A small molecule LS-1-2F promotes the endocytosis of macromolecules into tumor cells

In the previous research, we found that anticancer agent LS-1-2F could cause the vacuolation of tumor cells. Herein we investigated the effect of compound LS-1-2F on the endocytosis of macromolecules, including fluorescence quantum dots, human serum albumin, single-stranded RNA, and monoclonal antibody, into tumor cells. We found that LS-1-2F could accelerate the endocytosis of these large molecules by laser confocal microscope and flow cytometry. The effect of LS-1-2F on the improvement of the internalization efficiency of Herceptin biosimilar was particularly significant. Promoting endocytosis will help increase the efficiency of liquid-phase drug uptake in drug-resistant cancer cells and could potentially facilitate the use of drugs in nanoparticle delivery vehicles.     

Herceptin联合化疗治疗Her-2过度表达的晚期乳腺癌疗效观察

目的比较Herceptin联合紫杉醇（TAX）的生物化疗组和TAX单纯化疗组治疗人表皮生长因子受体2（Her-2）阳性表达的乳腺癌患者的疗效及毒性。方法选择免疫组化法检查Her-2为阳性的女性乳腺癌患者为研究对象,以36例接受Herceptin联合TAX方案治疗者为研究组,42例接受单纯TAX方案治疗者为对照组．分别观察上述两组患者疗效及毒副反应。结果Herceptin联合TAX治疗乳腺癌的客观有效率fRR％）、临床受益率（RR＋SD％）均明显高于单纯TAX组;生物化疗组中,免疫组化检测结果为HeP2（＋）、Her-2（＋＋）、Her-2（＋＋＋）的患者临床有效率分别为0％、57．1％和65．0％;单纯化疗组分别为16．7％、50．0％和50．0％;两者之间的临床疗效存在着显著性差异CP〈0．05）。结论对于Her-2阳性的晚期乳腺癌患者,Herceptin联合TAX方案组的疗效明显优于单纯TAX方案组,对Her-2（＋＋＋）的乳腺癌患者,Herceptin联合TAX治疗的有效率高于Her-2（＋＋）的患者,联合化疗安全可靠。     

Trastuzumab, ein neuer Behandlungsansatz beim Mammakarzinom

Zum Thema Der humanisierte monoklonale Antik?rper Trastuzumab (Herceptin^?) ist gegen den HER2/neu Membranrezeptor gerichtet, der bei etwa 25% der Patientinnen mit Mammakarzinom in überexpression vorliegt. Durch verschiedene Wirkungsmechanismen verhindert Trastuzumab das Tumorwachstum und erh?ht gleichzeitig die Chemosensibilit?t des Tumors. Trastuzumab ist seit Ende August 2000 in der EU für die beiden folgenden Indikationen zugelassen: Erstens als Monosubstanz zur Behandlung des HER2/neu überexprimierenden metastasierten Mammakarzinoms, wenn zuvor ein oder mehrere palliative Chemotherapieregime mit Anthrazyklinen oder Taxanen appliziert worden waren. Zweitens in Kombination mit Paclitaxel zur Behandlung des HER2/neu überexprimierenden metastasierten Mammakarzinoms, wenn keine palliative Chemotherapie vorangegangen ist und eine Therapie mit Anthrazyklinen nicht indiziert ist. In den Zulassungsstudien zeigten sich kardiale Nebenwirkungen, insbesondere wenn Trastuzumab mit Anthrazyklinen kombiniert wurde. Weltweit wird dieses Ph?nomen, sowie die Wirksamkeit von Trastuzumab mit anderen Kombinationspartnern, auch in der adjuvanten Situation untersucht.     

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。     

Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer

Background

A novel antibody–drug conjugate (trastuzumab-DM1, T-DM1) is currently in clinical trials for patients with trastuzumab resistant HER2-positive breast cancer. Since no clinical data is available from gastric cancer, we studied T-DM1 on HER2-positive human gastric cancer cells and xenograft tumors.

Methods

Effects of T-DM1 were studied in four HER2-positive gastric cancer cell lines (N-87, OE-19, SNU-216 and MKN-7) in vitro. Xenograft tumors from N-87 and OE-19 were studied to determine the effect of T-DM1 in vivo.

Results

T-DM1 was found more effective than trastuzumab in N-87 and OE-19, and moderately effective in MKN-7 cells. On SNU-216 cells both trastuzumab and T-DM1 showed limited efficacy. In xenograft tumor experiments, complete pathological response was observed in all OE-19 xenografted mice and in half of the N-87 xenografted mice. The results were equally good irrespective of the tumor burden at therapy initiation, or preceding trastuzumab treatment. T-DM1 treatment showed direct effects (apoptotic cell death and aberrant mitosis) as well as it mediated antibody-dependent cellular cytotoxcity (ADCC).

Conclusions

T-DM1 showed a promising anti-tumor effect in HER2-positive gastric cancer cell lines in vitro and in vivo, even in tumors which had developed resistance to trastuzumab. T-DM1 therapy may warrant clinical trials for HER2-positive gastric cancer patients.     

