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（根据申请人的摘要改编）：脉络膜黑色素瘤是成年人口中最常见的原发性眼癌。这是一个重要疾病，因为治疗可能会破坏受影响眼中的视力肿瘤可以转移。它的治疗非常有争议，并且目前是一项重大NEI临床试验的主题。摘除是一个常见的治疗，但最近只有重点要发展眼睛比较疗法。不幸的是，这些较新的治疗只有在避免视力的同时消除肿瘤方面的成功。这最终目标应该是改善治疗，以使更安全，更有效在疾病过程中，可以更快地应用治疗。能力更快，更积极地治疗可能最终增强患者生存。一些令人眼前的疗法（例如，放射疗法，光动力学治疗和免疫疗法）取决于氧气，但几乎没有了解该肿瘤的生理学，包括血液的机制流控制。在癌症研究的其他领域，最近有对一氧化氮（NO）调节肿瘤血流的兴趣和氧合以改善治疗。这些的主要缺点但是，策略是通常不得给予调节器系统地，副作用可能会限制其临床应用。自从脉络膜黑色素瘤通常可以使用episcleral进行治疗方法，利用与局部NO相关的化合物操纵该肿瘤的微环境特别吸引人，因为可以避免全身治疗。拟议的研究的目的是测试与NO对血流和氧合作用的影响有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。这要测试的假设是（1）在人类脉络膜黑色素瘤实质和/或脉管系统，（2）无角色在调节人脉络膜黑色素瘤中的微血管血流和（3）人体内的人类脉络膜黑色素瘤具有氧气张力为低（缺氧）和肿瘤的氧合作用取决于NO 可用性。这些研究的结果可能导致发展和基于选择性局部的脉络膜黑色素瘤的新疗法测试递送没有可用性并修改肿瘤血液的药物的递送氧合，从而增强了定向治疗的有效性求助受影响的眼睛。