法国研究人员15日公布的研究报告显示，人们可以用一种分子“诱饵”，模拟脱氧核糖核酸（DNA）受损，进而促使癌细胞自杀。
医生经常用化学疗法和放射性疗法破坏癌细胞，进而引起程序性细胞死亡。然而，一些时候，这些疗法给癌细胞造成的破坏程度不足以激起程序性细胞死亡，而幸存下的癌细胞能自我修复，使治疗过程徒劳无功。
为对付这种情况，法国巴黎居里研究所玛丽·杜特莱斯带领研究人员造出微小的DNA片断，模仿遗传密码双螺旋结构两端受损，使那些顽固的癌细胞认为它们受损严重，进而“自杀”，也就是程序性死亡。
这一研究成果发表在最新一期美国《临床癌症研究》上。研究人员说，一些恶性肿瘤对常规疗法具有抵抗性，这项研究为对付恶性肿瘤开辟了新道路。
在老鼠身上做的实验显示，给老鼠用放射性疗法前使用这种方法，能消灭75%到100%的癌细胞，而只用放射性疗法，仅能摧毁30%到50%的癌细胞。
杜特莱斯说，如果一切进展顺利，研究人员可能于2010年底开始在志愿者身上展开临床实验。（生物谷Bioon.com）
生物谷推荐原始出处：
Clinical Cancer Research, 10.1158/1078-0432.CCR-08-2108
Small-Molecule Drugs Mimicking DNA Damage: A New Strategy for Sensitizing Tumors to Radiotherapy
Maria Quanz 1, 4, 5, Nathalie Berthault 1, 2, Christophe Roulin 4, Maryline Roy 1, 4, 5, Aurélie Herbette 1, 4, 5, Céline Agrario 1, 4, 5, Christophe Alberti 1, 3, Véronique Josserand 6, Jean-Luc Coll 6, Xavier Sastre-Garau 7, Jean-Marc Cosset 8, Lionel Larue 1, 3, Jian-Sheng Sun 5, 9, 10, 11, Marie Dutreix 1, 2, 4*
Authors' Affiliations: 1Institut Curie, Centre de Recherche; Centre National de la Recherche 2UMR2027 and 3UMR146; 4Institut Curie H?pital, Département de transfert, Orsay, France; 5DNA Therapeutics, Genopole, Evry, France; 6Institut National de la Santé et de la Recherche Médicale U578, La Tronche, France; and MD, Institut Curie H?pital, Departments of 7Pathology and 8Radiotherapy; 9Muséum National d'Histoire Naturelle, USM503; 10Institut National de la Santé et de la Recherche Médicale U565; 11Centre National de la Recherche, UMR5153, Paris, France
Purpose: Enhanced DNA repair activity is often associated with tumor resistance to radiotherapy. We hypothesized that inhibiting DNA damage repair would sensitize tumors to radiation-induced DNA damage.
Experimental Design: A novel strategy for inhibiting DNA repair was tested. We designed small DNA molecules that mimic DNA double-strand breaks (called Dbait) and act by disorganizing damage signaling and DNA repair. We analyzed the effects of Dbait in cultured cells and on xenografted tumors growth and performed preliminary studies of their mechanism(s) of action.
Results: The selected Dbait molecules activate H2AX phosphorylation in cell culture and in xenografted tumors. In vitro, this activation correlates with the reduction of Nijmegen breakage syndrome 1 and p53-binding protein 1 repair foci formation after irradiation. Cells are sensitized to irradiation and do not efficiently repair DNA damage. In vivo, Dbait induces regression of radioresistant head and neck squamous cell carcinoma (Hep2) and melanoma (SK28 and LU1205) tumors. The combination of Dbait32Hc treatment and fractionated radiotherapy significantly enhanced the therapeutic effect. Tumor growth control by Dbait molecules depended directly on the dose and was observed with various irradiation protocols. The induction of H2AX phosphorylation in tumors treated with Dbait suggests that it acts in vivo through the induction of "false" DNA damage signaling and repair inhibition.
Conclusions: These data validate the concept of introducing small DNA molecules, which mimic DNA damage, to trigger "false" signaling of DNA damage and impair DNA repair of damaged chromosomes. This new strategy could provide a new method for enhancing radiotherapy efficiency in radioresistant tumors.