Recent advances in breast cancer radiotherapy: Evolution or revolution,or how to decrease cardiac toxicity?

Radiation therapy has a major role in the management of breast cancers. However, there is no consensus on how to irradiate and on volume definitions, and there are strong differences in strategies according to different centers and physicians. New treatment protocols and techniques have been used with the principal purpose of decreasing lung and heart toxicity and adapting radiation treatment to patients' anatomy. There is evidence that indicates internal mammary chain radiotherapy should be used carefully and that high quality techniques should be used for decreasing the dose delivered to the heart. This review of the literature presents the state of the art on breast cancer radiotherapy, with special focus on the indications, techniques, and potential toxicity.     

Salivary duct carcinoma: a clinical and histologic review with implications for trastuzumab therapy

BACKGROUND: Salivary duct carcinoma (SDC) is an aggressive tumor of the head and neck with a poor prognosis. The objective was to study SDC and recommend the use of trastuzumab as adjuvant therapy. METHODS: A retrospective chart review of patients seen between 1993 and 2006 was performed. Tumor specimens were examined for HER-2 protein overexpression via immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) methods. RESULTS: Of the 7 patients with SDC, 57% had tumors arising in the parotid gland, the majority having facial nerve paralysis, 71% with nodal disease, and 43% having recurrence. All samples were HER-2 positive on IHC. Three patients had FISH-positive tumors, recurrent disease, and received trastuzumab therapy; 1 of the 3 died after 20 months and a second has shown disappearance of metastatic disease. CONCLUSIONS: Trastuzumab is effective in treating HER-2-positive breast cancer. Given immunohistochemical similarities between SDC and ductal carcinoma of the breast, patients with FISH-positive HER-2/neu SDC should be considered for trastuzumab therapy.     

Herceptin与阿霉素联合应用对大鼠心脏毒性的影响

背景与目的:Herceptin是人源化的单克隆抗体,用于治疗人表皮生长因子受体2(humanepidermalgrowthfactorreceptor,HER-2)阳性的转移性乳腺癌。临床观察发现,Herceptin与阿霉素联合应用增加了乳腺癌患者心功能衰竭的发生率。本研究拟从多角度、多层次深入探讨Herceptin与阿霉素联合应用对大鼠心脏毒性的影响。方法:将36只SD雌性大鼠随机分为4组:对照组、Herceptin组、阿霉素组及Herceptin联合阿霉素组。采用硫代巴比妥酸(thiobarbituricacid,TBA)法测定心肌脂质过氧化产物丙二醛(malondialdehyde,MDA)含量;5,5'-二硫对-二硝基苯甲酸(5,5'-dithiobis-2-nitrobenzoicacid,DTNB)法测定心肌谷胱甘肽过氧化物酶(glutathioneperoxidase,GSH-Px)活性;采用透射电镜及DNA碎片末端缺口标记法(TdT-mediateddUTPnickendlabeling,TUNEL)观察心肌组织损伤程度及细胞凋亡的发生情况,结合流式细胞术定量检测心肌细胞凋亡率。结果:对照组MDA含量(0.70±0.03)nmol/mg,GSH-Px活性是(81.31±0.13)U/mg;Herceptin组MDA含量是(0.73±0.05)nmol/mg,GSH-Px活性是(78.43±0.15)U/mg,与对照组基本相似。阿霉素组和Herceptin联合阿霉素组MDA含量分别是(0.88±0.10)和(0.94±0.13nmol/mg,GSH-Px活性分别是(67.88±0.24)和(63.37±0.28)     

Optical fiber-based in vivo quantification of growth factor receptors

BACKGROUND:

Growth factor receptors such as epidermal growth factor receptor 1 and human epidermal growth receptor 2 (HER2) are overexpressed in certain cancer cells. Antibodies against these receptors (eg. cetuximab and transtuzumab [Herceptin]) have shown therapeutic value in cancer treatment. The existing methods for the quantification of these receptors in tumors involve immunohistochemistry or DNA quantification, both in extracted tissue samples. The goal of the study was to evaluate whether an optical fiber‐based technique can be used to quantify the expression of multiple growth factor receptors simultaneously.

METHODS:

The authors examined HER2 expression using the monoclonal antibody trastuzumab as a targeting ligand to test their system. They conjugated trastuzumab to 2 different Alexa Fluor dyes with different excitation and emission wavelengths. Two of the dye conjugates were subsequently injected intravenously into mice bearing HER2‐expressing subcutaneous tumors. An optical fiber was then inserted into the tumor through a 30‐gauge needle, and using a single laser beam as the excitation source, the fluorescence emitted by the 2 conjugates was identified and quantified by 2‐photon optical fiber fluorescence.

RESULTS:

The 2 conjugates bound to the HER2‐expressing tumor competitively in a receptor‐specific fashion, but they failed to bind to a similar cell tumor that did not express HER2. The concentration of the conjugate present in the tumor as determined by 2‐photon optical fiber fluorescence was shown to serve as an index of the HER2 expression levels.

CONCLUSIONS:

These studies offer a minimally invasive technique for the quantification of tumor receptors simultaneously. Cancer 2012;. © 2011 American Cancer Society.