 or c-raf-1 ASODN experimental group. Results: In terms of the c-erbB-2 post-irradiation experimental groups, the positive rate of Ki-67 were 42.7% in SODN group (VS control group p>0.05) and 19.8% in ASODN group (VS control group, p<0.01). Among c-raf-1 post-irradiation experimental groups, positive rates were 43.9% in SODN group (VS control group, p>0.05) and 19.8% in ASODN group(VS control group, p>0.05), while among c-erbB-2 experimental groups, positive rates of Bcl-2 were the 39.4% in SODN group (VS control group, p>0.05) and 20.7% in ASODN group(VS control group , p<0.01). Among c-raf-1
experimental groups, positive rates of Bcl-2 were 41.8% in SODN group(VS control group, p>0.05) and 21.7% in ASODN group(VS control group , p>0.05) respectively. Results: c-erbB-2 ASODN or c-raf-1 ASODN significantly inhibited the expression of Ki-67 and Bcl-2 protein in human ovarian cancer cells after ionizing
卵巢癌、宫颈癌是严重威胁妇女健康的恶性疾患，直接影响患者的寿命及生存质量，而肿瘤细胞对放射治疗具有一定的放射抵抗性以及由于放疗副反应限制了有效治疗剂量的增加是疗效不佳的重要原因，所以如何降低肿瘤细胞的辐射抗性，增加辐射敏感性一直是放射肿瘤学者研究和关注的课题。
第一部分
目的：探讨c-erbB-2、c-raf-1基因反义寡核苷酸对受照后人卵巢癌SKOV3细胞增殖的抑制作用及其分子机制。方法：实验分为四组：正常对照组（空白对照组）、Lipofectin组（仅加入等量的脂质体）、正义寡核苷酸治疗组、反义寡核苷酸治疗组。卵巢癌细胞在寡核苷酸处理前后c-raf-1、c-erbB-2表达水平和细胞周期的变化用RT-PCR和FCM检测；接受60Coγ射线不同剂量照射前后肿瘤细胞的存活分数、集落形成率、凋亡情况分别用MTT试验、平板克隆形成试验、电镜、荧光显微镜观察。结果：c-raf-1与c-erbB-2反义寡核苷酸能明显抑制c-raf-1和c-erbB2癌基因的表达，但两者引起的细胞周期阻滞并不一
致；反义寡核苷酸作用的卵巢癌细胞经60Coγ射线照射后其细胞存活分数、集落形成率和转染正义寡核苷酸+照射组及单纯照射组比较明显下降、凋亡率明显增加（p<0.01），而转染正义寡核苷酸+照射组与单纯照射组相比无明显差异（p>0.05）。结论：c-raf-1、c-erbB-2 反义寡核苷酸通过下调c-raf-1和c-erbB-2的表达抑制了人卵巢癌细胞株SKOV3的增殖，降低了辐射抗性。该作用可能与c-raf-1、c-erbB-2反义寡核苷酸抑制了引起细胞辐射抵抗的信号转导途径有关，而与改变受照前细胞周期分布关系不明确。
第二部分
目的：由于Ki-67反映肿瘤细胞的增殖能力，Bcl-2具有抗凋亡的作用，它们的表达程度可用于预测肿瘤细胞的放射疗效（即表达越高，辐射抗性越强），为此第二部分用免疫组织化学法检测与放射敏感性相关的Ki-67、Bcl-2蛋白，观察它们在c-erbB-2/ c-raf-1反义寡核苷酸作用后受照人卵巢癌SKOV3细胞的表达情况。结果：c-erbB-2反义寡核苷酸+照射组Ki-67、Bcl-2免疫组化阳性率分别为19.8%和20.7%（与照射组比较，p﹤0.01）；c-raf-1反义寡核苷酸+照射组两者的免疫组化阳性率分别为19.8%和21.7%（与照射组比较，p﹤0.01）。转染c-erbB-2/ c-raf-1正义寡核苷酸+照射组和照射组比较无明显差异(p>0.05)。结论：，脂质体介导的c-erbB-2/c-raf-1反义寡核苷酸能显著下调经60Coγ射线照射后卵巢癌细胞Ki-67、Bcl-2蛋白的表达。这可能是c-raf-1、c-erbB-2反义寡核苷酸对人卵巢癌细胞株SKOV3放射增敏的分子机制之一。
