甘氨双唑钠对鼻咽癌放疗增敏作用的临床研究

目的评价甘氨双唑钠对鼻咽癌放射增敏作用和毒副反应.方法 40例初诊经病理学确诊的鼻咽癌患者随机、双盲分为A组和B组.两组放射治疗方法、程式、剂量相同.破盲后证实A组为注射用甘氨双唑钠组,B组为安慰剂对照组.根据肿瘤退缩变化计算肿瘤部分缓解(PR)剂量和完全缓解(CR)剂量,每周检测血常规,每周检查肝肾功能、心电图,并按WHO毒性标准观察和评定毒副作用.结果 A组的鼻咽原发灶和颈淋巴转移灶CR率分别为90%(18/20)和85%(17/20),高于B组的75%(15/20)和60%(12/20)(P＜0.05),而且A组达到PR和CR的剂量低于B组(P＜0.05).鼻咽原发灶放射增敏比(SER)为5560.0/4322.2=1.29,颈淋巴转移灶SER为5150.0/4270.6=1.21.两组患者的主要毒副作用为黏膜、皮肤、血常规反应,差异无显著性,未发现神经系统毒性和心脏毒性.结论注射用甘氨双唑钠对鼻咽癌的放疗有肯定的放射增敏作用,未发现明显毒副反应,值得进一步深入研究,长期疗效亦有待于追踪和观察.     

Outcome and prognostic factors for children with supratentorial primitive neuroectodermal tumors treated with carboplatin during radiotherapy: A report from the Children's Oncology Group

Background

Supratentorial PNETs (sPNET) are uncommon embryonal malignancies of the central nervous system whose prognosis has historically been poor. We evaluated the outcome and prognostic factors of children with sPNET treated prospectively on a Children's Oncology Group trial.

Procedure

Following surgery, patients received craniospinal radiotherapy with concurrent carboplatin followed by six months of maintenance chemotherapy with cyclophosphamide and vincristine.

Results

Five‐year overall survival (OS) and progression‐free survival (PFS) for all patients was 58 ± 7% and 48 ± 7%. For patients with pineoblastoma (n = 23), five‐year OS and PFS was 81 ± 9% and 62 ± 11%. Extent of resection but not M‐stage was prognostic. Five‐year OS and PFS for 37 patients with non‐pineal tumors (NPsPNET) was 44 ± 8% and 39 ± 8%, significantly worse than for PB (P = 0.055 and 0.009 respectively). Extent of resection and major radiotherapy deviations were prognostic. Five year OS was 59 +/? 11.4% for those undergoing complete resection versus 10.4 +/? 7% for those who did not (P = 0.017). Central pathologic review called 14 (38%) “classic” sPNET, 8 (22%) “undifferentiated” and 13 (35%) “malignant gliomas.” There was no significant difference between the subgroups, although survival distributions approached significance when the combined “classic” and “undifferentiated” group was compared to the “malignant gliomas.”

Conclusions

Carboplatin during RT followed by 6 months of non‐intensive chemotherapy is a feasible treatment strategy for patients with sPNET. Aggressive surgical resection should be attempted if feasible. The classification of supratentorial small cell malignancies can be difficult. Pediatr Blood Cancer 2015;62:776–783. © 2015 Wiley Periodicals, Inc.

     

Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery

One of the promises of nanoparticle (NP) carriers is the reformulation of promising therapeutics that have failed clinical development due to pharmacologic challenges. However, current nanomedicine research has been focused on the delivery of established and novel therapeutics. Here we demonstrate proof of the principle of using NPs to revive the clinical potential of abandoned compounds using wortmannin (Wtmn) as a model drug. Wtmn is a potent inhibitor of phosphatidylinositol 3' kinase-related kinases but failed clinical translation due to drug-delivery challenges. We engineered a NP formulation of Wtmn and demonstrated that NP Wtmn has higher solubility and lower toxicity compared with Wtmn. To establish the clinical translation potential of NP Wtmn, we evaluated the therapeutic as a radiosensitizer in vitro and in vivo. NP Wtmn was found to be a potent radiosensitizer and was significantly more effective than the commonly used radiosensitizer cisplatin in vitro in three cancer cell lines. The mechanism of action of NP Wtmn radiosensitization was found to be through the inhibition of DNA-dependent protein kinase phosphorylation. Finally, NP Wtmn was shown to be an effective radiosensitizer in vivo using two murine xenograft models of cancer. Our results demonstrate that NP drug-delivery systems can promote the readoption of abandoned drugs such as Wtmn by overcoming drug-delivery challenges.     

泰素对放射所致鼻咽癌细胞周期阻滞、凋亡的影响

目的研究泰素对放射所致鼻咽癌细胞（CNE）细胞周期阻滞和凋亡的影响。方法采用流式细胞术和MTT法分别检测放射或放射联合泰素诱导的细胞周期阻滞、凋亡及其细胞存活率。结果泰素可使放射所致的;1）G2/M期阻滞峰值降低,阻滞时间缩短,有极显著的统计学意义（P〈0.01）;2）凋亡率明显升高,有极显著的统计学意义（P〈0.01）;3）细胞存活率明显降低,有显著的统计学意义（P〈0.05）且其Dq（实验组） 〈Dq（对照组）。结论泰素可作为鼻咽癌放射治疗的增敏剂。     

