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521.
Burris HA Tibbitts J Holden SN Sliwkowski MX Lewis Phillips GD 《Clinical breast cancer》2011,11(5):275-282
Increased understanding of the molecular mechanisms of tumorigenesis has led to the development of novel agents that target tumor cells with minimal effects on normal cells. The success of this approach is exemplified by the development of monoclonal antibodies directed toward antigens expressed selectively by tumor cells. The conjugation of these monoclonal antibodies with potent cytotoxic drugs has the potential to further improve efficacy while retaining a favorable safety profile. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) currently in clinical development. It combines the humanized antibody trastuzumab, which targets the human epidermal growth factor receptor 2 (HER2) receptor on cancer cells, and the potent antimicrotubule agent DM1 using a unique highly stable linker. When T-DM1 binds to HER2, a proportion of the receptors are thought to be internalized by the process of receptor endocytosis, followed by the intracellular release of an active form of DM1, which in turn kills the tumor cell. This review presents the rationale for the development of T-DM1 and summarizes the preclinical and clinical data for this novel agent for the treatment of breast cancer. 相似文献
522.
523.
Breast cancer is uncommonly diagnosed during pregnancy but when encountered, it poses several clinical conflicts. Managing patients with gestational breast cancer should not be associated with considerable risk of morbidity provided the choice of the right drug in the right time for the right patient. Due to its relative rarity, we lack a standardized approach to manage these patients. Previous reports have suggested that women can be offered treatment strategies similar to those offered in the “non-pregnant” setup. Nevertheless, generalizing treatment decisions is too hard and treatment of these cases should be tailored according to the clinical situation. In order to ensure proper counseling of these patients, there are several key points that need to be addressed. These include timing of chemotherapy administration, the scheduling of agents, and pregnancy monitoring. In this review, we provide some guidance on how to select the chemotherapy regimen and address the feasibility and safety of administering trastuzumab during pregnancy. We also discuss some practical points on monitoring these patients during the course of pregnancy. 相似文献
524.
Goel S Chirgwin J Francis P Stuart-Harris R Dewar J Mileshkin L Snyder R Michael M Koczwara B 《Breast (Edinburgh, Scotland)》2011,20(2):101-110
The management of HER2-positive metastatic breast cancer, a disease renowned for its aggressive natural history, has been revolutionized by the introduction of trastuzumab. Indeed, outcomes for patients with HER2-positive advanced breast cancer are now equivalent to, if not better than, those of their HER2-negative counterparts. Since the pivotal registration trial, a wealth of new clinical data has emerged regarding the use of trastuzumab in a variety of clinical contexts - adding to the evidence but also highlighting areas of uncertainly and debate. These include the optimal partner chemotherapy(ies) to trastuzumab; the effectiveness of combining trastuzumab with endocrine therapy; the benefits of continuing trastuzumab after progression on a trastuzumab-containing regimen; and the role of trastuzumab in locally advanced and inflammatory breast cancer. In this paper we review major clinical trials addressing these questions, clinical recommendations that can be made as a result, and the strength of evidence that supports them. Finally, we identify areas of ongoing uncertainty, and propose recommendations for future research in this field. 相似文献
525.
526.
Booy EP Johar D Maddika S Pirzada H Sahib MM Gehrke I Loewen S Louis SF Kadkhoda K Mowat M Los M 《Archivum immunologiae et therapiae experimentalis》2006,54(2):85-101
Gene amplification, over-expression, and mutation of growth factors, or the receptors themselves, causes increased signaling
through receptor kinases, which has been implicated in many human cancers and is associated with poor prognosis. Tumor growth
has been shown to be decreased by interrupting this process of extensive growth factor-mediated signaling by directly targeting
either the surface receptor or the ligand and thereby preventing cell survival and promoting apoptosis. Monoclonal antibodies
have long been eyed as a potential new class of therapeutics targeting cancer and other diseases. Antibody-based therapy initially
entered clinical practice when trastuzumab/Herceptin became the first clinically approved drug against an oncogene product
as a well-established blocking reagent for tumors with hyperactivity of epidermal growth factor signaling pathways. In the
first part of this review we explain basic terms related to the development of antibody-based drugs, give a brief historic
perspective of the field, and also touch on topics such as the “humanization of antibodie” or creation of hybrid antibodies.
