HIGH-RISK NEUROBLASTOMA: A DEVASTATING CHILDHOOD CANCER

我们的目标是开发新药，以改善神经母细胞瘤(NB)患者的预后。 这些癌症是儿童最常见的恶性交感神经系统肿瘤。他们 起源于神经脊，是生物学上的异质性肿瘤，而一些肿瘤 自发退化或分化。这些肿瘤中的大多数具有侵袭性生长、转移和 仍然对多模式治疗具有抵抗力；晚期疾病患者的存活率不到20%。尽管 目前采用自体强化清髓化疗的积极治疗策略 在骨髓移植中，大多数高危(4期)NB患者死于他们的疾病。根除 难治性显微疾病仍然是治疗高危疾病最大的挑战之一 神经母细胞瘤。为了改善这种疾病患者的预后，迫切需要 开发新药。与其他实体肿瘤相似，NB已知能产生促进生长的生长因子 血管生成。在肿瘤以外的靶向血管生成方面显示出相当的成功 几种实体瘤的治疗。 我们最近的努力导致了溴乙氧基钙二醇(B3CD)的开发，B3CD是一种非降钙性的，3- 钙化二醇的溴乙酰氧基酯衍生物，作为一种针对癌细胞和血管生成的细胞毒剂。在……里面 我们的初步研究B3CD，抑制了神经母细胞和内皮细胞的增殖(对 血管生成)。B3CD增强Caspase-3活性，快速诱导神经母细胞和 抑制内皮细胞和血管生成。此外，B3CD在SCID小鼠体内的应用 28天内没有引起任何毒性或血清钙水平升高，表明缺乏明显的 全身毒性。基于这些观察，我们假设B3CD作为一种新的治疗剂 在NB中，通过诱导细胞凋亡和抑制血管生成来实现。我们建议(A)进一步研究这些初步的 B3CD对NB细胞的细胞毒活性观察 参与其作用机制的途径(特别是导致生长抑制和细胞凋亡)，(B) 通过确定其对内皮细胞增殖的影响来确定B3CD的抗血管生成活性。 迁移、管状形成、主动脉环萌发和鸡绒毛膜尿囊膜(CAM)血管化， (C)测定B3CD在小鼠移植人NB模型中的体内疗效。 通过对新型无毒钙二醇衍生物--溴乙酰氧基钙二醇的研究，获得了如下认识 预计将帮助设计创新的治疗方法，用于治疗患有普通NB和高危NB的儿科患者 很特别。B3CD有可能单独使用或与标准化疗联合使用来治疗这种疾病 毁灭性的疾病。

Our goal is to develop new drugs in order to improve the outcomes of patients with neuroblastoma (NB). These cancers are the most common malignant sympathetic nervous system tumors of childhood. They originate from the neural crest and are biologically heterogeneous tumors while some tumors undergo spontaneous regression or differentiation. The majority of these tumors grow aggressively, metastasize and remain resistant to multimodal therapy; less than 20% of patients with advanced disease survive. Despite current aggressive treatment strategies employing intensive myeloablative chemotherapy with autologous bone marrow transplantation, most patients with high risk (Stage 4) NB die of their disease. Eradication of refractory microscopic disease remains one of the most significant challenges in the treatment of high-risk neuroblastoma. In order to improve the outcome for patients with this disease, there is an urgent need to develop new drugs. Similar to other solid tumors, NB is known to produce growth factors promoting angiogenesis. Targeting angiogenesis in addition to the tumor has shown considerable success in the treatment of several solid tumors. Our recent efforts have lead to the development of bromoacetoxycalcidiol (B3CD) a non-calcemic, 3- bromoacetoxy-ester derivative of calcidiol, as a cytotoxic agent that targets cancer cells and angiogenesis. In our preliminary studies B3CD, inhibited the proliferation of neuroblastic cells and endothelial cells (critical for angiogenesis). B3CD increased caspase-3 activity, rapidly induced apoptosis rapidly in neuroblastic and endothelial cells and inhibited angiogenesis. Furthermore, administration of B3CD to SCID mice over a period of 28 days did not cause any toxicity or increased serum calcium levels indicating a lack of apparent general toxicity. Based on these observations, we hypothesize that B3CD acts as a novel therapeutic agent in NB by inducing apoptosis and inhibiting angiogenesis. We propose to (a) further examine these initial observations of cytotoxic activity of B3CD in NB cells with particular emphasis on delineating cellular pathways involved in its mechanism of action (particulary leading to growth inhibition and apoptosis), (b) determine the anti-angiogenic activity of B3CD by ascertaining its effect on endothelial cell proliferation, migration, tube formation, aortic ring sprouting and chick chorioallantoic membrane (CAM) vascularization, and (c) to determine the in vivo efficacy of B3CD in mouse xenograft model of human NB. The knowledge gained from the study of bromoacetoxycalcidiol, a novel non-toxic calcidiol derivative, is expected to help design innovative treatments for pediatric patients with NB in general and high-risk NB in particular. B3CD could potentially be used alone or in combination with standard chemotherapy to treat this devastating illness.