第三部分
目的：体外测定实际上细胞脱离了其生长存在的体内微环境，许多决定其放射生物效应的因素将被改变，如氧合状态、周期分布、相关损伤修复的物理化学条件以及相关于增殖的细胞间接触效应等。临床一个肿瘤病灶的放疗疗效除取决于其本身固有的放射敏感性外，尚受到细胞内外，宿主情况等多种因素的影响，为此建立宫颈癌的皮下移植瘤动物模型，来研究c-erbB-2/c-raf-1基因反义寡核苷酸对小鼠宫颈癌皮下移植瘤放射治疗效应的影响。方法：将Balb/C小鼠随机分为六组：一组：对照组（腹腔注射等量脂质体），二组：腹腔注射正义寡核苷酸，三组：腹腔注射反义寡核苷酸，四组：照射组（腹腔注射等量脂质体），五组：腹腔注射正义寡核苷酸+照射，六组：腹腔注射反义寡核苷酸+照射。用原位杂交检测寡核苷酸作用前后的靶基因表达；通过观察肿瘤受60Coγ射线照射后肿瘤组织体积随时间的变化、肿瘤倍增时间、小鼠存活时间来研究c-erbB-2、c-raf-1基因反义寡核苷酸对小鼠宫颈癌皮下移植瘤放射治疗效应的影响。结果：c-erbB-2/c-raf-1基因反义寡核苷酸能明显抑制相应基因的表达。c-erbB-2/ c-raf-1反义寡核苷酸+照射组的抑瘤率、肿瘤的倍增时间、小鼠的存活时间比照射组明显增加(p﹤0.01)，而转染c-erbB-2/ c-raf-1正义寡核苷酸+照射组和照射组比较无明显差异(p>0.05)。结论：c-erbB-2/c-raf-1反义寡核苷酸作用后能使小鼠宫颈癌皮下移植瘤的生长明显受到抑制，小鼠生存期明显延长，提高了放疗疗效。
第四部分
目的：由于PCNA表达一定程度上可以反映放疗后肿瘤的增殖情况，而c-Jun、c-Fos能被包括辐射在内的外界刺激激活，导致辐射抗性增加，因此本部分探讨c-erbB-2/c-raf-1反义寡核苷酸对小鼠宫颈癌皮下移植瘤照射前后c-Jun、c-Fos、PCNA表达的影响及其意义。方法：实验分为照射前和照射后各四组。采用免疫组化SABC法检测c-Jun、c-Fos、PCNA表达情况。结果：转染c-erbB-2反义寡核苷酸后受照小鼠宫颈癌皮下移植瘤c-Jun、c-Fos、PCNA的阳性表达率分别为19.76 %、19.47 %、16.49 %（与单纯照射组比较，P<0.01），而转染c-raf-1反义寡核苷酸组的阳性率分别为20.06 %、20.23 %、14.89 %（与单纯照射组比较，P<0.01）。转染c-erbB-2/c-raf-1正义寡核苷酸+照射组各指标与照射组无统计学显著性差异。结论：c-erbB-2、c-raf-1?
Radiotherapy plays an important role in the treatment of malignant tumors. About 70 percent tumor patients would receive radiotherapy in the progress of disease. The average cure rate is only 50 percent when adopting the bearable dosage of normal tissue。
Ovarian cancer and cervical cancer are the most common malignant gynecological tumors, seriously threatening women’ lives. Owing to high frequency of abdominal cavity metastasis and the existence of side complications, the life span, quality and survival of patients have been affected directly, while the radioresistance of these diseases has a bad effect on the radiotherapy. So how to increase the radiosensitivity has attracted significant interest to radiobiological research in recent years.
