Differential effect of soy isoflavones in enhancing high intensity radiotherapy and protecting lung tissue in a pre-clinical model of lung carcinoma

Background

Radiotherapy of locally-advanced non-small cell lung cancer is limited by radiation-induced pneumonitis and fibrosis. We have further investigated the role of soy isoflavones to improve the effect of a high intensity radiation and reduce lung damage in a pre-clinical lung tumor model.

Methods

Human A549 NSCLC cells were injected i.v. in nude mice to generate a large tumor burden in the lungs. Mice were treated with lung irradiation at 10 Gy and with oral soy. The therapy effect on the tumor cells and surrounding lung tissue was analyzed on lung sections stained with H&E, Ki-67 and Masson’s Trichrome. Pneumonitis and vascular damage were evaluated by measurements of alveolar septa and immunofluorescent staining of vessel walls.

Results

Combined soy and radiation caused a significantly stronger inhibition of tumor progression compared to each modality alone in contrast to large invasive tumor nodules seen in control mice. At the same time, soy reduced radiation injury in lung tissue by decreasing pneumonitis, fibrosis and protecting alveolar septa, bronchioles and vessels.

Conclusions

These studies demonstrate a differential effect of soy isoflavones on augmenting tumor destruction induced by radiation while radioprotecting the normal lung tissue and support using soy to alleviate radiotoxicity in lung cancer.     

Soy isoflavones and cancer prevention

Epidemiological studies have shown a significant difference in cancer incidence among different ethnic groups, which is believed to be partly attributed to dietary habits. The incidences of breast and prostate cancers are much higher in the United States and European countries compared with Asian countries such as Japan and China. One of the major differences in diet between these populations is that the Japanese and the Chinese consume a traditional diet high in soy products. Soy isoflavones have been identified as dietary components having an important role in reducing the incidence of breast and prostate cancers. Genistein, the predominant isoflavones found in soy, has been shown to inhibit the carcinogenesis in animal models. There are growing body of experimental evidence that show the inhibition of human cancer cells by genistein through the modulation of genes that are related to the control of cell cycle and apoptosis. Moreover, it has been shown that genistein inhibits the activation of NF-κB and Akt signaling pathways, both of which are known to maintain a homeostatic balance between cell survival and apoptosis. Genistein is commonly known as phytoestrogen, which targets estrogen- and androgen-mediated signaling pathways in the processes of carcinogenesis. Furthermore, genistein has been found to have antioxidant property, and shown to be a potent inhibitor of angiogenesis and metastasis. Taken together, both in vivo and in vitro studies have clearly shown that genistein, one of the major soy isoflavones, is a promising reagent for cancer chemoprevention and/or treatment. In this article, we attempt to provide evidence for these effects of genistein in a succinct manner to provide comprehensive state-of-the-art knowledge of the biological and molecular effects of the isoflavone genistein in cancer cells.     

大豆异黄酮摄入与乳腺癌发生风险的Meta分析

目的探讨大豆异黄酮摄入与乳腺癌发生风险的关系。方法应用Meta分析的方法,对近10年来国内外发表的关于大豆异黄酮摄入与乳腺癌发生风险的病例对照研究资料,以乳腺癌组与对照组大豆异黄酮摄入的优势比（OR）为效应指标,经一致性检验后进行OR合并,并进行偏倚评估。结果符合人选标准的病例对照研究一共有13项,病例数6328,对照数8987。以进食大豆异黄酮的量分为常食组与偶食组,经Meta分析后,合并后OR为0．79,经常食用大豆异黄酮人群乳腺癌发生风险低于不食或偶食者（Z=2．65,p=0．008）。结论大豆异黄酮摄入是乳腺癌发生的保护性因素,常进食者乳腺癌发生风险降低。     

