mda-7 gene transfer sensitizes breast carcinoma cells to chemotherapy, biologic therapies and radiotherapy:: correlation with expression of bcl-2 family members
mda-7 gene transfer sensitizes breast carcinoma cells to chemotherapy, biologic therapies and radiotherapy:: correlation with expression of bcl-2 family members
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DOI：
10.1038/sj.cgt.7700915
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发表时间：
2006-05-01
影响因子：
6.4
通讯作者：
Hunt, KK
中科院分区：
文献类型：
--
作者：
Chada, S;Mhashilkar, AM;Hunt, KK
目前用于治疗乳腺癌的疗法受到全身毒性、快速药物代谢以及内在和获得性耐药性的限制。我们先前已经证明，腺病毒介导的黑色素瘤分化相关基因7（mda-7）的转移可促进各种肿瘤类型的生长抑制和凋亡。在这里，我们评估的影响，单独和与其他疗法相结合，对面板的9个乳腺癌细胞系和他们的正常同行，我们报告选择性的Ad-mda 7介导的p53非依赖性生长抑制，G2/M期细胞周期阻滞，和凋亡。在体内，Ad-mda 7在多种异种移植模型中诱导p53非依赖性肿瘤生长抑制（P < 0.004）。然后，我们评估了Ad-mda 7与通常用于治疗乳腺癌的药物的组合：放疗（XRT），他莫昔芬，泰索帝，阿霉素和赫赛汀。这些药物表现出不同的作用模式，包括形成大体积加合物、抑制DNA复制（阿霉素，XRT）、损伤微管（泰索帝）、非甾体雌激素拮抗剂（他莫昔芬）或Her 2/neu受体阻断剂（赫赛汀）。用常规抗癌药物或放射治疗后，表达MDA-7的细胞显示出与BCL-2表达降低和BAX上调相关的附加或协同细胞毒性和细胞凋亡。在体内，接受Ad-mda 7和XRT的动物经历了肿瘤生长的显著减少（P < 0.002）。这是首次报道Ad-mda 7联合化疗或放疗对人乳腺癌细胞的协同作用。
Current therapies used in the treatment of breast cancer are limited by systemic toxicity, rapid drug metabolism and intrinsic and acquired drug resistance. We have previously shown that adenoviral-mediated transfer of the melanoma differentiation-associated gene-7 (mda-7) elicits growth inhibition and apoptosis in various tumor types. Here, we evaluate the effects of Ad-mda7, alone and in combination with other therapies, against a panel of nine breast tumor cell lines and their normal counterparts; we report selective Ad-mda7-mediated p53-independent growth inhibition, G2/M cell cycle arrest, and apoptosis. In vivo, Ad-mda7 induced p53-independent tumor growth inhibition (P < 0.004) in multiple xenograft models. We then evaluated the combination of Ad-mda7 with agents commonly used to treat breast cancer: radiotherapy (XRT), Tamoxifen, Taxotere, Adriamycin, and Herceptin. These agents exhibit diverse modes of action, including formation of bulky adducts, inhibition of DNA replication (Adriamycin, XRT), damage to microtubules (Taxotere), nonsteroidal estrogen antagonists (Tamoxifen), or Her2/neu receptor blockade (Herceptin). Treated with conventional anticancer drugs or radiation, MDA-7-expressing cells display additive or synergistic cytotoxicity and apoptosis that correlates with decreased BCL-2 expression and BAX upregulation. In vivo, animals that received Ad-mda7 and XRT underwent significant reduction of tumor growth (P < 0.002). This is the first report of the synergistic effects of Ad-mda7 combined with chemotherapy or radiotherapy on human breast carcinoma cells.