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Cli Cancer Res:治疗乳腺癌脑转移的新策略

  1. 乳腺癌
  2. 转移

来源:生物谷 2013-08-06 21:59

2013年8月7日讯 /生物谷BIOON/--近日,加州大学洛杉矶分校琼森综合癌症中心的研究人员已经在一小鼠模型系统中成功地将结合细胞治疗和基因治疗方法结合起来开展治疗,这为制定针对已经扩散到病人大脑的乳腺癌患者可行的治疗策略带来了新思路。

2013年8月7日讯 /生物谷BIOON/--近日,加州大学洛杉矶分校琼森综合癌症中心的研究人员已经在一小鼠模型系统中成功地将结合细胞治疗和基因治疗方法结合起来开展治疗,这为制定针对已经扩散到病人大脑的乳腺癌患者可行的治疗策略带来了新思路。

神经外科和琼森癌症中心、加州大学洛杉矶分校脑研究所成员Carol Kruse教授领导完成了这项研究,相关论文发表在8月1日的Clinical Cancer Research杂志上。

乳腺癌是妇女癌症最常见的形式,转移是疾病恶化和患者死亡的一个主要原因。脑转移难以治疗的主要原因:循环网络(血脑屏障)阻止许多抗癌药物到达大脑区域。

细胞疗法是一种免疫治疗,使用免疫系统的“卫兵”--T细胞开展治疗,这些T细胞在实验室中已被致敏能杀死乳腺癌细胞。这些致敏的T细胞注入脑中。研究表明,T细胞可以穿过组织,识别和直接杀灭肿瘤细胞。

运用基因治疗,癌细胞被一种叫5-氟胞嘧啶(5-FC)的药物杀死。为了将基因转入进癌细胞,研究人员首先将它插入到一个病毒中,此病毒可以感染肿瘤细胞。在病毒感染细胞后,无毒性的5-FC给予病人。

被病毒感染的肿瘤细胞将无毒的药物转换成毒性形式,杀死癌细胞。加州大学洛杉矶分校医学部教授Noriyuki Kasahara博士在他的实验室开发此基因治疗方法。

虽然这两种方法分别单独运用能在小鼠模型中发挥功效,但当细胞和基因治疗相结合时,却能最大程度地减少脑转移性肿瘤大小。

癌症脑转移的研究显著缺乏联邦资助,即使人类转移性脑肿瘤发生的几率经常比原发性脑肿瘤高10倍以上。这些病人预后极差,因为大脑是一个治疗盲点,在许多情况下化疗药物是无效的。

这两个实验性疗法正在单独进行原发性恶性脑肿瘤的临床试验测试,这带来了一个独特的机会,能迅速将这些技术从实验室转换到诊所中运用,治疗癌症转移。(生物谷:Bioon.com)

Combined Alloreactive CTL Cellular Therapy with Prodrug Activator Gene Therapy in a Model of Breast Cancer Metastatic to the Brain

Michelle J. Hickey, Colin C. Malone1, Kate L. Erickson, Amy Lin, Horacio Soto, Edward T. Ha, Shuichi Kamijima, Akihito Inagaki, Masamichi Takahashi, Yuki Kato, Noriyuki Kasahara, Barbara M. Mueller, and Carol A. Kruse

Purpose: Individual or combined strategies of cellular therapy with alloreactive CTLs (alloCTL) and gene therapy using retroviral replicating vectors (RRV) encoding a suicide prodrug activating gene were explored for the treatment of breast tumors metastatic to the brain.

Experimental Design: AlloCTL, sensitized to the HLA of MDA-MB-231 breast cancer cells, were examined in vitro for antitumor functionality toward breast cancer targets. RRV encoding the yeast cytosine deaminase (CD) gene was tested in vivo for virus spread, ability to infect, and kill breast cancer targets when exposed to 5-fluorocytosine (5-FC). Individual and combination treatments were tested in subcutaneous and intracranial xenograft models with 231BR, a brain tropic variant.

Results: AlloCTL preparations were cytotoxic, proliferated, and produced IFN-γ when coincubated with target cells displaying relevant HLA. In vivo, intratumorally placed alloCTL trafficked through one established intracranial 231BR focus to another in contralateral brain and induced tumor cell apoptosis. RRV-CD efficiently spread in vivo, infected 231BR and induced their apoptosis upon 5-FC exposure. Subcutaneous tumor volumes were significantly reduced in alloCTL and/or gene therapy–treated groups compared to control groups. Mice with established intracranial 231BR tumors treated with combined alloCTL and RRV-CD had a median survival of 97.5 days compared with single modalities (50–83 days); all experimental treatment groups survived significantly longer than sham-treated groups (median survivals 31.5 or 40 days) and exhibited good safety/toxicity profiles.

Conclusion: The results indicate combining cellular and suicide gene therapies is a viable strategy for the treatment of established breast tumors in the brain.

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