A new method for delivery of selinium for prevention of melanoma

描述（由申请人提供）： 硒作为一种化学预防剂，对许多不同的癌症，包括前列腺癌、结肠癌和肺癌，显示出巨大的潜力。然而，在1996年的营养预防癌症试验中，口服硒补充剂未能预防黑色素瘤和非黑色素瘤皮肤癌，这尤其令人失望，因为预防皮肤癌是该试验的主要目标。在预防黑色素瘤的潜在药物的新研究过程中，发现培养中的黑色素瘤细胞对硒的生长抑制作用的敏感性与其他肿瘤类型的报道相当。本申请中提出的工作将测试黑色素瘤对硒的化学预防作用敏感的假设;没有显示这些作用的人体试验失败，因为有效剂量的硒没有被递送到皮肤，并且有效递送到皮肤将预防黑色素瘤。为了检验这一假设，将进行三个具体的目标：目标1：确定硒对培养的黑色素瘤细胞的影响。硒对培养的黑色素瘤细胞的影响将特别强调细胞凋亡和未折叠蛋白反应（UPR）。这些研究将巩固我们总体假设的分子基础，并为目标3中动物研究结果的评价提供重要的生物标志物。目的2：评价硒-甲基硒代半胱氨酸（SeMSec）和硒代蛋氨酸（SeMet）的新制剂用于将硒递送至小鼠皮肤。对SeMSec和SeMet新制剂的初步评估表明，它们可有效增加成年C57 BL/6（B6）小鼠皮肤中的总硒。这些研究将扩大，以确定一种治疗方案，可用于提高硒在新生小鼠的皮肤，使我们可以研究硒对黑色素瘤的B6小鼠转基因肝细胞生长因子（HGF）的目的3。目的3：评价硒代氨基酸作为HGF小鼠黑色素瘤预防剂的有效性。HGF转基因小鼠在新生儿紫外线照射后发展为黑色素瘤，将用于测试SeMSec和SeMet新制剂预防黑色素瘤的功效。黑色素瘤是一种高度侵袭性的皮肤癌，在后期诊断时预后不良。迄今为止确定的唯一预防策略是避免阳光照射。不幸的是，许多黑色素瘤被认为是由已经过去的初始事件引起的，例如儿童晒伤。这就需要有效预防癌前病变进展的药物。该提案重新审视硒作为黑色素瘤预防剂，并更新了分子理性和新策略，用于将该药剂递送至靶器官，皮肤。

DESCRIPTION (provided by applicant): Selenium shows great promise as a chemopreventive agent for a number of different cancers including those of the prostate, colon, and lung. However, the failure of an oral selenium supplement to prevent melanoma and non-melanoma skin cancers in the Nutritional Prevention of Cancer trial of 1996 was particularly disappointing in light of the fact that skin cancer prevention was the primary goal of that trial. In the course of new studies of potential agents for prevention of melanoma, the sensitivity of melanoma cells in culture to the growth-inhibitory effects of selenium was found to be comparable to those reported for other tumor types. The work proposed in this application will test the hypothesis that melanoma is sensitive to the chemopreventive effects of selenium; that human trials which did not show those effects failed because an effective dose of selenium was not delivered to the skin, and that efficient delivery to the skin will prevent melanoma. In order to test this hypothesis, three specific aims will be performed: Aim 1: Determine the effects of selenium on melanoma cells in culture. The effects of selenium on melanoma cells in culture will be interrogated with particular emphasis on apoptosis and the unfolded protein response (UPR). These studies will solidify the molecular basis for our overall hypothesis and provide important biomarkers for the evaluation of results from the animal studies in Aim 3. Aim 2: Evaluate new formulations of Se- methylselenocysteine (SeMSec) and selenomethionine (SeMet) for the delivery of selenium to the skin of mice. Preliminary evaluations of new formulations of SeMSec and SeMet showed that they were effective at increasing total selenium in the skin of adult C57BL/6 (B6) mice. These studies will be expanded in order to identify a treatment regimen that can be used to elevate selenium in the skin of neonatal mice so that we can study the effects of selenium on melanoma in B6 mice transgenic for hepatocyte growth factor (HGF) in Aim 3. Aim 3: Evaluate the efficacy of selenoaminoacids as melanoma-preventive agents in HGF mice. HGF transgenic mice, which develop melanoma after neonatal UV irradiation, will be used to test the efficacy of new formulations of SeMSec and SeMet for the prevention of melanoma. Melanoma is a highly aggressive form of skin cancer with poor prognosis when diagnosed at later stages. The only preventive strategy identified to date is avoidance of sun exposure. Unfortunately many melanomas are thought to arise from initiating events already past such as childhood sunburn. This creates the need for agents that are effective at preventing the progression of premalignant lesions. This proposal revisits selenium as a melanoma preventive agent with an updated molecular rational and new strategy for delivery of this agent to the target organ, the skin.