Hermann Robert Michael, Fest Jan, Christiansen Hans, Hille Andrea, Rave-Fränk Margret, Nitsche Mirko, Gründker Carsten, Viereck Volker, Jarry Hubertus, Schmidberger Heinz
Department of Radiotherapy and Radiooncology, Georg August University, Göttingen, Germany.
Strahlenther Onkol. 2007 Apr;183(4):195-202. doi: 10.1007/s00066-007-1561-0.
Simultaneous radiotherapy with chemotherapy is a standard treatment for inoperable non-small cell lung cancer (NSCLC), but the clinical outcome still remains poor. To further intensify treatment, substances need to be identified, which increase the effect of radiation on tumor cells without further enhancing toxicity to normal tissue. Hormones have a different toxicity profile than radiation or cytostatic drugs. As NSCLC often express estrogen receptors (ERs), the combination of genistein or estradiol and radiation in vitro was investigated.
A549 NSCLC cells with an inducible expression of a mutated TP53 and fibroblasts of a male donor (DF-18) were examined. ER expression was immunocytologically confirmed in all studied cell lines. Clonogenic survival was measured after incubation of the cells with genistein or estradiol (0.01 microM and 10 microM as maximum clinically applicable dose) and irradiation with different doses (0-4 Gy). The differentiation state of fibroblasts after combined therapy was analyzed.
A549 cells expressing mutated TP53 were more radioresistant than TP53 wild-type cells. Incubation of nonfunctional TP53 cells with genistein or estradiol increased radiosensitivity in both tested concentrations. By contrast, radiosensitivity of A549 with wild-type TP53 and DF-18 was not altered by hormonal incubation. In DF-18 radiation induced growth arrest that was not increased by additional hormonal incubation.
NSCLC cells with nonfunctional TP53 might be sensitized against radiation by genistein or estradiol. As genistein is better tolerable than estradiol in patients, additional studies are warranted to assess potential gains of this combination therapy.
同步放化疗是不可切除非小细胞肺癌（NSCLC）的标准治疗方法，但临床疗效仍较差。为进一步强化治疗，需要鉴定出能增强辐射对肿瘤细胞的作用而又不进一步增加对正常组织毒性的物质。激素具有与辐射或细胞毒性药物不同的毒性特征。由于NSCLC常表达雌激素受体（ERs），因此研究了染料木黄酮或雌二醇与辐射在体外的联合作用。
检测了可诱导表达突变型TP53的A549 NSCLC细胞和男性供体的成纤维细胞（DF-18）。通过免疫细胞化学方法在所有研究的细胞系中证实了ER的表达。在用染料木黄酮或雌二醇（0.01微摩尔和10微摩尔作为最大临床适用剂量）孵育细胞并给予不同剂量（0 - 4 Gy）的辐射后，测量克隆形成存活率。分析联合治疗后成纤维细胞的分化状态。
表达突变型TP53的A549细胞比TP53野生型细胞对辐射更具抗性。用染料木黄酮或雌二醇孵育无功能TP53细胞，在两种测试浓度下均增加了放射敏感性。相比之下，野生型TP53的A549细胞和DF-18细胞的放射敏感性未因激素孵育而改变。在DF-18细胞中，辐射诱导生长停滞，额外进行激素孵育并未使其增加。
具有无功能TP53的NSCLC细胞可能对染料木黄酮或雌二醇的辐射敏感。由于染料木黄酮在患者中的耐受性优于雌二醇，因此有必要进行更多研究以评估这种联合治疗的潜在获益。