Soy isoflavones enhance radiotherapy in a metastatic prostate cancer model

We previously reported that genistein, the bioactive isoflavone of soybeans, acts as a radiosensitizer for prostate cancer. Pretreatment of tumor cells with genistein potentiated radiation-induced killing in vitro and in orthotopic models in vivo. However, pure genistein promoted increased lymph node metastasis, when administered alone in vivo. We investigated in vitro and in vivo the effects of soy isoflavones (genistein, daidzein and glycitein) as soy pills of similar composition are used in human interventions but not pure genistein. Soy isoflavones inhibited cell survival and potentiated radiation cell killing in PC-3 tumor cells, in vitro. Increased cell killing correlated with inhibition of antiapoptotic molecules Bcl-xL and survivin, upregulation of proapoptotic Bax molecule and PARP cleavage, suggesting activation of apoptotic pathways. In vivo, using the PC-3 orthotopic metastatic mouse model, soy isoflavones and prostate tumor irradiation led to enhanced control of primary tumor growth and metastasis, as observed with pure genistein and radiation. Interestingly, treatment with soy isoflavones did not increase metastasis to para-aortic lymph nodes in contrast to the consistent increase caused by pure genistein. Histologically prostate tumors, treated with soy isoflavones and radiation, showed tumor destruction and in situ tissue alterations, comparable with genistein and radiation effects. However, genistein, but not soy isoflavones, caused induction of HIF1-alpha in prostate tumors, suggesting that induction of hypoxia by pure genistein could contribute to increased metastasis. Our studies demonstrate the safety and potential role of soy isoflavones for enhancing the therapeutic effect of radiotherapy in prostate cancer.     

Study on soy isoflavone consumption and risk of breast cancer and survival

Aim: Isoflavones in soy foods are part of a larger class of flayonoid compounds that have have been demonstrated to be potent dietary anti-cancer agents, and the effect of soy intake on the survival of ovarian cancer is conflicting. Therefore, we aimed to explore the whether soy intake is related to the risk of death of breast cancer. Methods: A prospective study was conducted. A total of 256 patients included in this study had breast cancer and were recruited between January 2004 and January 2006. All of them were followed up from since January 2011. A univariate Cox’s regression analysis was used to assess the association between soy intake and survival. Results: The education level, menopausal status, ER/PR status and TNM stage were significant difference in the survival of breast cancer. The highest soy isoflavone was associated with a decreased death risk of breast cancer (OR=0.25, 95% CI=0.09-0.54). Moreover, the higher consumption of soy protein also presented a trend decreased breast cancer risk, and the highest consumption significantly reduced the cancer risk compared with the lowest consumption (OR=0.38, 95% CI=0.17-0.86). Conclusion: The present study suggests soy intake is associated with a significant reduced death risk of breast cancer in Chinese population. Further large sample studies are warranted to confirm the inverse association of soy consumption and breast cancer survival by menopausal status.     

肺灌注显像检查预测肺癌放射性肺损伤的价值

目的探讨肺癌患者肺灌注显像的特点及其放射治疗过程中的变化,观察其与放射性肺损伤发生的关系。方法31例接受根治性放疗的肺癌患者接受了肺灌注显像检查,其中8例仅在放疗前接受了此项检查。以照射前后计算区域的肺灌注平均计数值占相应全肺平均计数值的百分比,比较照射前后肺灌注的变化。放射性肺损伤的评价按美国肿瘤放射治疗组（RTOG）急性放射性肺炎标准评定。结果31例患者中,中央型22例,周围型9例。病理类型：鳞癌12例,腺癌1例,小细胞肺癌15例,未分型3例。Ⅰ、Ⅱ期8例,Ⅲa期9例,Ⅲb期14例。行适形放疗26例,常规放疗5例;照射剂量32—72Gy,中位剂量58Gy。6例发生2级或3级放射性肺炎,无放射性肺炎死亡病例。全部患者治疗前均有不同程度的灌注受损,中央型肺癌患者灌注受损范围≥2级者占68．2％（15／99）,而周围型仅占22．2％（2／9,P=0．04）。受损范围为1级和2级以上者,分别有40．0％（6／15）和37．5％（6／16）的患者发生2级以上放射性肺损伤。在两次行肺灌注检查的23例中,肺灌注受损有所改善者占70．0％（16／23）,其中2级以上放射性肺炎发生率为31．3％（5／16）;在肺灌注受损加重者中,2级以上放射性肺炎发生率为42．9％（3／7）。结论灌注受损是肺癌患者的常见表现,中央型肺癌灌注受损较重,放射治疗后多数病例肺灌注受损有所改善;放疗前和放疗中,肺灌注受损范围的变化和放射性肺损伤的发生无明显相关性。     

