Tai Isabella T, Dai Meiru, Owen David A, Chen Lan Bo
Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada.
J Clin Invest. 2005 Jun;115(6):1492-502. doi: 10.1172/JCI23002. Epub 2005 May 12.
Overcoming resistance to chemotherapy and radiation therapy has been a difficult but important goal in the effort to cure cancer. We used gene-expression microarrays to identify differentially expressed genes involved in colorectal cancer resistance to chemotherapy and identified secreted protein, acidic and rich in cysteine (osteonectin) (SPARC) as a putative resistance-reversal gene by demonstrating low SPARC expression in refractory human MIP101 colon cancer cells. We were able to achieve restoration of their radiosensitivity and sensitivity to 5-fluorouracil and irinotecan by reexpression of SPARC in tumor xenografts. Moreover, treatment of mice with SPARC conferred increased sensitivity to chemotherapy and led to significant regression of xenografted tumors. The results show that modulation of SPARC expression affects colorectal cancer sensitivity to radiation and chemotherapy. SPARC-based gene or protein therapy may ameliorate the emergence of resistant clones and eradicate existing refractory clones and offers a novel approach to treating cancer.
克服对化疗和放疗的耐药性一直是癌症治疗中一个艰巨但重要的目标。我们使用基因表达微阵列来鉴定参与结直肠癌化疗耐药的差异表达基因，并通过证明难治性人MIP101结肠癌细胞中SPARC（富含半胱氨酸的酸性分泌蛋白，即骨连接蛋白）表达低，将其鉴定为一个假定的耐药逆转基因。通过在肿瘤异种移植中重新表达SPARC，我们能够恢复它们对放疗的敏感性以及对5-氟尿嘧啶和伊立替康的敏感性。此外，用SPARC治疗小鼠可提高对化疗的敏感性，并导致异种移植肿瘤显著消退。结果表明，SPARC表达的调节影响结直肠癌对放疗和化疗的敏感性。基于SPARC的基因或蛋白质疗法可能改善耐药克隆的出现并根除现有的难治性克隆，为癌症治疗提供了一种新方法。
