Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Rikshospitalet University Hospital, and Faculty Division The Norwegian Radium Hospital, University in Oslo, Oslo, Norway.
Clin Cancer Res. 2009 Dec 1;15(23):7161-9. doi: 10.1158/1078-0432.CCR-08-2816. Epub 2009 Nov 17.
In osteosarcoma, aggressive preoperative and postoperative multidrug chemotherapy given to all patients has improved patient survival rate to the present level of approximately 60%. However, no tumor marker is available that reliably can identify those patients who will or will not respond to chemotherapy.
In an attempt to find leads to such markers, we have obtained microarray gene expression profiles from a panel of 10 different human osteosarcoma xenografts and related the results to their sensitivity to ifosfamide, doxorubicin, and cisplatin.
The expression data identified genes with highly significant differential expression between poor and good responder xenografts to the three different drugs: 85 genes for doxorubicin, 74 genes for cisplatin, and 118 genes for ifosfamide. Technical validation with quantitative reverse transcription-PCR showed good correlation with the microarray expression data. Gene Ontology-guided analysis suggested that properties of the poorly responsive xenografts were resistance to undergo programmed cell death and, particularly for ifosfamide, a drive toward dedifferentiation and increased tumor aggressiveness. Leads toward metabolic alterations and involvement of mitochondrial pathways for apoptosis and stress response were more prominent for doxorubicin and cisplatin. Finally, small interfering RNA-mediated gene silencing of IER3 and S100A2 sensitized the human osteosarcoma cell line OHS to treatment with 4-hydroperoxyifosfamide.
The expression profiles contained several novel biomarker candidates that may help predict the responsiveness of osteosarcoma to doxorubicin, cisplatin, and ifosfamide. The potential of selected candidates will be further validated on clinical specimens from osteosarcoma patients.
在骨肉瘤中，对所有患者进行积极的术前和术后多药化疗，已将患者的生存率提高到目前的约 60%。然而，目前还没有可靠的肿瘤标志物能够识别出那些对化疗有反应或无反应的患者。
为了寻找这些标志物的线索，我们从一组 10 种不同的人骨肉瘤异种移植瘤中获得了微阵列基因表达谱，并将结果与其对异环磷酰胺、阿霉素和顺铂的敏感性相关联。
表达数据确定了在三种不同药物中对不良和良好反应的异种移植瘤具有高度差异表达的基因：阿霉素 85 个基因、顺铂 74 个基因、异环磷酰胺 118 个基因。用定量逆转录-PCR 进行的技术验证显示与微阵列表达数据具有良好的相关性。基于基因本体论的分析表明，不良反应的异种移植瘤具有抵抗程序性细胞死亡的特性，特别是对于异环磷酰胺，其向去分化和增加肿瘤侵袭性的趋势更为明显。阿霉素和顺铂更突出的是代谢改变和涉及凋亡和应激反应的线粒体途径的参与。最后，IER3 和 S100A2 的小干扰 RNA 介导的基因沉默使骨肉瘤细胞系 OHS 对 4-羟基异环磷酰胺的治疗更为敏感。
表达谱中包含了几个可能有助于预测骨肉瘤对阿霉素、顺铂和异环磷酰胺反应的新型生物标志物候选物。将进一步在骨肉瘤患者的临床标本上验证选定候选物的潜力。
