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。 一种完全植入的药物输送系统的开发重新点燃了 对肝动脉化疗感兴趣并产生了一个大病人 人口愿意接受旨在更有效的区域治疗的研究。 我们最近对肝癌患者进行的断层扫描核素研究 肝动脉注射示踪微球后的药物扫描 这表明，与正常肝脏相比，肿瘤往往是多血管的。我们的 目标是开发利用这种潜力的治疗方法 肝肿瘤微循环与肿瘤微循环的选择性差异 肝脏正常。肝动脉灌注血管活性的能力 药物(肾上腺素，去甲肾上腺素，血管紧张素)，以分流血液和 从正常肝脏到肝脏肿瘤结节的微球将被 检查过了。肝动脉注射~(90)Y微球将 作为一种提供内部放射治疗的手段而被研究，以及 肝动脉灌注溴脱氧尿嘧啶核苷选择性治疗 将探索这些微球对肿瘤的放射增敏作用。广泛性 兔VX2肿瘤的临床前研究(肝内注射) 植入)，并将用于合理支持犬的发育 (和FDA批准)侵入性临床方案。兔子 模型将用于血管收缩疗法的研究，以检查BUDR 药效学，并调查联合用药的比较反应 治疗。这只狗将作为研究药物动力学的大型动物模型。 研究和建立治疗方案的相对毒性 肝动脉Y_(90)微球与局部组织的结合 放射增敏疗法。临床工作将包括最初的 Y-90微球的第一阶段单独研究和最终进展 到有理组合素的第一阶段研究，由 临床前模型。预计这些措施的结果 调查将为大规模随机第三阶段提供基础 试验(在合作组中)以及区域应用 放射增敏剂-放射治疗方案在其他肿瘤治疗中的应用 区域性肿瘤，如头颈癌、脑肿瘤和 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.