Telomere homolog oligonucleotides induce apoptosis in malignant but not in normal lymphoid cells: mechanism and therapeutic potential.
Telomere homolog oligonucleotides induce apoptosis in malignant but not in normal lymphoid cells: mechanism and therapeutic potential.
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DOI：
10.1002/ijc.23946
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发表时间：
2009-01-15
影响因子：
6.4
通讯作者：
Denis, Gerald V.
中科院分区：
文献类型：
--
作者：
Longe, Harold O.;Romesser, Paul B.;Rankin, Andrew M.;Faller, Douglas V.;Eller, Mark S.;Gilchrest, Barbara A.;Denis, Gerald V.
使用与端粒同源的DNA寡核苷酸（TTAGGG重复序列；“T-oligo”）单独或与标准的、广泛使用的抗癌化疗药物联合治疗人类B细胞或t细胞淋巴瘤系和原发性小鼠淋巴瘤。T-oligo诱导培养的人或小鼠B或t淋巴瘤细胞系和原代肿瘤细胞的细胞周期阻滞和凋亡，但对正常的人或小鼠原代淋巴细胞没有可检测到的毒性。假设暴露于t寡核苷酸可以模拟暴露于3 '端粒重复序列，激活共济失调毛细血管扩张突变激酶，使下游效应物如p53磷酸化，但影响并不仅仅依赖于功能性p53。T-oligo引起早期s期阻滞，并与G2或m期特异性抗癌药物配合良好；当以常规剂量的1/10联合使用时，长春新碱和t -寡核苷酸对人或小鼠淋巴瘤细胞的杀伤作用大于添加剂（6小时后78%的细胞发生凋亡，对照组细胞为5%）。在小鼠中，环磷酰胺、阿霉素、长春新碱和强的松标准组合的常规剂量的1/10与低剂量T-oligo联合使用时，效果是常规剂量的两倍。因此，T-oligo使肿瘤对传统的抗癌药物敏感，并代表了侵袭性淋巴瘤治疗武器库的潜在重要新补充。
Human B- or T-cell lymphoma lines and primary murine lymphomas were treated with DNA oligonucleotides homologous to the telomere (TTAGGG repeat; “T-oligo”), either alone or in combination with standard, widely-used anticancer chemotherapeutic agents. T-oligo induces cell cycle arrest and apoptosis in cultured human or murine B or T-lymphoma cell lines and primary tumor cells, but exerts no detectable toxicity on normal human or murine primary lymphocytes. Exposure to T-oligo is hypothesized to mimic exposure of the 3′ telomere repeat sequence, activating the ataxia telangiectasia mutated kinase, which phosphorylates downstream effectors such as p53, but effects are not dependent solely on functional p53. T-oligo causes early S-phase arrest and cooperates well with G2- or M-phase-specific anticancer agents; when combined at 1/10th of the conventional dose, vincristine and T-oligo produce greater-than-additive killing of human or murine lymphoma cells (78% of cells undergoing apoptosis after 6 hr vs. 5% of control cells). In mice, 1/10th of the conventional dose of a standard combination of cyclophosphamide, adriamycin, vincristine and prednisone is twice as effective when used in combination with low dose T-oligo. Thus, T-oligo sensitizes tumors to traditional anticancer agents and represents a potentially important new addition to the therapeutic arsenal for aggressive lymphomas.
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影响因子：
10.5
作者：
Siliciano, JD;Canman, CE;Kastan, MB
通讯作者：
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11.5
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DOI：
10.1073/pnas.92.20.9363
发表时间：
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11.1
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7.4
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20.3
作者：
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