Part One
Objective: To explore the effect and the mechanism of lipofectin-c-erbB2 or c-raf-1 antisense oligodeoxynucleotides on radiosensitivity in human ovarian cancer cell line SKOV3. Methods: There were four groups in the study: normal control group,
Lipofectin control group, c-erbB-2 SODN (sense oligodeoxynucleotides) or c-raf-1 SODN experimental group, c-erbB-2 ASODN (antisense oligodeoxynucleotides) or c-raf-1 ASODN experimental group. The expression of c-erbB2 or c-raf-1 was detected by means of RT-PCR; cellular response to irradiation was evaluated by the colony forming test and MTT assay; Apoptosis and cell cycle were observed by flow cytometry, electronic microscope, fluorescent microscope. Results: Lipofectin- c-erbB2 or c-raf-1 ASODN could suppress the expression of c-erbB2 or c-raf-1, leading to different cell cycle arrests. They significantly decreased the proliferation rate and statistically increased the apoptosis rate of human ovarian cancer cells after ionizing irradiation (vs control group, p<0.01), while non-treament and the SODNs groups did not decrease the radio-resistance level of SKOV3 cell line (vs control group, p>0.05). Conclusions: c-erbB2 or c-raf-1 antisense oligodeoxynucleotides sensitized the SKOV3 to ionizing irradiation through decreasing the expression of c-erbB2 or c-raf-1, which might be the result of the fact that antisense oligodeoxynucleotides inhibit the celluar signal transduction pathway relating to the radiation-resistant phenotype, but there was no clear relationship between cell cycle distribution led by c-erbB2 or c-raf-1ASODNs and the radiosensitivity.
Part Two
Objective: It was reported that the expressions of Ki-67 and Bcl-2 protein are associated with the resistance of radiotherapy, that is to say, the higher overexpression of Ki-67 or Bcl-2, the more resistant tumor cells might be. In the second part of the study, we investigated the effect of c-erbB-2 or c-raf-1 antisense oligodeoxynucleotides on expression of Ki-67,Bcl-2 protein in irradiated human ovarian cancer cell line SKOV3. Methods: Immunohistochemical method was performed to analysis expression of Ki-67, Bcl-2 protein in pre-or post-irradiated human ovarian cancer cells. There were four groups in the study, normal control group, Lipofectin control group, c-erbB-2 or c-raf-1 SODN experimental group, c-erbB-2 or c-raf-1 ASODN experimental group. Results: In terms of the c-erbB-2 post-irradiation experimental groups, the positive rate of Ki-67 were 42.7% in SODN group (VS control group p>0.05) and 19.8% in ASODN group (VS control group, p<0.01). Among c-raf-1 post-irradiation experimental groups, positive rates were 43.9% in SODN group (VS control group, p>0.05) and 19.8% in ASODN group(VS control group, p>0.05), while among c-erbB-2 experimental groups, positive rates of Bcl-2 were the 39.4% in SODN group (VS control group, p>0.05) and 20.7% in ASODN group(VS control group , p<0.01). Among c-raf-1
experimental groups, positive rates of Bcl-2 were 41.8% in SODN group(VS control group, p>0.05) and 21.7% in ASODN group(VS control group , p>0.05) respectively. Results: c-erbB-2 ASODN or c-raf-1 ASODN significantly inhibited the expression of Ki-67 and Bcl-2 protein in human ovarian cancer cells after ionizing
引文
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survival and its targeting with antisense oligonucleotides in ovarian cancer. Br J Cancer, 2001, 85(11):1753-1758.
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[2] Wilson JR, Carring ER, eds. Obstetrics and Gynecology. 9th ed. St Louis: Mosby Year Book, 1991, 605-615.
[3] Parker SL, Tong T, Bolden S, et al. Cancer statistics,1996. CA, 1996,46:5.
[4] Yancik R. Ovarian cancer. Age contrasts in incidence , histology, disease stage at diagnosis ,and mortality. Cancer,1993, 71: 517.
[5] Parazzini F, Franceschi S, Vecchia CL, et al. The epidemiology of ovarian cancer. Gynecol Oncol, 1991, 43: 9.
[6] Wadler S. New developments in treatment of ovarian cancer . Expert Opin Investig Drugs, 2001,10(6): 1167-72.
