ROLES OF NITRIC OXIDE AND OXYGEN IN OCULAR MELANOMA

描述(摘自申请者摘要)：脉络膜黑色素瘤 成人中最常见的原发眼癌。这是一个 重要的疾病，因为治疗可能会破坏受影响眼睛的视力 而且肿瘤可能会转移。它的治疗方法非常有争议，而且 目前是一项重要的NEI临床试验的主题。摘除眼球是一种 常见的治疗方法，但直到最近才开始重视开发 保护眼睛的疗法。不幸的是，这些新的治疗方法只是 在保留视力的同时，略微成功地根除了肿瘤。这个 最终目标应该是改进治疗，以便更安全、更有效 在病程中可以更早地应用治疗方法。一种能力 更早、更积极地治疗可能最终会提高患者的病情 生死存亡。一些保护眼睛的疗法(例如，放射疗法、光动力疗法 治疗和免疫治疗)依赖氧气，但实际上什么都不依赖 已知这种肿瘤的生理学，包括血液机制 流量控制。在癌症研究的其他领域，最近出现了 对一氧化氮(NO)调节肿瘤血流量的兴趣 和氧合，以改善治疗。这些产品的一个主要缺点是 然而，策略是通常不能给出调制器 从系统来看，副作用可能会限制它们的临床应用。自.以来 脉络膜黑色素瘤通常可以使用巩膜外切除术进行治疗。 方法，与NO有关的化合物在当地的利用 操纵这种肿瘤的微环境特别吸引人，因为 全身治疗是可以避免的。拟议研究的目的是 关于一氧化氮对血流和氧合作用影响的测试假说 人脉络膜黑色素瘤生长在裸鼠的脉络膜上。这个 有待检验的假设是：(1)没有合成酶(NOS)在 人脉络膜黑色素瘤实质和/或血管系统，(2)NO发挥作用 在调节人脉络膜黑色素瘤微血管血流中的作用 活体人脉络膜黑色素瘤的氧分压 低(缺氧)和肿瘤的氧合依赖于NO 可用性。这些研究的结果可能会导致发展和 基于选择性局部治疗脉络膜黑色素瘤的新疗法的测试 调节NO可获得性和改变肿瘤血液的药物的输送 氧合，从而提高定向治疗的有效性 抢救受影响的眼睛。

DESCRIPTION (Adapted from applicant's abstract): Choroidal melanoma is the most common primary ocular cancer among the adult population. It is an important disease, because treatment may destroy vision in the affected eye and the tumor can metastasize. Its treatment is very controversial and is currently the subject of a major NEI clinical trial. Enucleation is a common treatment, but there has only been recent emphasis to develop eye-sparing therapies. Unfortunately, these newer treatments have been only marginally successful in eradicating the tumor while sparing vision. The ultimate goal should be to improve therapy so that safer, more efficacious treatments can be applied sooner in the course of the disease. The ability to treat sooner and more aggressively may ultimately enhance patient survival. Some eye-sparing therapies (e.g., radiation therapy, photodynamic therapy, and immunotherapy) are dependent on oxygen, yet virtually nothing is known about the physiology of this tumor, including mechanisms for blood flow control. In other areas of cancer research, there has been recent interest in the modulation of nitric oxide (NO) to modify tumor blood flow and oxygenation to improve treatment. One major drawback of these strategies, however, is that NO modulators must typically be given systemically, and side effects may limit their clinical application. Since choroidal melanomas are often accessible to treatment using an episcleral approach, the utilization of compounds associated with NO to locally manipulate the microenvironment of this tumor is especially appealing, since systemic treatment can be avoided. The purpose of the proposed study is to test hypotheses relating to the effects of NO on blood flow and oxygenation in human choroidal melanoma growing in the choroid of the athymic rat. The hypotheses to be tested are that (1) NO synthetase (NOS) is expressed in human choroidal melanoma parenchyma and/or vasculature, (2) NO plays a role in regulating microvascular blood flow in human choroidal melanoma and (3) human choroidal melanoma in vivo has areas in which the oxygen tension is low (hypoxia) and the oxygenation of the tumor is dependent on NO availability. The results of these studies could lead to development and testing of new therapies for choroidal melanoma, based upon selective, local delivery of agents which modulate NO availability and modify tumor blood oxygenation, thereby enhancing the effectiveness of treatments directed toward salvage of the affected eye.