肺癌与食管癌螺旋断层放疗致放射性肺炎的临床观察

目的 探讨螺旋断层放疗（HT）治疗肺癌与食管癌致放射性肺炎的发生情况及与双肺剂量体积（DVH）和临床病理特征的关系。方法 回顾性分析HT 治疗的19例肺癌和14食管癌患者的临床资料。全组患者中13例仅行HT治疗,20例联合化疗。放疗剂量：小细胞肺癌54～61.8Gy／27～28次,非小细胞肺癌54～66Gy／25～31次,食管癌60～66Gy／28～30次。结果 全组33例患者中,发生0级放射性肺炎8例（24.2％）,1级15例（45.4％）,2级1例（3.0％）,3级5例（15.2％）,5级4例（12.1％）。DVH参数分析显示,发生≥2级放射性肺炎与V30～V45有关,与V5～V25、双肺平均剂量（MLD）、计划靶区（PTV）无关。临床病理特征中,发生≥2级放射性肺炎与ECOG评分有关,与病种、性别、年龄、吸烟、慢性阻塞性肺病和化疗情况无关。结论 HT治疗肺癌与食管癌未明显增加放射性肺炎的发生率,一般状态差、分期晚的患者应严格限制DVH。     

Once-a-week irradiation for locally advanced lung cancer

Twenty-eight patients with very advanced lung cancer were treated with 500 rad once weekly to a total dose of 6000 rad (2050 ret). Twenty-one of the 28 patients (75%) achieved at least a partial local response. There were 9 patients (32%) who achieved a complete response and 12 patients (43%) who achieved a partial response. The responses were 9/11 for squamous cell carcinoma, 5/10 for adenocarcinoma, 5/5 for large cell carcinoma, and 2/2 for small cell carcinoma patients. Treatment was very well tolerated and in fact, no acute radiation related complications were observed during the 10-12 week treatment duration. Radiation induced fibrosis of various degrees has occurred but it has been mostly asymptomatic and similar to what is normally seen using conventional continuous schedules. In this group of very advanced lung cancer patients, failures have mostly resulted from metastatic progression; only one patient progressed locally in the irradiated field without evidence of metastatic disease. A preliminary analysis indicates that this treatment yields results that are similar to those achieved with conventional fractionation regimens and should be explored further.     

男性肺癌血中内分泌激素的测定

 从1991年10月-1993年6月对45岁以上男性，44例正常人和87例肺癌患者血中8种内分泌激素进行测定，肺癌病人治疗前Cort、β-HC、Gluc和PRL明显高于正常人群。87例肺癌治疗前按不同病理比较，腺癌β-HCG明显高于其它病理类型，鳞癌PRL高于其它，小细胞未分化Gast高于其它。43例肺癌治疗后，TSH、PRL、Cort和Glue都明显降低，而GH则升高，11例治疗后肿瘤复又增大或远处转移的肺癌患者，再次测定激素水平表明，PRL、Cort和Glue复又升高。这些结果说明部分内分泌激素，可用于男性肺癌的早期诊断或鉴别诊断，有些激素可作为肺癌病理分类的参考。     

Dose-volume histogram analysis as predictor of radiation pneumonitis in primary lung cancer patients treated with radiotherapy

PURPOSE: To determine the relationship between various parameters derived from lung dose-volume histogram analysis and the risk of symptomatic radiation pneumonitis (RP) in patients undergoing radical radiotherapy for primary lung cancer. METHODS AND MATERIALS: The records of 156 patients with lung cancer who had been treated with radical radiotherapy (>/=45 Gy) and for whom dose-volume histogram data were available were reviewed. The incidence of symptomatic RP was correlated with a variety of parameters derived from the dose-volume histogram data, including the volume of lung receiving 10 Gy (V(10)) through 50 Gy (V(50)) and the mean lung dose (MLD). RESULTS: The rate of RP at 6 months was 15% (95% confidence interval 9-22%). On univariate analysis, only V(30) (p = 0.036) and MLD (p = 0.043) were statistically significantly related to RP. V(30) correlated highly positively with MLD (r = 0.96, p < 0.001). CONCLUSION: V(30) and MLD can be used to predict the risk of RP in lung cancer patients undergoing radical radiotherapy.     