[7] Harries M, Kaye SB. Recent advances in the treatment of epithelial ovarian cancer. Expert Opin Investig Drugs ,2001,10(9):1715-1724.
[8] Gupta AK ,Bakanauskas VJ, Cerniglia GJ, et al. The ras radiation resistance pathway. Cancer Res.2001 May 15,61(10):4278-4282.
[9] Granna TM, Rusyn EV, Zhou H, et al. Ras mediates radioresistance through both phosphatidylinositol 3-kinase-dependent and Raf-dependent but mitogen-activated
protein kinase/extracelluar signal-regulated kinase kinase-independent signaling pathways. Cancer Res,2002,62(14):4142-4150.
[10] Bhattacharya RK. Signal transduction events in mammalian cells in response to ionizing radiation. Indian J Exp Biol, 2001, 39(8):727-734.
[11] Gupta AK ,Bakanauskas VJ, Cerniglia GJ; et al.The ras radiation resistance pathway. Cancer Res.2001 May 15,61(10):4278-4282.
[12] Bhattacharya RK. Signal transduction events in mammalian cells in response to ionizing radiation. Indian J Exp Biol, 2001, 39(8):727-734.
[13] Grana TM, Rusyn EV, Zhou H et al. Ras mediates radioresistance through both phosphatidylinositol 3-kinase-dependent and raf-dependent but mitogen-activated protein kinase/extracelluar signal-regulated kinase kinase-independent signaling pathways. Cancer Res,2002, 62(14):4142-4150.
[14] Koka V, Potti A, Forseen SE, et al. Role of her-2/neu overexpression and clinical determinants of early mortality in glioblastoma multiforme. Am J Clin Oncol. 2003 Aug;26(4):332-335.
[15] Lee KE, Lee HJ, Kim YH, et al. Prognostic significance of p53, nm23, PCNA and c-erbB-2 in gastric cancer. Jpn J Clin Oncol. 2003 Apr;33(4):173-179.
[16] Arnould L, Denoux Y, MacGrogan G, et al. Agreement between chromogenic in situ hybridisation (CISH) and FISH in the determination of HER2 status in breast cancer. Br J Cancer. 2003 May 19;88(10):1587-1591.
[17] Ramos Soler D, Navarro Fos S, Villamon Fort R, et al. Comparative study of P 53, Bcl-2, and C-erbB-2 expression in low-grade papillary bladder tumors. Arch Esp Urol. 2003 Apr;56(3):277-285.
[18] Aas T, Geisler S, Eide GE, et al. Predictive value of tumour cell proliferation in locally advanced breast cancer treated with neoadjuvant chemotherapy. Eur J Cancer. 2003 Mar;39(4):438-446.
[19] Galleshaw J. New options in the prevention and treatment of breast carcinoma. J Med Assoc Ga. 2003 Winter-Spring;92(1):19-22.
[20] Takahashi S, Hatake K, Sugimoto Y. Gene therapy for breast cancer Gan To Kagaku Ryoho,2003 Apr,30(4):468-477.
[21] Yang SP, Song ST, Song HF. Advancements of antisense oligonucleotides in treatment of breast cancer. Acta Pharmacol Sin. 2003 Apr;24(4):289-295.
[22] Rait AS, Pirollo KF, Xiang L, et al. Tumor-targeting, systemically delivered antisense HER-2 chemosensitizes human breast cancer xenografts irrespective of HER-2 levels. Mol Med,2002 Aug;8(8):475-486.
[23] Cheng LS, Liu AP, Yang JH, et al. tumor surface antigen, p185(c-erbB-2).et al. Construction, expression and characterization of the engineered antibody against.Cell Res. 2003 Feb;13(1):35-48.
[24] Meenakshi A, Kumar RS, Ganesh V, et al. Preliminary study on radioimmunodiagnosis of experimental tumor models using technetium-99m-labeled anti-C-erbB-2 monoclonal antibody. Tumori. 2002 Nov-Dec;88(6):507-512.
[25] Horton J. Trastuzumab use in breast cancer: clinical issues. Cancer Control. 2002 Nov-Dec;9(6):499-507.
