分子靶向性药物赫赛汀治疗乳腺癌临床应用新进展

赫赛汀(Herceptin)是乳腺癌治疗领域的第1个分子靶向性药物.现综述Herceptin联合化疗的最新临床研究结果及正在进行的各项临床研究.     

赫赛汀诱导子宫内膜癌Ishikawa细胞凋亡并增强其对化疗的敏感性

目的:研究赫赛汀单独或联合阿霉素(adriamycin,ADR)、顺铂(cisplatin,DDP)及紫杉醇(paclitaxel,PTX)对子宫内膜癌细胞凋亡和化疗敏感性的影响,为临床应用赫赛汀治疗子宫内膜癌提供理论依据。方法:MTT法检测赫赛汀、ADR、DDP及PTX处理子宫内膜癌Ishikawa细胞的IC50。进一步应用1/2 IC50量的赫赛汀与各1/2 IC50量的ADR、DDP及PTX药物联合,流式细胞术检测细胞周期与凋亡变化。结果:赫赛汀抑制子宫内膜癌Ishikawa细胞生长,引起细胞G1期阻滞,诱导细胞凋亡。子宫内膜癌Ishikawa细胞应用赫赛汀、ADR、DDP及PTX的IC50分别为57.12 mg/L、0.572μmol/L、67.4μmol/L和719.5 nmol/L,赫赛汀联合化疗后显著提高各组化疗药的杀伤效果,诱导细胞凋亡,与单纯化疗组相比差异有统计学意义(P0.05)。结论:赫赛汀诱导子宫内膜癌细胞凋亡,并提高子宫内膜癌细胞株对化疗的敏感性。     

Rat Muc4 (sialomucin complex) reduces binding of anti-ErbB2 antibodies to tumor cell surfaces,a potential mechanism for herceptin resistance

Muc4 (also called sialomucin complex), the rat homolog of human MUC4, is a heterodimeric glycoprotein complex that consists of a peripheral O-glycosylated mucin subunit, ASGP-1, tightly but noncovalently linked to a N-glycosylated transmembrane subunit, ASGP-2. The complex is expressed in a number of normal, vulnerable epithelial tissues, including mammary gland, uterus, colon, cornea and trachea. Muc4/SMC is also overexpressed or aberrantly expressed on a number of human tumors including breast tumors. Overexpression of Muc4/SMC has been shown to block cell-cell and cell-matrix interactions, protect tumor cells from immune surveillance and promote metastasis. In addition, as a ligand for ErbB2, Muc4/SMC can potentiate phosphorylation of ErbB2 and potentially alter signals generated from this receptor. Using A375 human melanoma cells and MCF7 human breast adenocarcinoma cells stably transfected with tetracycline regulatable Muc4, we have investigated whether overexpression of Muc4/SMC can repress antibody binding to cell surface-expressed ErbB2. Overexpression of Muc4/SMC does not affect the level of ErbB2 expression in either cell line, but it does reduce binding of a number of anti-ErbB2 antibodies, including Herceptin. Interestingly, overexpression of ErbB2 does not block binding of other unrelated antibodies of the same isotype, suggesting that the reduction in ErbB2 antibody binding is due to complex formation of Muc4/SMC and ErbB2. Furthermore, capping of Muc4/SMC with anti-Muc4/SMC antibodies reduces antibody binding to ErbB2 instead of increasing binding, again suggesting that reduced antibody binding to ErbB2 is due to steric hindrance from complex formation of Muc4/SMC and ErbB2. Thus, overexpression of Muc4/SMC on tumor cells may have both prognostic and therapeutic relevance.     

赫赛汀治疗HER2高表达晚期恶性肿瘤临床观察

目的探讨赫赛汀（Herceptin）治疗HER2高表达晚期恶性肿瘤的疗效及毒性。方法单用Herceptin 4mg／kg，wk1，以后每周2mg／kg，一直到病情进展；联合紫杉醇，紫杉醇每周期（circle）135mg／m^2或每周期用紫杉醇75mg／m^2，前3wk给药1次／wk，休息1wk，4wk为lcircle。结果近期疗效：CR1例，PR3例，PD2例，SD2例，CR＋PR=4例，总有效率50．0％，症状改善率87．5％。单药病情稳定率50.0％，症状改善率50．0％，联合紫杉醇症状改善率83．7％，有效率63.3％，Herceptin单药对转移性乳癌的有效率仅15．0％，紫杉醇单药有效率仅25．0％左右，而两药合用有效率高达57．3％。不良反应，8例均未见畏寒发热反应，2例单药未见任何相关毒性，联合紫杉醇6例，1例出现室性早博，5例均有骨髓抑制，1例出现室性早博可能与Herceptin有关；骨髓抑制、恶心呕吐与紫杉醇相关性较大。结论Herceptin对于HER2过度表达的恶性肿瘤病人是一个疗效肯定，毒副作用轻微的单抗类抗肿瘤药，应尽快应用到HER2过表达的恶性肿瘤辅助治疗中，以提高这类病人的临床治愈率。     

