红霉素逆转乳腺癌多药耐药的临床研究

目的：研究红霉素逆转乳腺癌多药耐药（MDR）的临床疗效，方法：采用免疫组化SP法检测乳腺癌P－糖蛋白（P-gp)表达，将P-gp表达阳性者随机分两组：红霉素加化疗组（试验组）28例，单纯化疗组（对照组）14例，采用CAF方案化疗，结果：试验组CR＋PR 19例（67．9％），对照组4例（28．6％），两组比较差异有显著性（P＜0．05），结论：红霉素对逆转乳腺癌MDR具有一定的作用。     

逆转乳腺癌内分泌治疗耐药研究进展北大核心CSCD

乳腺癌内分泌治疗耐药的管理在乳腺癌治疗中具有相当的挑战,内分泌耐药的逆转也是当今研究的热点。耐药发生的机制错综复杂,为逆转耐药、维持或增强内分泌治疗的疗效,研究者们在体内体外肿瘤生长抑制、信号转导、凋亡诱导、细胞周期阻滞等多个层面进行了大量尝试。目前内分泌联合分子靶向药物已然成为重点研究方向。本文就既往乳腺癌内分泌耐药逆转的研究作一概述,并探讨未来研究可能的发展方向。     

大黄素对乳腺癌多药耐药细胞株MCF-7/Adr的耐药逆转作用

目的：探讨中药成分大黄素(Emodin，EMD)对乳腺癌多药耐药细胞株MCF-7／Adr的耐药逆转作用。方法：药物敏感试验采用四唑氮盐(MTT)比色法，P糖蛋白以Western-blot法检测。结果：EMD在0～20μmol／L浓度时作用14天后对MCF-7／Adr未见明显毒性作用；EMD在10μmol／L浓度时，其耐药逆转倍数为1．7倍。EMD在20μmol／L浓度时，处理MCF-7／Adr2、4、6和11天后，检测P糖蛋白发现自第4天起P糖蛋白表达下降，至第11天无法检测到P糖蛋白的表达。结论：EMD具有逆转MCF-7／Adr多药耐药性的作用，可明显下调P糖蛋白的表达，且逆转作用持久。     

补骨脂素逆转K562/ADM多药耐药细胞系耐药性研究

目的:研究补骨脂素对白血病细胞阿霉素耐药株(K562/ADM)多药耐药(multidrug resistance,MDR)性的逆转作用及其机制.方法:采用MTT法检测药物细胞毒性作用,计算其逆转倍数.结果:补骨脂素在1～20μmol·L-1范围内,对K562和K562/ADM无明显细胞毒作用,但与ADM联合用药可使ADM对K562/ADM的IC50明显下降,补骨脂素(1～20μmol·L-1)能不同程度地降低ADM对K562/ADM细胞的IC50值.结论:补骨脂素能逆转K562/ADM细胞的多药耐药.     

微波热疗合并化疗治疗乳腺癌疗效分析

乳腺癌根治术后胸部复发率仍高达 10～ 2 0 % ,部分失去了再手术机会 ,另外某些晚期原发乳腺癌不宜手术治疗 ,对这类患者我们采用微波热疗与化疗相配合 ,取得了较明显的疗效 ,现报告如下 :一、一般资料 :本组 45例均为女性 ,全部病例均经病理学检查确诊。年龄 2 5～ 76岁 ,其中导管内癌 7例 ,单纯癌 2 3例 ,浸润性导管癌 10例 ,骨髓样癌 5例。临床分期Ⅲａ 2 4例 ,Ⅲｂ13例 ,Ⅳ 8例。Ｋａｒｎｏｆｓｋｇ评分≥ 60分。二、治疗方法 :采用大连为尔福公司产ＷＥ -2 10 2多功能微波治疗机 ,频率 40 0ＭＨＺ ,功率为 15 0～ 3 0 0Ｗ ,辐射器直径…     

乳腺癌内分泌治疗的耐药机制及对策

内分泌治疗是激素敏感型乳腺癌患者的重要治疗手段,临床实践及基础研究均发现内分泌治疗存在原发或继发耐药,导致内分泌治疗失败,本文主要介绍内分泌治疗代表药物选择性雌激素受体和芳香化酶抑制剂的耐药机制及相应对策.     