[26] Montemurro F, Choa G, Faggiuolo R, et al. Safety and activity of docetaxel and trastuzumab in HER2 overexpressing metastatic breast cancer: a pilot phase II study. Am J Clin Oncol, 2003 Feb,26(1):95-97.
[27] Koukourakis MI, Giatromanolaki A, Galazios G, et al. Molecular analysis of local relapse in high-risk breast cancer patients: canradiotherapy fractionation and time factors make a difference? Br J Cancer. 2003 Mar 10;88(5):711-717.
[28] Koukourakis MI. Hypofractionated and accelerated radiotherapy with amifostine cytoprotection (HypoARC): a new concept in radiotherapy and encouraging results in breast cancer. Semin Oncol, 2002 Dec, 29(6 Suppl 19):42-46.
[29] Nakano T, Oka K, Taniguchi N. Manganese superoxide dismutase expression correlates with p53 status and local recurrence of cervical carcinoma treated with radiation therapy. Cancer Res,1996 Jun 15,56(12):2771-2775.
[30] Nishioka T, West CM, Gupta N, et al. Prognostic significance of c-erbB-2 protein expression in carcinoma of the cervix treated with radiotherapy. J Cancer Res Clin Oncol,1999,125(2):96-100.
[31] Formenti SC, Spicer D, Skinner K, et al. Low HER2/neu gene expression is associated with pathological response to concurrent paclitaxel and radiation therapy in locally advanced breast cancer. Int J Radiat Oncol Biol Phys. 2002 Feb 1;52(2):397-405.
[32] Nakano T, Oka K, Ishikawa A, et al. Immunohistochemical prediction of radiation response and local control in radiation therapy for cervical cancer. Cancer Detect Prev. 1998;22(2):120-128.
[33] Burke HB, Hoang A, Iglehart JD, et al. Predicting response to adjuvant and radiation therapy in patients with early stage breast carcinoma. Cancer. 1998 Mar 1;82(5):874-877.
[34] Milas L, Mason KA, Ang KK. Epidermal growth factor receptor and its inhibition in radiotherapy: in vivo findings. Int J Radiat Biol. 2003 Jul;79(7):539-545.
[35] Sartor CI. Biological modifiers as potential radiosensitizers: targeting the epidermal growth factor receptor family. Semin Oncol. 2000 Dec;27(6 Suppl 11):15-20; discussion 92-100.
[36] Giglione C, Parmeggiani A. Raf-1 is involved in the regulation of the interaction between guanine nucleotide exchange factor and Ha-ras. Evidences for a function of Raf-1 and phosphatidylinositol 3-kinase upstream to Ras. J Biol Chem, 1998 Dec 25,273(52):34737-34744.
[37] Cho-Chung YS. Antisense oligonucleotide inhibition of serine/threonine kinases: an innovative approach to cancer treatment. Pharmacol Ther. 1999 May-Jun;82(2-3):437-449.
[38] Wang H, Prasad G, Buolamwini JK, et al. Antisense anticancer oligonucleotide therapeutics. Curr Cancer Drug Targets. 2001 Nov;1(3):177-196.
[39] O'Dwyer PJ, Stevenson JP, Gallagher M, et al. c-raf-1 depletion and tumor responses in patients treated with the c-raf-1 antisense oligodeoxynucleotide ISIS 5132 (CGP 69846A). Clin Cancer Res. 1999 Dec;5(12):3977-3982.
[40] Mcphillips F, Mullen P, Monia BP, et al. Association of c-raf expression with
survival and its targeting with antisense oligonucleotides in ovarian cancer. Br J Cancer, 2001, 85(11):1753-1758.
[41] Funato T, Kozawa K, Fujimaki S, et al. Increased sensitivity to cytosine arabinoside in human leukemia by c-raf-1 antisense oligonucleotides. Anticancer Drugs. 2001 Apr;12(4):325-329.
[42] Pirollo KF, Garner R, Yuan SY, et al. raf involvement in the simultaneous genetic transfer of the radioresistant and transforming phenotypes. Int J Radiat Biol. 1989 May;55(5):783-796.
