OPENING OF THE BLOOD-BRAIN BARRIER TO ANTITUMOR AGENTS

脑肿瘤的治疗因脑内肿瘤的存在而变得复杂。 血脑屏障（BBB），其阻碍 化疗剂对中枢神经系统（CNS）的作用。 渗透性血脑屏障破坏（BBBD）是一种递送药剂的方法， 穿过大脑和脑内肿瘤 在这份提案中，LX- 1 人小细胞肺癌裸鼠移植瘤模型 用于检查将抗肿瘤剂递送到脑中的问题 肿瘤，并评估治疗方法的疗效。 具体目标1的目标是确定BBD为什么更少 在荷瘤大鼠脑中与在正常大鼠脑中一致。 我们 将评估药理学和生理学的影响 参数对脑内荷瘤裸鼠中BBBD的影响。 这一目标的目的是获得一贯的高百分比， 实验动物中的BBBD，也将描述 可能在患者BBBD手术中发生改变。 具体目标2 我们将研究化疗途径的影响 给药对治疗效果的影响。 在过去的融资 我们发现颈动脉内给药对于 增加药物输送，但动脉内输送与 与BBBD最大限度地提高药物输送到肿瘤浸润区域， 肿瘤周围的大脑 我们将测试这种增加的药物 递送与增加的抗肿瘤功效相关， 裸鼠脑内肿瘤模型。 具体目标3是测试 放射治疗和BBBD化疗顺序对 在裸鼠模型中的抗肿瘤功效。 他们以前的研究 在正常大鼠中显示，化疗前的放疗 减少药物向CNS的递送，增加神经毒性 与BBBD化疗之前的反向序列相比， 放疗 他们将检验一个假设， 放疗后化疗的疗效也会降低。 总之，建议的研究旨在增加我们的 以患者为导向的研究的积极记录。 临床试验，基于 根据之前的BBB项目临床前结果，已经证明 在患者中可以获得完全和持久的反应， 患有恶性脑肿瘤，没有放射治疗， 认知丧失，当使用BBBD最大化递送时。 这 修改后的竞争性续约是外科手术的延续， CREG。

Therapy for brain tumors is complicated by the presence of the blood-brain barrier (BBB), which impedes delivery of chemotherapeutic agents to the central nervous system (CNS). Osmotic BBB disruption (BBBD) is a method to deliver agents through brain and intracerebral tumor. In this proposal, the LX- 1 human small cell lung carcinoma xenograft model in nude rats will be used to examine issues in delivery of antitumor agents to brain tumors and to evaluate the efficacy of therapeutic approaches. The goal of specific aim 1 is to determine why BBD is less consistent in tumor-bearing rat brain then in normal rat brain. We will assess the impact of pharmacologic and physiologic parameters on BBBD in intracerebral tumor-bearing nude rats. This aim is designed to obtain a consistently high percentage of BBBD in experimental animals, will also delineate factors that might be altered in patient BBBD procedures. In specific aim 2 we will investigate the impact of route of chemotherapy administration on therapeutic efficacy. During the past funding period we found intracarotid administration is important for increased drug delivery, but intraarterial delivery in combination with BBBD maximizes drug delivery to tumor-infiltrated areas of brain around the tumor. We will test whether this increased drug delivery is associated with increased anti-tumor efficacy in the nude rat intracerebral tumor model. Specific Aim 3 is to test the effects of sequencing of radiotherapy and BBBD chemotherapy on anti-tumor efficacy in the nude rat model. Their previous studies in normal rats showed that radiation prior to chemotherapy decreased drug delivery to the CNS and increased neurotoxicity compared to the reverse sequence of BBBD chemotherapy prior to radiotherapy. They will test the hypothesis that initial radiotherapy then chemotherapy will also have reduced efficacy. Altogether, the proposed studies are designed to add to our positive record of patient oriented research. Clinical trials, based on previous BBB program preclinical results, have demonstrated that a complete and durable response can be attained in patients with malignant brain tumors, without radiation and without cognitive loss, when delivery is maximized with BBBD. This revised competitive renewal is the continuation of a surgical CREG.