The second part of the review gives an overview of the clinical usage of bispecific antibodies and antibodies “armed” with
cytotoxic agents or enzymes. Further within this section, cancer-specific, site-specific, or signaling pathway-specific therapies
are discussed in detail. Among other antibody-based therapeutic products, we discuss: Avastin (bevacizumab), CG76030, Theragyn
(pemtumomab), daclizumab (Zenapax), TriAb, MDX-210, Herceptin (trastuzumab), panitumumab (ABX-EGF), mastuzimab (EMD-72000),
Erbitux (certuximab, IMC225), Panorex (edrecolomab), STI571, CeaVac, Campath (alemtuizumab), Mylotarg (gemtuzumab, ozogamicin),
and many others. The end of the review deliberates upon potential problems associated with cancer immunotherapy. 相似文献
527.
Carola W.N. Damen Ellen J.B. Derissen Jan H.M. Schellens Hilde Rosing Jos H. Beijnen 《Journal of pharmaceutical and biomedical analysis》2009,50(5):861-866
For the quantification of therapeutic monoclonal antibodies in biological specimens, enzyme-linked immunosorbent assay (ELISA) is the most widely used technique. ELISA's have some limitations and therefore alternative analytical techniques are being explored. In this study we describe the development of a bioanalytical assay using high-performance liquid chromatography (HPLC) coupled with fluorescence detection for the bioanalysis of the monoclonal antibody trastuzumab. Different extraction procedures were explored, like isolation using protein A and protein G. Finally a method using immuno-affinity purification has been developed. Trastuzumab is isolated from human serum using sepharose coupled with anti-trastuzumab idiotype antibodies. After extraction samples are injected onto a Zorbax 300SB C8 column at 75 °C using the organic solvents isopropanol and acetonitrile with high eluotropic strengths. The assay quantifies trastuzumab from 5 to 40 μg/mL in human serum with accuracies <20%. Samples with concentrations above the upper limit of quantification (>ULOQ; >40 μg/mL) can be diluted 5 times with control human serum prior to sample pre-treatment. The assay can now be used to analyse serum samples of patients treated with trastuzumab. The obtained results are comparable to those obtained using ELISA. This is the first report describing a bioanalytical assay using HPLC and fluorescence detection for the quantification of a monoclonal antibody at the intact protein level in human serum. This unique approach has the advantage compared to ELISA that a HPLC separation step is introduced to improve the selectivity. This method is a potential alternative to ELISA to support pharmacokinetic evaluations. However, for purification of trastuzumab from serum anti-idiotype antibodies are necessary. These anti-idiotype antibodies are also used in ELISA and as ELISA is more sensitive and less labor-intensive, ELISA probably remains the analytical technique of first choise. 相似文献
528.
目的探讨曲妥珠单抗(trastuzumab)对细胞膜p185人表皮生长因子受体2(HER-2)强阳性表达,以及HER-2胞外域(ECD)水平不同的肿瘤细胞系SKBR3和SKOV3细胞的生长、克隆形成及细胞内HER-2蛋白水平的影响。方法SKBR3和SKOV3细胞经曲妥珠单抗处理后,统计细胞数目及克隆形成率。双抗夹心ELISA法检测细胞培养上清中HER-2 ECD水平,Western blot检测细胞HER-2蛋白水平。结果高HER-2 ECD水平的SKBR3细胞生长及克隆形成率明显被曲妥珠单抗抑制,在相对分子质量为90 000和40 000左右分别有1条未知磷酸化蛋白明显降低或基本消失,而细胞生长及克隆形成率未受影响的SKOV3细胞中此蛋白无明显变化。SKBR3和SKOV3细胞中p185 HER-2蛋白、磷酸化-p185蛋白、磷酸化-p95蛋白水平并未见明显降低。曲妥珠单抗不仅与SKOV3细胞培养上清中的HER-2 ECD反应,也与p68/ECDⅢa蛋白反应。经曲妥珠单抗处理后,SKBR3细胞HER-2 ECD水平明显降低,但将曲妥珠单抗处理前、后的细胞数目调整到基本一致时,HER-2 ECD水平未发生明显变化。结论曲妥珠单抗抑制肿瘤细胞生长可能与阻止相对分子质量为90 000和40 000左右的未知磷酸化蛋白表达有关;p68/ECDⅢa蛋白也可能存在曲妥珠单抗识别位点;HER-2 ECD水平降低可能与SKBR3细胞数目减少有关。 相似文献
529.