肿瘤耐药及逆转耐药的新策略

肿瘤细胞对多种化疗药物产生交叉耐药性（Ｍｕｌｔｉｄｒｕｇ ｒｅ－ｓｉｓｔａｎｃｅ,ＭＤＲ）是造成肿瘤化疗失败的主要原因,有关资料统计约９０％以上肿瘤患者死因或多或少都与耐药有关,逆转ＭＤＲ成为肿瘤治疗亟待解决的问题。“八五”和“九五”期间,我国把肿瘤细胞耐药基因的研究列为攻关课题,我所是承担单位,现结合我们近年来的主要研究进展和成果,对下世纪我国肿瘤耐药及逆转耐药的发展趋势作一展望。１肿瘤细胞耐药机制的研究 自２０世纪７０年代发现ＭＤＲ现象以来,国内外对肿瘤ＭＤＲ的发生机制进行了深入研究,提出了许…     

中医药逆转大肠癌耐药的实验研究进展

0引言 在世界范围内,大肠癌的发病率男女均处于恶性肿瘤的第3位,在我国,大肠癌的发病率亦呈上升态势,居恶性肿瘤的第4位[1].虽然目前该病仍以手术治疗为主,但术后5年生存率却一直停留在50%左右[2].对于手术后及失去手术机会或术后复发的肠癌,化疗是重要的治疗手段.但在化疗药物不断更新的今天,疗效仍不理想.     

红霉素逆转乳腺癌多药耐药的临床研究

目的 :研究红霉素逆转乳腺癌多药耐药 (MDR)的临床疗效。方法 :采用免疫组化SP法检测乳腺癌P 糖蛋白 (P gp)表达 ,将P gp表达阳性者随机分两组 :红霉素加化疗组 (试验组 ) 2 8例 ,单纯化疗组 (对照组 ) 14例 ,采用CAF方案化疗。结果 :试验组CR PR 19例 ( 67.9% ) ,对照组 4例 ( 2 8 6% ),两组比较差异有显著性 (P <0 0 5)。结论 :红霉素对逆转乳腺癌MDR具有一定作用。     

褪黑素逆转人乳腺癌细胞MCF-7／ADM对阿霉素耐药的作用机制

目的:探讨生理浓度(10-9 mol/L)和药理浓度(≥10-5 mol/L)褪黑素对耐阿霉素乳腺癌细胞系MCF-7/ADM 耐药的逆转作用及其机制.方法:应用四甲基偶氮唑蓝(MTT)法检测经不同浓度的褪黑素孵育后,阿霉素对MCF-7/ADM 细胞系半数抑制浓度IC50的改变.在电镜下观察单用阿霉素(20ug/ml)以及药理浓度的褪黑素(10-5mol/l)孵育后再应用阿霉素(20ug/ml)后MCF-7/ADM 细胞超微结构的变化.应用分光光度法测定MCF-7/ADM 和MCF-7/s细胞内GSH水平及褪黑素孵育后MCF-7/ADM和MCF-7/s细胞内GSH水平变化.结果:褪黑素孵育前阿霉素作用于MCF-7/ADM的IC50值为24.41ug/ml.经生理浓度(10-9mol/l)的褪黑素孵育后阿霉素IC50值为20.92ug/ml,两者经比较未见显著性差异(P=0.356).经浓度为10-5mol/L 和10-3mol/L的褪黑素孵育后阿霉素作用于MCF-7/ADMIC50值分别成为12.25ug/ml和10.46ug/ml,与孵育前阿霉素作用于MCF-7/ADM的IC50(24.41ug/ml)相比差异均具有显著性(P＜0.01).在电镜下均可观察到,经药理浓度(10-5mol/l)的褪黑素孵育后,阿霉素(20ug/ml)对细胞的损伤更为严重.经分光光度法测得MCF-7/ADM细胞内GSH水平明显高于MCF-7/s,生理浓度褪黑素并不能使MCF-7/ADM和MCF-7/s细胞内GSH水平明显降低(P=0.965),而药理浓度的褪黑素可以显著降低MCF-7/ADM和MCF-7/s细胞内GSH水平且具有一定的浓度依赖性(P＜0.01).结论:生理浓度的褪黑素对MCF-7/ADM的耐药未见明显影响,药理浓度的褪黑素对MCF-7/的ADM耐药性具有较明显逆转作用,其逆转机制可能与褪黑素对细胞内CSH水平调控有关.     

