Chemopreventive treatment of familial melanoma

描述(由申请人提供)： 几种肿瘤类型与特定的基因突变有关。高危个体可以选择切除目标器官，以努力减少相关癌症类型的发生率。家族性黑色素瘤患者不能进行选择性手术，因为容易发生恶性转化的细胞分散在表皮的基底层。在这里，我们建议选择性地消除皮肤中的黑素细胞，以防止家族性黑色素瘤患者的肿瘤发生。黑素细胞及其恶性衍生物独特地表达酪氨酸酶，酪氨酸酶是负责黑素合成的限速酶。已经描述了几种通过竞争性抑制酪氨酸酶而导致皮肤脱色的化合物。当这些化合物被酪氨酸酶转化为有毒的邻苯二酚时，对黑素细胞具有细胞毒性。因此，细胞死亡选择性地导致黑素细胞和黑色素瘤细胞。虽然这种前药本身在全身使用时可能是有毒的，但漂白酚已被批准用于进行性白癜风患者的皮肤脱色乳膏。这些化合物选择性地消耗表皮中的黑素细胞。漂白酚的细胞毒活性进一步有助于产生黑素细胞特异性分化抗原，这些抗原由皮肤浸润性树突状细胞处理，进而导致对黑素细胞的自身免疫反应和皮肤色素沉着的进行性丧失。白癜风通常被认为是一种不受欢迎的自身免疫性疾病，但进行性色素脱失的发展是黑色素瘤患者积极的预后标志。在这里，我们假设局部应用具有良好特性的脱色剂可以通过二步法通过激发对肿瘤的抗肿瘤免疫反应和通过耗尽黑色素瘤前体细胞来治疗黑色素瘤。因此，这种方法对于携带p16/Arf或CDK4基因突变导致家族性黑色素瘤的患者尤其重要，在这些患者中，黑素细胞的存在是对未来肿瘤发展的持续关注。我们建议根据以下特定目标验证我们的假设：1)通过杂交白化Ink4a/Arf-/-Tyr-Ras TG小鼠×黑色K14-SCF TG小鼠，产生自发发展为黑色素瘤并表达色素表皮黑素细胞的小鼠。[目的]评价SCF转基因小鼠对已被批准用于白癜风脱色的氢苯二酚单苯甲醚(MBEH)和已知的职业性白癜风致病因素4-叔丁基苯酚(4-TBP)的皮肤脱色反应。[目的]研究漂白剂和IL-2对小鼠黑色素瘤生长的影响及免疫学参数(细胞因子的分泌)。

DESCRIPTION (provided by applicant): Several tumor types are associated with specific gene mutations. At-risk individuals can opt to have the targeted organs removed in an effort to reduce the incidence of associated cancer types. Elective surgery is not available to familial melanoma patients, where cells prone to undergo malignant transformation are dispersed throughout the basal layer of the epidermis. Here we propose to selectively eliminate melanocytes from the skin to prevent tumorigenesis in familial melanoma patients. Melanocytes and their malignant derivatives uniquely express tyrosinase, the rate-limiting enzyme responsible for melanogenesis. Several compounds have been described that cause depigmentation of the skin through competitive inhibition of the tyrosinase enzyme. These same compounds are cytotoxic to melanocytic cells when converted into toxic orthoquinones by tyrosinase. Cell death thus results selectively in melanocytes and melanoma cells. Whereas such prodrugs can themselves be toxic upon systemic use, bleaching phenols have been approved for topical use in skin depigmenting creams for patients with progressive vitiligo. These compounds selectively deplete melanocytes from the epidermis. The cytotoxic activity of bleaching phenols further contributes to generating a source of melanocyte specific differentiation antigens that are processed by skin infiltrating dendritic cells which leads, in turn, to an autoimmune response to melanocytes and progressive loss of skin pigmentation. Vitiligo is commonly considered an undesirable autoimmune condition, yet the development of progressive depigmentation is a positive prognostic sign for melanoma patients. Here we hypothesize that topical application of well characterized depigmenting agents can be used to treat melanoma by a 2-tierd approach, through eliciting anti-tumor immune responses to the tumor and through depletion of melanoma precursor cells. This approach is thus of particular importance for patients that carry mutations in p16/Arf or CDK4 genes contributing to familial melanoma, where the presence of melanocytes is a constant concern for the development of future tumors. We propose to test our hypothesis according to the following specific aims: 1] To generate mice that spontaneously develop melanoma tumors and express pigmented epidermal melanocytes by cross breeding albino Ink4A/Arf -/- Tyr-RAS tg mice x black k14-SCF tg mice. 2] To assess skin depigmentation in SCF transgenic mice in response to monobenzyl ether of hydroquinone (MBEH), approved for depigmentation in vitiligo and in response to 4-tertiary butyl phenol (4-TBP), a known causative agent in occupational vitiligo. 3] To quantify melanoma tumor growth and measure immunologic parameters (cytokine secretion by ELISA and ELISPOT) in mice treated with bleaching agents and IL-2.