Reassessment of radiation therapy for the management of lung cancer in patients with chronic pulmonary disease

Surgery has remained the mainstay of definitive treatment for lung cancer. Radiation therapy has been advocated when the location of the lung cancer precludes resection or the severity or the cardiopulmonary impairment indicates that the patient cannot withstand the proposed resection. Extended field irradiation has been shown to improve tumor control and survival. However, in patients with chronic pulmonary disease, extended field irradiation may exacerbate pulmonary insufficiency and compromise survival. Between 1975 and 1980, 29 patients with lung cancer and chronic pulmonary disease were treated by involved field irradiation (IFR). This was compared to the experience of 41 patients who had been treated prior to 1975 by extended field irradiation (EFR). The frequency of subjective response and tumor control were comparable in each group. One patient treated by IFR developed a marginal recurrence. Radiation pneumonitis was observed in $\text{7}\text{14}$ (17%) EFR patients versus $\text{2}\text{29}$ (7%) IFR. Treatment related death occurred in $\text{2}\text{41}$ (5%) EFR versus $\text{1}\text{29}$ (3.3%) [FR. One year disease free survival was $\text{8}\text{41}$ (19%) EFR values $\text{12}\text{29}$ (41 % ) IFR. Two of 14 (14 %) [FR patients at risk five years are alive without evidence of disease.     

肺癌放化疗中放射性肺损伤的临床预测因素

放射性肺损伤是肺癌放化疗综合治疗中常见并发症，放化疗因素、临床因素在肺损伤中预测作用如何未有统一意见，剂量参数是目前唯一肯定的预测因子。     

肺癌放化疗中放射性肺损伤的临床预测因素

放射性肺损伤是肺癌放化疗综合治疗中常见并发症,放化疗因素、临床因素在肺损伤中预测作用如何未有统一意见,剂量参数是目前唯一肯定的预测因子。     

Results of A trial with topotecan dose escalation and concurrent thoracic radiation therapy for locally advanced, inoperable nonsmall cell lung cancer

: To conduct a dose escalation clinical study with topotecan and concurrent standard dose thoracic irradiation to assess its feasibility and toxicity in the treatment of patients with locally advanced, inoperable nonsmall cell lung cancer (NSCLCA).

: Between April 1993 and August 1994, 12 patients with inoperable, loco-regionally advanced NSCLCA were entered in a prospective dose escalation trial and assigned to receive concurrent thoracic radiotherapy and topotecan. Patients received thoracic irradiation to a total tumor dose of 60 Gy in 30 fractions. Initial fields were to encompass the gross disease plus the mediastinum. Topotecan was delivered by bolus injection days 1 through 5, and days 22 through 26, beginning on the same day as the radiation therapy. The initial dose level was 0.5 mg/m². Two additional dose levels of 0.75 mg/m² and 1.0 mg/m² were tested.

: Six patients were accessioned to the 0.5 mg/m² dose level, three patients to the 0.75 mg/m² dose level, and three patients to the 1.0 mg/m² dose level. At the 0.5 mg/m² dose level, zero of six patients had ≥Grade 4 hematologic toxicity. One of the six had Grade 3 esophagitis. At the 0.75 mg/m² dose level, two of three patients had ≥Grade 3 nonhematologic toxicity including anorexia, fatigue, nausea, vomiting, and weakness; zero patients experienced ≥Grade 4 hematologic toxicity. At the 1.0 mg/m² dose level one of three patients had ≥Grade 3 esophagitis, and two of three patients experienced Grade 4 neutropenia. With a follow-up of 12 to 24 months, two patients are alive and free of disease, three patients are alive with disease (two with distant metastasis, one with local disease and distant metastasis), and the remaining seven patients are dead of disease.

