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首页> 外文期刊>Photodiagnosis and Photodynamic Therapy >Impact of genotypic and phenotypic differences in sarcoma models on the outcome of photochemical internalization (PCI) of bleomycin
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Impact of genotypic and phenotypic differences in sarcoma models on the outcome of photochemical internalization (PCI) of bleomycin

机译：肉瘤模型中基因型和表型差异对博来霉素光化学内在化（PCI）结果的影响

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摘要

The low curative response to current treatment regimens for most soft tissue sarcomas indicates a strong need for alternative treatment strategies and predictive markers for treatment outcome. PCI (photochemical internalization) is a novel treatment strategy to translocate drugs into cytosol that otherwise would have been degraded in lysosomes. Two highly geno-and phenotypically different uterine and vulvar leiomyosarcoma cell lines, MES-SA and SK-LMS-1, were treated with bleomycin (BLM) activated by PCI (PCIBLM). The MES-SA cells were much more sensitive to PCIBLM than the SK-LMS-1 cells and the treatment induced a 7-8 fold higher increase in DNA double-strand breaks at the same dose of light as measure by gamma H2AX staining. A 3-fold higher induction of apoptosis and stronger activation of Bax and p21 was also measured in the P53WT MES-SA cells, compared to the P53mut SK-LMS-1 cells. The basal formation of reactive oxygen species (ROS) was 3-fold higher in SK-LMS-1 cells than in the MES-SA cells and SK-LMS-1 cells expressed glutathione peroxidase 1 (GPx1) and more superoxide dismutase 2 (SOD2) than the MES-SA cells. Glutathione depletion with the glutathione synthetase inhibitor buthionine sulfoximine increased the cytotoxic effect of the photochemical treatment (PDT) most strongly in the SK-LMS-1 cells, and reduced PCIBLM-induced H2AX activation in the MES-SA cells, but not in the SK-LMS-1 cells. The results indicate PCIBLM as a potential novel treatment strategy for soft tissue sarcomas, with antioxidant enzymes, in particular GPx1, and the P53 status as potential predictive markers for response to PCIBLM.
机译：大多数软组织肉瘤对当前治疗方案的治愈率低，这表明强烈需要替代治疗策略和治疗结果的预测指标。 PCI（光化学内在化）是一种新颖的治疗策略，可以将药物转移到胞质溶胶中，否则在溶酶体中会被降解。用PCI（PCIBLM）激活的博来霉素（BLM）处理了两种基因和表型不同的子宫平滑肌肉瘤和外阴平滑肌肉瘤细胞系MES-SA和SK-LMS-1。 MES-SA细胞对PCIBLM的敏感性要比SK-LMS-1细胞高得多，并且在相同剂量的光照射下，该处理诱导的DNA双链断裂增加了7-8倍。与P53mut SK-LMS-1细胞相比，在P53WT MES-SA细胞中还检测到3倍更高的凋亡诱导诱导力以及Bax和p21的更强活化。 SK-LMS-1细胞中活性氧（ROS）的基础形成比MES-SA细胞高3倍，SK-LMS-1细胞表达谷胱甘肽过氧化物酶1（GPx1）和更多的超氧化物歧化酶2（SOD2） ），而不是MES-SA单元。谷胱甘肽合成酶抑制剂丁硫氨酸磺胺嘧啶对谷胱甘肽的消耗最强烈地增加了光化学处理（PDT）在SK-LMS-1细胞中的细胞毒性作用，并降低了MES-SA细胞中PCIBLM诱导的H2AX活化，但在SK中却没有-LMS-1细胞。结果表明，PCIBLM是一种具有抗氧化酶（特别是GPx1）的软组织肉瘤的潜在新治疗策略，而P53的状态是对PCIBLM响应的潜在预测标志。

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