HEPATIC TUMOR MICROCIRCULATION AND MICROSPHERE THERAPY

癌症累及肝脏是发病率和死亡率的主要来源。 完全植入式给药系统的发展已经重新点燃 肝动脉化疗的兴趣，并产生了一个大的病人 适合进行旨在更有效的区域治疗的研究的人群。 我们最近的研究在肝癌患者中使用断层核成像 肝动脉注射示踪剂微球后的药物扫描 表明与正常肝脏相比，肿瘤通常是多血管的。 我们 目的是开发利用这种潜在的治疗方法， 肝肿瘤微循环的选择性差异， 正常肝脏 肝动脉灌注血管活性物质的能力 分流血流的药物（肾上腺素、去甲肾上腺素、血管紧张素）， 从正常肝脏到肝肿瘤结节的微球递送将是 考察 钇90微球经肝动脉给药， 作为一种手段进行研究，提供内部放射治疗， 肝动脉灌注溴脱氧尿苷（BUDR）选择性 将探索这些微球对肿瘤的放射增敏作用。 广泛 在携带VX 2肿瘤的兔中的临床前研究（肝内 植入）和犬中用于合理支持开发 (and FDA批准）的临床试验方案。 兔子 模型将用于血管收缩剂方案研究，以检查BUDR 药效学，并研究比较反应， 治疗 犬将作为药代动力学的大型动物模型 研究和确定治疗方案的相对毒性 肝动脉钇90微球联合局部 放射增敏剂方案。 临床工作将包括一个初步的 第一阶段研究钇90微球单独，然后最终进展 第一阶段理性组合研究 临床前模型。 预计，这些结果 研究将为大规模随机III期研究提供基础 试验（在合作小组中）以及适用区域 放射增敏剂-放射治疗方案在治疗其他 局部局限性肿瘤，如头颈癌、脑瘤， 四肢肿瘤

Liver involvement by cancer is a major source of morbidity and mortality. The development of a totally implanted drug delivery system has rekindled interest in hepatic arterial chemotherapy and generated a large patient population amenable to studies aimed at more effective regional therapy. Our recent studies in patients with liver cancer using tomographic nuclear medicine scans after hepatic arterial injection of tracer microspheres indicate that tumors are often hypervascular compared to normal liver. Our objective is to develop therapeutic approaches exploiting such potentially selective differences between the microcirculation of hepatic tumors and normal liver. The ability of hepatic arterial infusion of vasoactive agents (epinephrine, norepinephrine, angiotensin) to shunt blood flow and microsphere delivery from normal liver to hepatic tumor nodules will be examined. Hepatic arterial administration of yttrium 90 microspheres will be studied as a means to deliver internal radiotherapy and, the ability of hepatic arterial infusion of bromodeoxyuridine (BUDR) to selectively radiosensitize tumor to these microspheres will be explored. Extensive preclinical studies in rabbits bearing the VX2 tumor (intrahepatically implanted) and in dogs will be used to rationally support the development (and FDA approval) of invesstigational clinical protocols. The rabbit model will be used for vasoconstrictor regimen studies, to examine BUDR pharmacodynamics, and to investigate comparative response to combined therapies. The dog will serve as a large animal model for pharmacokinetic studies and to establish the relative toxicities of therapeutic regimens combining hepatic arterial yttrium 90 microspheres with regional radiosensitizer regimens. Clinical efforts will consist of an initial phase I study of yttrium 90 microspheres alone and then ultimately progress to phase I studies of rational combinatins as directed by studies in the preclinical models. It is anticipated that the results of these investigations will provide a basis for large scale randomized phase III trials (in cooperative groups) as well as for the application of regional radiosensitizer-radiotherapy regimens in the treatment of other regionally-confined tumors such as head and neck cancer, brain tumors, and tumors of the extremities.