: The combination of topotecan and thoracic radiotherapy for nonsmall lung cancer, in the manner given by this protocol, could be safely given at a dose level of only 0.5 mg/m² days 1 to 5 and 22 to 26 with 60 Gy of external beam radiotherapy. Higher doses of topotecan were associated with high hematologic and gastrointestinal toxicity. Distant metastasis was the primary pattern of failure.     

Exhaled nitric oxide predicts radiation pneumonitis in esophageal and lung cancer patients receiving thoracic radiation

Background and purpose

Radiation pneumonitis is a significant toxicity following thoracic radiotherapy with no method to predict individual risk.

Materials and methods

Sixty-five patients receiving thoracic radiation for lung or esophageal cancer were enrolled in a phase II study. Each patient received respiratory surveys and exhaled nitric oxide measurements before, on the last day of, and 30-60 days after completing radiotherapy (RT). Pneumonitis toxicity was scored using the common terminology criteria for adverse events, version 4.0. The demographics, dosimetric factors, and nitric oxide ratio (NOR) of end RT/pre-RT were evaluated for correlation with symptomatic patients (Grade ?2).

Results

Fifty patients completed the trial. The pneumonitis toxicity score was: Grade 3 for 1 patient, Grade 2 for 6 patients, Grade 1 for 18 patients, and Grade 0 for 25 patients. Dosimetric factors were not predictive of symptoms. The NOR was 3.0 ± 1.8 (range 1.47-6.73) for the symptomatic and 0.78 ± 0.29 (range 0.33-1.37) for the asymptomatic patients (p = 0.006). A threshold NOR of 1.4 separated symptomatic and asymptomatic patients (p < 0.001). The average error was 4%.

Conclusions

Elevation in eNO on the last day of radiotherapy predicted subsequent symptomatic radiation pneumonitis weeks to months after treatment.     

Meta-analysis of human lung cancer microRNA expression profiling studies comparing cancer tissues with normal tissues

ABSTRACT: BACKGROUND: Lung cancer is the major cause of cancer death globally, it is often diagnosed at an advanced stage and has one of the lowest survival rates of any type of cancer. The common interest in the field of lung cancer research is the identification of biomarkers for early diagnosis and accurate prognosis. There is increasing evidence to suggest that microRNAs play important and complex roles in lung cancer. METHODS: A meta-analysis was conducted to review the published microRNA expression profiling studies that compared the microRNAs expression profiles in lung cancer tissues with those in normal lung tissues. A vote-counting strategy that considers the total number of studies reporting its differential expression, the total number of tissue samples used in the studies and the average fold change was employed. RESULTS: A total of 184 differentially expressed microRNAs were reported in the fourteen microRNA expression profiling studies that compared lung cancer tissues with normal tissues, with 61 microRNAs were reported in at least two studies. In the panel of consistently reported up-regulated microRNAs, miR-210 was reported in nine studies and miR-21 was reported in seven studies. In the consistently reported down-regulated microRNAs, miR-126 was reported in ten studies and miR-30a was reported in eight studies. Four up-regulated microRNAs (miR-210, miR-21. miR-31 and miR-182) and two down-regulated mcroiRNAs (miR-126 and miR-145) were consistently reported both in squamous carcinoma and adenocarcinoma-based subgroup analysis, with the other 14 microRNAs solely reported in one or the other subset. CONCLUSIONS: In conclusion, the top two most consistently reported up-regulated microRNAs were miR-210 and miR-21. The results of this meta-analysis of human lung cancer microRNA expression profiling studies might provide some clues of the potential biomarkers in lung cancer. Further mechanistic and external validation studies are needed for their clinical significance and role in the development of lung cancer.     

Radiotherapy for lung cancer

The role of radiation therapy in the management of lung cancer was reviewed at a workshop held in Cambridge, England, in June 1984. It was concluded that there was a continuing role for radiation therapy in the primary management of small cell lung cancer, including the loco-regional treatment for patients with limited disease. Radical radiotherapy for patients with non-small cell carcinoma could be curative for a proportion of patients with limited disease. Careful planning and quality control was essential. Palliative radiotherapy provided useful treatment for many other patients. Other related aspects of treatment are also presented.