ROLES OF NITRIC OXIDE AND OXYGEN IN OCULAR MELANOMA

一氧化氮和氧气在眼黑色素瘤中的作用

基本信息

批准号：
6498319
负责人：
RODNEY D BRAUN
金额：
$ 11.18万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-02-01 至 2004-01-31
项目状态：
已结题

项目摘要

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.

描述（改编自申请人的摘要）：脉络膜黑色素瘤是成年人中最常见的原发性眼癌。它是一个重要疾病，因为治疗可能会破坏受影响眼睛的视力并且肿瘤可以转移。其治疗方法颇具争议，目前是 NEI 一项主要临床试验的主题。摘除术是常见的治疗方法，但直到最近才强调开发保护眼睛的疗法。不幸的是，这些新的治疗方法仅在保留视力的同时根除肿瘤方面取得了一定的成功。这最终目标应该是改进治疗，使治疗更安全、更有效在病程中可以尽早进行治疗。能力更早、更积极地治疗可能最终会改善患者的病情生存。一些保护眼睛的疗法（例如放射疗法、光动力疗法）疗法和免疫疗法）都依赖于氧气，但实际上什么都不依赖了解这种肿瘤的生理学，包括血液的机制流量控制。在癌症研究的其他领域，最近出现了对调节一氧化氮（NO）以改变肿瘤血流感兴趣和氧合以改善治疗。这些的一个主要缺点然而，策略是通常必须给予 NO 调节剂全身性的，副作用可能限制其临床应用。自从脉络膜黑色素瘤通常可以使用巩膜外层治疗方法，利用与 NO 相关的化合物来局部治疗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与 NO 对血流和氧合影响相关的假设在无胸腺大鼠脉络膜中生长的人类脉络膜黑色素瘤中。这待检验的假设是 (1) NO 合成酶 (NOS) 表达于人脉络膜黑色素瘤实质和/或脉管系统，(2) NO 发挥作用调节人脉络膜黑色素瘤的微血管血流和 (3) 体内人类脉络膜黑色素瘤的某些区域的氧张力为低（缺氧）且肿瘤的氧合依赖于 NO 可用性。这些研究的结果可能会导致发展和基于选择性、局部性测试脉络膜黑色素瘤的新疗法递送调节 NO 可用性和改变肿瘤血液的药物氧合，从而提高定向治疗的有效性以挽救受影响的眼睛。