Herceptin联合顺铂对高表达Her-2／neu卵巢癌体外作用的实验研究

 目的 筛选高表达Her-2／neu的卵巢癌细胞株，观察Herceptin联合顺铂（DDP）对该细胞株体外生长的抑制作用。方法 采用反转录-聚合酶链反应技术，检测人卵巢癌细胞株3AO，SKOV3，OVCAR Her-2／neu的表达情况，筛选出高表达Her-2／neu的人卵巢癌细胞株。采用四甲基偶氮唑蓝（MTT）法测定Herceptin，DDP以及联合用药对高表达Her-2／neu的人卵巢癌细胞株体外生长抑制率并进行比较。结果 人卵巢癌细胞株SKOV3 Her-2／neu呈高表达；Herceptin 可有效抑制SKOV3的生长，具有浓度依赖性（P = 0.001），联合用药组的生长抑制率为79.41 %，明显高于二者单独作用（P = 0.0001）。结论 人卵巢癌细胞株 SKOV3 Her-2／neu呈高表达。Herceptin，DDP均能有效抑制SKOV3的生长，联合用药组疗效更佳。     

Herceptin治疗转移性乳腺癌3例临床报告

为观察Ｈｅｒｃｅｐｔｉｎ治疗Ｈｅｒ ２阳性晚期乳腺癌的疗效。我们用Ｈｅｒｃｅｐｔｉｎ初始剂量为４ｍｇ／ｋｇ,以后２ｍｇ／ｋｇ,每周１次 ,３～４周为１周期。同时分别配合用泰素加异环磷酰胺 ;去甲长春花碱或泰索帝 ,治疗３例转移性乳腺癌 ,现报道如下。临床资料例１,５０岁 ,１９９９年１月１１日左乳癌改良根治术 ,术后病理 :左乳腺浸润性导管癌 ,肿瘤位于外上象限约２ｃｍ×１ｃｍ×１ｃｍ ,ＥＲ(- ) ,ＰＲ(- ) ,ｐ５３(+) ,Ｈｅｒ ２(++)左腋窝淋巴结转移４／１０。术后行ＣＡＦ方案３周期辅助化疗及放疗。２０００年３月胸ＣＴ发…     

Enhanced Anti-tumor Effect of Trastuzumab in Combination with Cisplatin

The oncogenenic transmembrane tyrosine kinase receptor HER–2/neu is a promising target for treatment of HER–2–overexpressing cancers. The humanized anti-HER–2/neu antibody Trastuzumab is under clinical evaluation in combination with chemotherapy against breast cancer. The combination of Trastuzumab and cisplatin is expected to be active against HER–2/neu-expressing tumors. We examined the mechanisms of this combination effect against human solid tumor cells in the presence of human peripheral blood mononuclear cells (PBMCs) using an in vitro MTT assay. The growth-inhibitory effects of cisplatin (CDDP) on the tumor cells were not significantly affected by Trastuzumab in the absence of effector cells. CDDP alone at a dose of less than 12.5 μ M did not affect the viability of PBMCs, as determined by MTT assay, suggesting that PBMCs could exert antibody-dependent cell-mediated cytotoxicity (ADCC) at this CDDP concentration. The combination of Trastuzumab and CDDP showed higher cytotoxic effects against the tumor cells in the presence of PBMCs. The CDDP concentration required to inhibit tumor cell growth by 50% was reduced to ∼20% by Trastuzumab in the presence of PBMCs at an effector/target ratio of 10. It may be important to select combined chemotherapeutic agents which do not diminish the ADCC activity of Trastuzumab via PBMCs. Both the expression of HER–2/neu and the ADCC activity may be important determinants of the therapeutic benefit of the Trastuzumab/CDDP combination.     

乳腺癌HER2基因的研究进展及其靶点治疗

HER2和抗HER2单克隆抗体Herceptin为近年来乳腺癌研究热点。HER2被认为是新的判断乳腺癌预后的独立标志物和治疗靶点,抗HER2单克隆抗体Herceptin对晚期、复发性及转移性乳腺癌的治疗显示出了巨大的前景。     

The clinical evaluation of HER‐2 status: which test to use?

Accurate determination of the status of the type I receptor tyrosine kinase HER-2 in breast carcinomas provides significant insight into patient prognosis and may also inform selection of chemotherapeutic and hormonal treatments. At present, however, the single most important application of HER-2 testing is in the selection of patients for treatment with targeted therapies such as Herceptin. Although, based on current literature, fluorescence in situ hybridization (FISH) detection of HER-2 gene amplification may provide more accurate information in this context, this method is not yet widely available. Therefore, screening by immunohistochemistry (IHC) for HER-2 protein, backed by rigorous quality controls and FISH testing of equivocal cases with intermediate staining intensity, remains the current practice. In laboratories with highly standardized testing and quality assurance procedures, this protocol appears highly effective. Improvements in fixation procedures, standardization of antibodies, and use of automated image analysis may all increase the precision of IHC testing. However, on the basis of current data, there is a case to be made for the wider implementation of FISH testing to determine HER-2 status in breast cancer.     

注射用曲妥珠单抗治疗晚期乳腺癌临床验证结果

目的 验证单克隆抗体制剂注射用曲妥珠单抗(trastuzumab,商品名赫赛汀^*)对晚期乳腺癌的疗效和不良反应。方法 对经病理诊断的晚期乳腺癌应用赫赛汀^*治疗。第1次给予负荷剂量4mg／kg静脉滴注,以后剂量改为2mg／kg,每周1次。注射3个月以上评价临床疗效。结果 3l例患者中,治疗后完全缓解(CR)2例,部分缓解(PR)6例,稳定(SD)7例,进展(PD)16例,CR PR共8例,有效率为25.8％(ITT分析)。患者年龄、一般状况对疗效有一定影响,而病理类型、病变部位、既往治疗和病理her-2阳性程度对疗效无明显影响。该药不良反应轻微,而且和一般化疗不同。结论 赫赛汀^*对中国乳腺癌患者疗效肯定,安全性较好,为一较安全、有效的新型乳腺癌治疗药物。