汉防己甲素配合放射线增敏治疗鼻咽癌的临床研究

目的：观察汉防己甲素用于鼻咽癌放疗的增敏作用及其毒副反应。方法：112例鼻咽癌患者随机分为治疗组和对照组。治疗组在放疗第1天开始服用汉防己甲素，每次40mg，每天3次，直至放疗结束，放疗采用6MV-X线常规分割外放射治疗，鼻咽部DT66～72Gy／33～36F／6～7w，颈部淋巴结转移灶治疗量DT60～66Gy／30～33F／6～7W。对照组单纯放疗，其设野和剂量均同治疗组。结果：放疗结束后1个月鼻咽部MRI复查评价疗效，近期有效率治疗组为89．3％，对照组为69．6％，治疗组近期疗效明显，差异有显著意义（P〈0．05）；治疗组放疗期间骨髓抑制、放射性皮炎、口干、咽痛和消化道反应等同对照组比较无显著性差异（P〉0．05）。结论：鼻咽癌放疗中汉防己甲素是一种理想的放射增敏剂，值得在临床上进一步应用推广。     

1alpha,25-dihydroxyvitamin D(3) (calcitriol) and its analogue, 19-nor-1alpha,25(OH)(2)D(2), potentiate the effects of ionising radiation on human prostate cancer cells

Radiotherapy with external beam radiation or brachytherapy is an established therapeutic modality for prostate cancer. Approximately 30% of patients with localised prostate cancer relapse at the irradiated site. Secondary effects of ionising radiation (IR), for example, bowel and bladder complications, are common. Thus, the search for biological response modifiers that could potentiate the therapeutic effects of radiation and limit the occurrence of serious side effects is an important task in prostate cancer therapy. 1alpha,25-Dihydroxyvitamin D(3) (calcitriol), the active metabolite of vitamin D, and its analogues are under investigation for the treatment of several malignancies including prostate cancer. Here, we report that 1alpha,25-dihydroxyvitamin D(3) and its less calcaemic analogue 19-nor-1alpha,25-(OH)(2)D(2) (Zemplar) act synergistically with IR to inhibit the growth of the human prostate cancer cells in vitro. 1alpha,25-dihydroxyvitamin D(3) potentiated IR-induced apoptosis of LNCaP cells, and nanomolar doses of 1alpha,25-dihydroxyvitamin D(3) and 19-nor-1alpha,25-(OH)(2)D(2) showed synergistic inhibition of growth of LNCaP cells at radiobiologically relevant doses of IR (1-2 Gy). At higher doses of IR, the combination of 1alpha,25-dihydroxyvitamin D(3) and IR or 19-nor-1alpha,25-(OH)(2)D(2) and IR resulted in moderate antagonism. The synergistic effect at radiobiologically relevant doses of radiation suggests that a combination of 1alpha,25-dihydroxyvitamin D(3) or 19-nor-1alpha,25-(OH)(2)D(2) with IR could permit a reduction in the dose of radiation given clinically and thus potentially reduce treatment-related morbidity.     

甘氨双唑钠对局部复发性鼻咽癌再程放疗的增敏作用

目的研究甘氨双唑钠（CMNa）对局部复发鼻咽癌再程放疗的增敏作用以及不良反应。方法2006年4月至2007年6月,将60例病理确诊的鼻咽癌首程治疗完全缓解（CR）后局部（鼻咽）复发患者,随机分为试验组和对照组,每组30例。对照组：6MVX线体外放射治疗,放疗剂量：64～66GY/6.4～7.0周,每周照射5天,每天1次,10GY/周,设野根据患者临床和CT/MRI扫描所示病变范围,采用低熔点铅挡块不规则野,采用小野、多野等技术。试验组：将注射用甘氨双唑钠800mg/m2,用100ml生理盐水稀释溶解,30min内完成静脉滴注后于1～3小时内行常规放疗（方案同对照组）,每周3次（周一、三、五）,从放疗开始连续用药至放疗结束,约7周,共21次。观察疗效及不良反应。结果60例均可评价。鼻咽复发灶CR试验组和对照组分别为86.7%（26/30）、63.3%（19/30）,P〈0.05;1年生存率试验组和对照组分别为83.3%（25/30）、56.7%（17/30）,P〈0.05;1年无瘤生存率试验组和对照组分别为80.0%（24/30）、53.3%（16/30）,P〈0.05;两组患者的主要不良反应为粘膜、皮肤反应,但两组无显著差异（P〉0.05）。结论甘氨双唑钠可以增加局部复发鼻咽癌的放疗敏感性,可以提高复发鼻咽癌近期疗效,无严重不良反应,能否提高长期生存率仍需进一步临床观察。     

2，6-二取代-1，4-苯醌类化合物的合成及其体外放射增敏作用

马蔺子甲素是一种２,６－二取代苯醌类化合物,具有明显的乏氧细胞放射增敏作用。通过对马蔺子甲素的化学结构进行修饰,合成了１２个２,６－二取代苯醌类化合物,初步药理实验结果显示：它们具有较高的放射增敏作用,但是乏氧选择性细胞毒作用较低。     

Inhibition of hypoxia-induced miR-155 radiosensitizes hypoxic lung cancer cells

miR-155 is a prominent microRNA (miRNA) that regulates genes involved in immunity and cancer-related pathways. miR-155 is overexpressed in lung cancer, which correlates with poor patient prognosis. It is unclear how miR-155 becomes increased in lung cancers and how this increase contributes to reduced patient survival. Here, we show that hypoxic conditions induce miR-155 expression in lung cancer cells and trigger a corresponding decrease in a validated target, FOXO3A. Furthermore, we find that increased levels of miR-155 radioprotects lung cancer cells, while inhibition of miR-155 radiosensitizes these cells. Moreover, we reveal a therapeutically important link between miR-155 expression, hypoxia, and irradiation by demonstrating that anti-miR-155 molecules also sensitize hypoxic lung cancer cells to irradiation. Our study helps explain how miR-155 becomes elevated in lung cancers, which contain extensive hypoxic microenvironments, and demonstrates that inhibition of miR-155 may have important therapeutic potential as a means to radiosensitize hypoxic lung cancer cells.