[43] Kasid U, Pfeifer A, Weichselbaum RR, et al. The raf oncogene is associated with a radiation-resistant human laryngeal cancer. Science. 1987 Aug 28;237(4818):1039-1041.
[44] Patel BK, Kasid U. Nucleotide sequence analysis of c-raf-1 cDNA and promoter from a radiation-resistant human squamous carcinoma cell line: deletion within exon 17. Mol Carcinog. 1993;8(1):7-12.
[45] Pfeifer A, Mark G, Leung S, et al. Effects of c-raf-1 and c-myc expression on radiation response in an in vitro model of human small-cell-lung carcinoma. Biochem Biophys Res Commun. 1998 Nov 18;252(2):481-486.
[46] Chang EH, Pirollo KF, Zou ZQ, et al. Oncogenes in radioresistant, noncancerous skin fibroblasts from a cancer-prone family. Science. 1987 Aug 28;237(4818):1036-1039.
[47] Kasid U; Suy S; Dent P; et al. Activation of raf by ionizing radiation[J]. Nature .1996 August ,29(382):813-816.
[48] Belka C, Knippers P, Rudner J, et al. MEK1 and Erk1/2 kinases as targets for the modulation of radiation responses. Anticancer Res. 2000 Sep-Oct;20(5A):3243-3249.
[49] Johnes HA; Hahm SM; Bernhard E; et al. Ras inhibitors and radiation therapy[J]. Semin Radiat Oncol. 2 001 Oct,11(4):328-337.
[50] Cassoni AM Oncogene and radiosensitivity[J]. Eur J Cancer.1994,30(1):279-283.
[51] Gokhale PC, McRae D, Monia BP, et al. Antisense raf oligodeoxyribonucleotide is a radiosensitizer in vivo. Antisense Nucleic Acid Drug Dev. 1999 Apr, 9(2):191-201.
[52] Soldatenkov VA, Dritschilo A, Wang FH, et al. Inhibition of Raf-1 protein kinase by antisense phosphorothioate oligodeoxyribonucleotide is associated with sensitization of human laryngeal squamous carcinoma cells to gamma radiation. Cancer J Sci Am. 1997 Jan-Feb;3(1):13-20.
[53] Warenius HM, Browning PG, Britten RA, et al. C-raf-1 proto-oncogene expression relates to radiosensitivity rather than radioresistance. Eur J Cancer. 1994;30A(3):369-75.
[54] Leadon SA, Dunn AB, Ross CE. A novel DNA repair response is induced in human cells exposed to ionizing radiation at the G1/S phase border. Radiat Res,1996;146:123.
[55] Cheong N, Wang Y, Jackson M et al. Radiation sensitive irs mutants rejoin DNA double-strand breaks with efficiency similar to that of parental v79 cells but show altered response to radiation-induced G2 delay. Mutat Res,1992;274:111.
[56] Cheong N, Weng ZC, Wang Y, et al. Evidence for factors modulating radiation-induced G2-delay : potential as radioprotectors. Phys Med, 2001,17(suppl 1):205.
[57] Vijayakumar S, Czerski L, Majors A et al. Phosphorous metabolite and cell cycle kinetic response of two human squamous cell carcinomas to radiation. Cancer Res,1992;52:5299.
[58] Mckenna WG, Iliakis G, Weiss MC et al. Increased G2 delay in radiation-resistant cells obtained by transformation of primary rat embryo cells with the oncogenes H-ras and V-myc.Radiat Res,1991;125:283.
[59] Ma BB, Bristow RG, Kim J, et al. Combined-modality treatment of solid tumors using radiotherapy and molecular targeted agents. J Clin Oncol. 2003 Jul 15;21(14):2760-2776.
[60] Raju U, Nakata E, Mason KA, et al. Flavopiridol, a cyclin-dependent kinase inhibitor, enhances radiosensitivity of ovarian carcinoma cells. Cancer Res. 2003 Jun 15;63(12):3263-3267.
[51] Geldof AA, Plaizier MA, Duivenvoorden I, et al. Cell cycle perturbations and radiosensitization effects in a human prostate cancer cell line. J Cancer Res Clin Oncol. 2003 Mar;129(3):175-182.
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