Therapeutic potential of antisense oligodeoxynucleotides to down-regulate thymidylate synthase in mesothelioma
Therapeutic potential of antisense oligodeoxynucleotides to down-regulate thymidylate synthase in mesothelioma
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DOI：
10.1158/1535-7163.mct-06-0073
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发表时间：
2006-06-01
影响因子：
5.7
通讯作者：
Koropatnick, James
中科院分区：
文献类型：
--
作者：
Flynn, Janet;Berg, Randal W.;Koropatnick, James
恶性间皮瘤是一种侵袭性肿瘤的servellous表面的肺，心脏和腹部。存活率很低，没有有效的治疗方法。然而，最近针对恶性间皮瘤患者的胸苷酸合成酶的治疗方案已经显示出希望。我们报道了一种靶向TS mRNA的反义寡核苷酸（反义TS ODN 83）对人肿瘤细胞生长的抑制作用。为了测试反义靶向TS mRNA治疗恶性间皮瘤的潜力，我们评估并比较了反义TS ODN 83对三种人恶性间皮瘤细胞系（211 H、H2052和H28）和人非恶性间皮瘤细胞（HT29结肠直肠腺癌、HeLa宫颈癌和MCF 7乳腺肿瘤细胞系）的作用。我们报告，ODN 83作为一个单一的代理应用有效地降低恶性间皮瘤细胞系TS mRNA和蛋白。此外，它抑制恶性间皮瘤的生长显着更有效地比它抑制非恶性间皮瘤人肿瘤细胞系的生长：敏感性的差异，没有观察到在响应与TS蛋白靶向药物治疗。在恶性间皮瘤细胞中，反义TS诱导细胞凋亡和增殖减少。在非恶性间皮瘤细胞中，仅观察到增殖减少。因此，反义TS介导的凋亡诱导可能是恶性间皮瘤对TS反义靶向的高敏感性的基础。进一步的临床前和临床研究的TS反义寡核苷酸，单独和联合TS靶向化疗药物，间皮瘤是必要的。
Malignant mesothelioma is an aggressive tumor of the serosal surfaces of the lungs, heart, and abdomen. Survival rates are poor and effective treatments are not available. However, recent therapeutic regimens targeting thymidylate synthase ITS) in malignant mesothelioma patients have shown promise. We have reported the use of an antisense oligodeoxynucleotide targeting TS mRNA (antisense TS ODN 83) to inhibit growth of human tumor cells. To test the potential for antisense targeting of TS mRNA in treatment of malignant mesothelioma, we assessed and compared the effects of antisense TS ODN 83 on three human malignant mesothelioma cell lines (211H, H2052, and H28) and human nonmalignant mesothelioma cells (HT29 colorectal adenocarcinoma, HeLa cervical carcinoma, and MCF7 breast tumor cell lines). We report that ODN 83 applied as a single agent effectively reduced TS mRNA and protein in malignant mesothelioma cell lines. Furthermore, it inhibited malignant mesothelioma growth significantly more effectively than it inhibited growth of nonmalignant mesothelioma human tumor cell lines: a difference in susceptibility was not observed in response to treatment with TS protein-targeting drugs. In malignant mesothelioma cells, antisense TS both induced apoptotic cell death and reduced proliferation. In nonmalignant mesothelioma cells, only reduced proliferation was observed. Thus, antisense TS-mediated induction of apoptosis may be the basis for the high malignant mesothelioma sensitivity to antisense targeting of TS. Further preclinical and clinical study of TS antisense oligodeoxynucleotides, alone and in combination with TS-targeting chemotherapy drugs, in mesothelioma is warranted.