Anti-cancer effect of hyperthermia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immunoliposomes

Background We have constructed anti-HER2 immunoliposomes containing magnetite nanoparticles (HML) that generate heat in an alternating magnetic field (AMF). The effective targeting and cytocidal abilities of HML have been achieved using cell culture models. This study aimed to investigate feasibility of this modality for breast cancer treatment using tumor-bearing mouse models. Material and methods The subcutaneous cancer nodules of BT474 (high HER2 expression) or SKOV3 (low HER2 expression) cells in nude mice were employed as models. HMLs were injected into these cancer nodules and were then exposed to an AMF for 30 min twice at 24 h intervals. Accumulation of magnetite and tumor growth rates were examined. Histological findings of the thermal effect were also examined. Results HMLs accumulated in only BT474 tumors. The tumor temperature increased to 45°C whereas the body temperature remained at around 38°C. Tumor regression was observed in the hyperthermic group and was sustained for 10 weeks after hyperthermia. Conclusion These results suggest that hyperthermia using HML is an effective and specific therapy for breast cancer overexpressing HER2. This therapy may provide an alternative way to treat recurrent cancer refractory to other modalities.     

Homocamptothecin-daunorubicin association overcomes multidrug-resistance in breast cancer MCF7 cells

The multidrug-resistance (MDR) status of a novel camptothecin analogue, homocamptothecin (hCPT), was investigated in human colon adenocarcinoma HT29 cells, myelogenous leukemia K562 cells and breast carcinoma MCF7 cells. The cytotoxicity of hCPT was not sensitive to the MDR status in K562 cell lines. However, its cytotoxicity was altered by MRP1, but not Pgp, in naturally MRP1-expressing HT29 cells, and etoposide- and doxorubicin-resistant MCF7/VP and MCF7/DOX cells, respectively. These cells were sensitized to hCPT in presence of MK571, probenecid but not verapamil. These results led to consider hCPT as a substrate for MRP1 and a potential modulator of MRP1 activity. The relationship between the cytotoxic effect of anthracyclines and their nuclear localization had been previously demonstrated. We show that MRP1 mediated the daunorubicin (DNR) efflux in MCF7/VP and MCF7/DOX cells. The combination of sub-toxic doses of hCPT with DNR resulted in the potentiation of DNR activity, well-correlated with an increase in its nuclear accumulation in MCF7/VP cells. Simultaneous pattern was shown to provide higher cytotoxic response than sequential one. In agreement, hCPT increased also the DNR nuclear accumulation in low MRP1-expressing MCF7/DOX cells. However, the enhancement of cytotoxicity in the DNR-hCPT combination was poorly correlated with the nuclear concentration of DNR in MCF7/DOX cells. In addition to the increase in DNR accumulation, the potentiation of DNR activity by hCPT in MCF7/DOX cells implied a synergistic mechanism between both drugs. These data suggest that the present topoisomerase I/II inhibitors combination may be of clinical interest to overcome MDR phenotype in DNR-treated breast cancer patients.     

Metamaterial lens applicator for microwave hyperthermia of breast cancer

Artificial left-handed metamaterial (LHM) provides a new perspective for microwave hyperthermia. Four flat LHM slab lenses can be used to form a focus-flexible applicator for breast tumour hyperthermia. By adjusting microwave sources behind the four flat LHM lenses, microwaves emitted from the sources can be focused tightly at different points in the breast tissue so that necessary heating depth in breast tissue can be achieved. Numerical simulations with a two-dimensional finite-difference time-domain method indicate that hyperthermia with the proposed four-lens applicator of moderate LHM losses could be effective in achieving desired power deposition in a heterogeneous breast model. Temperature distribution obtained by solving the bio-heat transfer equation demonstrates that temperature above 43°C can be maintained in the tumour volume for specific periods of time. Flat slab LHM lenses offer a feasible alternative to traditional mechanically scanned lens applicator and electronically scanned phased-array applicators.     

泰索帝合并温热对肺腺癌细胞的杀伤效应

目的研究泰索帝合并温热对SPC—A-1肺腺癌细胞的杀伤效应。方法不同浓度（0．05μg／ml～10μg／ml）泰索帝合并温热（39—42℃）作用后,应用MTT法测定其对细胞的杀伤效应,用流式细胞仪和Feulgen染色法检测5μg／ml泰索帝合并41℃对细胞周期影响,并用考马氏亮蓝法观察细胞骨架的形态变化。结果40℃以上温热作用60min,可抑制SPC—A-1细胞生长,其效应随温度的升高逐渐增强,以42℃最明显;24h后,各组抑制效应均较即时组更明显。泰索帝单独作用对肺癌细胞的杀伤效应在5μg／ml出现,停药后24h杀伤效应有所降低。低浓度泰索帝与39℃-42℃合并可见显著抑瘤协同效应,24h后协同效应仍存在。合并作用可使更多细胞阻滞于分裂期,细胞形态变圆,可出现骨架蛋白凝聚、细胞伸展不良,细胞分裂异常,可见较多微核、多核细胞。结论泰索帝与温热合并有协同效应,可提高泰索帝对SPC—A-1肺腺癌细胞的杀伤效应,降低用药浓度,其机制可能与细胞骨架功能障碍及温热增加膜对药物通透性有关。     

