Yacoub Adly, Mitchell Clint, Lister Andrea, Lebedeva Irina V, Sarkar Devanand, Su Zao-Zhong, Sigmon Carter, McKinstry Robert, Ramakrishnan Viswanathan, Qiao Liang, Broaddus William C, Gopalkrishnan Rahul V, Grant Steven, Fisher Paul B, Dent Paul
Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia 23298-0058, USA.
Clin Cancer Res. 2003 Aug 15;9(9):3272-81.
Despite therapeutic interventions including surgery, chemotherapy, and radiotherapy, glioblastoma multiforme (GBM) has a very poor prognosis and novel therapies are required.
Melanoma differentiation-associated 7 (mda-7) (interleukin 24), when expressed via a recombinant replication-defective adenovirus, adenovirus (Ad).mda-7, has profound antiproliferative and cytotoxic effects in a variety of tumor cells but not in nontransformed cells. The present studies examined the combined impact of Ad.mda-7 and ionizing radiation on the proliferation and survival of GBM cell lines.
Ad.mda-7 caused a dose-dependent reduction in the proliferation of glioma cells in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. The antiproliferative effects of Ad.mda-7 were enhanced by radiation in a greater than additive fashion. These effects were not observed in cultures of nontransformed primary astrocytes. Purified MDA-7 protein caused a similar dose-dependent reduction in GBM cell growth that was enhanced after radiation exposure. The enhanced reduction in growth correlated with increased necrosis and DNA degradation. These modifications in cell phenotype correlated with reduced expression of Bcl-(XL) and enhanced expression of BAX. Overexpression of Bcl-(XL) protected cells from the antiproliferative and cytotoxic effects of Ad.mda-7 + radiation. Incubation of cells with N-acetyl cysteine abolished the enhancing effects of radiation. In vitro, Ad.mda-7 and radiation reduced colony formation ability, which was significantly increased when the two treatments were combined. In vivo, Ad.mda-7 enhanced the survival of Fischer 344 rats implanted intracranially with glioma cells. Radiation did not alter survival in control infected animals, whereas it prolonged survival in those infected with Ad.mda-7.
These findings demonstrate that mda-7 reduces the proliferation and enhances the radiosensitivity of GBM cells in vitro and in vivo.
尽管有包括手术、化疗和放疗在内的治疗干预措施，但多形性胶质母细胞瘤（GBM）的预后仍然很差，需要新的治疗方法。
黑色素瘤分化相关因子7（mda-7）（白细胞介素24），当通过重组复制缺陷型腺病毒腺病毒（Ad）.mda-7表达时，在多种肿瘤细胞中具有显著的抗增殖和细胞毒性作用，但在未转化细胞中则无此作用。本研究检测了Ad.mda-7与电离辐射对GBM细胞系增殖和存活的联合影响。
在3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐检测中，Ad.mda-7导致胶质瘤细胞增殖呈剂量依赖性降低。Ad.mda-7的抗增殖作用在辐射作用下以大于相加的方式增强。在未转化的原代星形胶质细胞培养物中未观察到这些效应。纯化的MDA-7蛋白导致GBM细胞生长呈类似的剂量依赖性降低，辐射暴露后这种降低作用增强。生长的增强降低与坏死增加和DNA降解相关。细胞表型的这些改变与Bcl-（XL）表达降低和BAX表达增强相关。Bcl-（XL）的过表达保护细胞免受Ad.mda-7 + 辐射的抗增殖和细胞毒性作用。用N-乙酰半胱氨酸孵育细胞消除了辐射的增强作用。在体外，Ad.mda-7和辐射降低了集落形成能力，当两种处理联合时集落形成能力显著增加。在体内，Ad.mda-7提高了颅内植入胶质瘤细胞的Fischer 344大鼠的存活率。辐射未改变对照感染动物的存活率，而延长了感染Ad.mda-7动物的存活时间。
这些发现表明，mda-7在体外和体内均可降低GBM细胞的增殖并增强其放射敏感性。
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