Bartsch R Rottenfusser A Wenzel C Dieckmann K Pluschnig U Altorjai G Rudas M Mader RM Poetter R Zielinski CC Steger GG 《Journal of neuro-oncology》2007,85(3):311-317
Background: Brain metastases are frequently encountered in Her2 positive advanced breast cancer. It is still not clear, if trastuzumab
treatment should be continued following their diagnosis. In this analysis we evaluated if trastuzumab was able to influence
time to in-brain progression (TTP) and overall survival (OS). For this reason, we compared patients who continued on trastuzumab
with a historical control group.
Patients and Methods: Seventeen Her2 positive patients receiving whole brain radiotherapy for brain metastases and continuing on trastuzumab were
identified. As historical control group, thirty-six patients treated before 2002 were identified from a breast cancer database.
We performed a multivariate analysis (Cox regression) to explore which factors were potentially able to significantly influence
TTP and OS.
Results: Median TTP was 6 months, range 1–33+ months. Median OS was 7 months, range 1–38 months. Seventeen patients received trastuzumab
after WBRT. Factors associated with prolonged TTP were KPS (p = 0.001), and intensified local treatment (p = 0.004). A trend towards longer TTP was observed in patients treated with trastuzumab (p = 0.068). OS was significantly influenced by KPS (p < 0.001), and continued antibody therapy (p = 0.001).
Conclusion: Two parameters were significantly associated with prolonged OS: KPS and trastuzumab. While there was a trend towards prolonged
TTP in patients with trastuzumab treatment after WBRT, this did not reach statistical significance. It appears therefore reasonable
to suggest continuation of antibody therapy in patients with good performance status despite disease spreading to the brain.
Concerning activity of trastuzumab in brain metastases themselves, no final conclusion is possible. 相似文献
530.
Timolati F Ott D Pentassuglia L Giraud MN Perriard JC Suter TM Zuppinger C 《Journal of molecular and cellular cardiology》2006,41(5):845-854
Treatment of metastatic breast cancer with doxorubicin (Doxo) in combination with trastuzumab, an antibody targeting the ErbB2 receptor, results in an increased incidence of heart failure. Doxo therapy induces reactive oxygen species (ROS) and alterations of calcium homeostasis. Therefore, we hypothesized that neuregulin-1 beta (NRG), a ligand of the cardiac ErbB receptors, reduces Doxo-induced alterations of EC coupling by triggering antioxidant mechanisms. Adult rat ventricular cardiomyocytes (ARVM) were isolated and treated for 18-48 h. SERCA protein was analyzed by Western blot, EC coupling parameters by fura-2 and video edge detection, gene expression by RT-PCR, and ROS by DCF-fluorescence microscopy. At clinically relevant doses Doxo reduced cardiomyocytes contractility, SERCA protein and SR calcium content. NRG, similarly as the antioxidant N-acetylcystein (NAC), did not affect EC coupling alone, but protected against Doxo-induced damage. NRG and Doxo showed an opposite modulation of glutathione reductase gene expression. NRG, similarly as NAC, reduced peroxide- or Doxo-induced oxidative stress. Specific inhibitors showed, that the antioxidant action of NRG depended on signaling via the ErbB2 receptor and on the Akt- and not on the MAPK-pathway. Therefore, NRG attenuates Doxo-induced alterations of EC coupling and reduces oxidative stress in ARVM. Inhibition of the ErbB2/NRG signaling pathway by trastuzumab in patients concomitantly treated with Doxo might prevent beneficial effects of NRG in the myocardium. 相似文献