热作用对人肝癌MHCC97细胞增殖、凋亡及NDRG2表达的影响

目的：探讨热作用对人肝癌细胞株MHCC97细胞的增殖、凋亡以及NDRG2蛋白表达的影响。方法：MHCC97细胞分为5组,43℃恒温分别加热0h（对照组）、0.5h、1h、1.5h、2h。各组热处理后继续37℃恒温培养。于3h、6h、9h、12h、24h,使用倒置显微镜观察细胞形态变化,MTT法检测各处理组细胞增殖情况,流式细胞仪检测细胞凋亡,Western blot检测NDRG2蛋白量的表达。结果：热处理后,细胞形态出现明显改变,细胞体积缩小,部分细胞脱落,加热2h培养24h者最为显著;热处理后,细胞增殖受抑制,以加热1h培养24h者最为明显（67.1%）;流式细胞仪检测显示,凋亡百分比在加热2h培养12h者达最大值（58.4%）;Western blot检测提示,加热1h培养24h者,NDRG2蛋白表达量最低。结论：热疗对肿瘤细胞具有杀伤和增殖抑制作用,并且能够诱导其凋亡,降低NDRG2蛋白的表达,以加热1h后培养24h效果最明显。     

多西他赛诱导乳腺癌Bcap37细胞凋亡作用的研究

目的：探讨多西他赛（≤10μmol／L）体外对人乳腺癌Bcap37细胞凋亡的作用及其机制。方法：采用琼脂糖凝胶电泳观察Bcap37细胞凋亡情况；原位末端标记（TUNEL）法测定Bcap37细胞凋亡指数（apoptotic index，AI）；流式细胞仪检测Bcap37细胞周期。结果：与对照组相比，实验组琼脂糖凝胶电泳显示凋亡特有的梯状图谱；实验组显示细胞核染成棕色的凋亡细胞，且AI较对照组显著增大，具有量效依赖性，P〈0．001。实验组G2／M期细胞比例较对照组显著升高，G1、S期细胞比例显著降低，P〈0．01。结论：多西他赛（≤10μmol／L）诱导人乳腺癌Bcap37细胞凋亡，细胞周期阻滞在G2／M期。     

胰岛素对人乳腺癌细胞影响的体外实验研究

目的:探讨胰岛素能否促进人乳腺癌细胞增殖。方法:将胰岛素直接作用于体外培养的人乳腺癌细胞株(MDA-MB-543),运用四氮唑盐,直接细胞计数及流式细胞仪测定等方法观察胰岛素对MDA-MB-543细胞株活力,细胞总数,细胞周期等的影响。结果:胰岛素(0.5~16mu/ml,8~18小时)使MDA-MB-543细胞株活力,细胞总数增加,呈明显的量效关系,流式检测证实胰岛素(7.5mu/ml)使S期细胞增多。结论:在体外,胰岛素可诱导人乳腺癌细胞株MDA-MB-543增殖。     

Re-irradiation and hyperthermia after surgery for recurrent breast cancer

Purpose

Evaluation of efficacy and side effects of combined re-irradiation and hyperthermia electively or for subclinical disease in the management of locoregional recurrent breast cancer.

Methods and materials

Records of 198 patients with recurrent breast cancer treated with re-irradiation and hyperthermia from 1993 to 2010 were reviewed. Prior treatments included surgery (100%), radiotherapy (100%), chemotherapy (42%), and hormonal therapy (57%). Ninety-one patients were treated for microscopic residual disease following resection or systemic therapy and 107 patients were treated electively for areas at high risk for local recurrences. All patients were re-irradiated to 28–36 Gy (median 32) and treated with 3–8 hyperthermia treatments (mean 4.36). Forty percent of the patients received concurrent hormonal therapy. Patient and tumor characteristics predictive for actuarial local control (LC) and toxicity were studied in univariate and multivariate analysis.

Results

The median follow-up was 42 months. Three and 5 year LC-rates were 83% and 78%. Mean of T90 (tenth percentile of temperature distribution), maximum and average temperatures were 39.8 °C, 43.6 °C, and 41.2 °C, respectively. Mean of the cumulative equivalent minutes (CEM43) at T90 was 4.58 min. Number of previous chemotherapy and surgical procedures were most predictive for LC. Cumulative incidence of grade 3 and 4 late toxicity at 5 years was 11.9%. The number of thermometry sensors and depth of treatment volume were associated with acute hyperthermia toxicity.

Conclusions

The combination of re-irradiation and hyperthermia results in a high LC-rate with acceptable toxicity.