ROLES OF NITRIC OXIDE AND OXYGEN IN OCULAR MELANOMA

描述（改编自申请人的摘要）：脉络膜黑色素瘤是一种 是成年人中最常见的原发性眼癌。 这是一 重要的疾病，因为治疗可能会破坏视力在受影响的眼睛 肿瘤会转移 它的治疗是非常有争议的， 目前是NEI一项主要临床试验的对象。 摘除是一种 常见的治疗方法，但最近才强调开发 眼睛保护疗法 不幸的是，这些新的治疗方法 在保留视力的同时勉强成功地根除了肿瘤。 的 最终目标应该是改进治疗， 可以在疾病过程中更早地应用治疗。 的能力 更早更积极地治疗可能最终会提高患者的 生存 一些保护眼睛的疗法（例如，放射疗法，光动力学的 治疗和免疫疗法）都依赖于氧气，但实际上 对这种肿瘤的生理学，包括血液循环机制， 流量控制 在癌症研究的其他领域， 感兴趣的是调节一氧化氮（NO）以改变肿瘤血流 和氧合来改善治疗。 这些的一个主要缺点是 然而，策略是通常必须给予NO调节剂， 并且副作用可能限制其临床应用。 以来 脉络膜黑色素瘤通常可以使用巩膜外膜治疗 方法，利用与NO相关的化合物， 操纵这种肿瘤的微环境特别有吸引力，因为 可以避免全身治疗。 拟议研究的目的是 测试有关NO对血流和氧合作用的假设 生长在无胸腺大鼠脉络膜中的人类脉络膜黑色素瘤。 的 待检验的假设是：（1）NO合成酶（NOS）在 人脉络膜黑色素瘤实质和/或血管，（2）NO发挥作用 在调节人脉络膜黑色素瘤的微血管血流量和（3） 体内的人脉络膜黑色素瘤具有氧张力被抑制的区域， 低（缺氧），肿瘤的氧合依赖于NO 空房的 这些研究的结果可能会导致发展， 测试脉络膜黑色素瘤的新疗法，基于选择性，局部 调节NO可用性和改变肿瘤血液的药剂的递送 氧合，从而提高治疗的有效性， 挽救受影响的眼睛

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.