Wakamatsu Kazumasa, Ito Akira, Tamura Yasuaki, Hida Tokimasa, Kamiya Takafumi, Torigoe Toshihiko, Honda Hiroyuki, Ito Shosuke, Jimbow Kowichi
Institute for Melanin Chemistry, Fujita Health University, Toyoake 470-1192, Aichi, Japan.
Department of Chemical Systems Engineering, School of Engineering, Nagoya University, Nagoya 464-8603, Aichi, Japan.
Cancers (Basel). 2022 Nov 14;14(22):5588. doi: 10.3390/cancers14225588.
Malignant melanoma is one of the most malignant of all cancers. Melanoma occurs at the epidermo-dermal interface of the skin and mucosa, where small vessels and lymphatics are abundant. Consequently, from the onset of the disease, melanoma easily metastasizes to other organs throughout the body via lymphatic and blood circulation. At present, the most effective treatment method is surgical resection, and other attempted methods, such as chemotherapy, radiotherapy, immunotherapy, targeted therapy, and gene therapy, have not yet produced sufficient results. Since melanogenesis is a unique biochemical pathway that functions only in melanocytes and their neoplastic counterparts, melanoma cells, the development of drugs that target melanogenesis is a promising area of research. Melanin consists of small-molecule derivatives that are always synthesized by melanoma cells. Amelanosis reflects the macroscopic visibility of color changes (hypomelanosis). Under microscopy, melanin pigments and their precursors are present in amelanotic melanoma cells. Tumors can be easily targeted by small molecules that chemically mimic melanogenic substrates. In addition, small-molecule melanin metabolites are toxic to melanocytes and melanoma cells and can kill them. This review describes our development of chemo-thermo-immunotherapy based on the synthesis of melanogenesis-based small-molecule derivatives and conjugation to magnetite nanoparticles. We also introduce the other melanogenesis-related chemotherapy and thermal medicine approaches and discuss currently introduced targeted therapies with immune checkpoint inhibitors for unresectable/metastatic melanoma.
恶性黑色素瘤是所有癌症中恶性程度最高的癌症之一。黑色素瘤发生于皮肤和黏膜的表皮-真皮交界处，此处小血管和淋巴管丰富。因此，从疾病发作开始，黑色素瘤就很容易通过淋巴和血液循环转移至全身其他器官。目前，最有效的治疗方法是手术切除，而其他尝试过的方法，如化疗、放疗、免疫疗法、靶向疗法和基因疗法，尚未取得足够的效果。由于黑色素生成是一条仅在黑素细胞及其肿瘤对应物（黑色素瘤细胞）中起作用的独特生化途径，开发靶向黑色素生成的药物是一个有前景的研究领域。黑色素由黑色素瘤细胞始终合成的小分子衍生物组成。无色素沉着反映了颜色变化（色素减退）的宏观可见性。在显微镜下，无色素性黑色素瘤细胞中存在黑色素色素及其前体。肿瘤很容易被化学模拟黑色素生成底物的小分子靶向。此外，小分子黑色素代谢产物对黑素细胞和黑色素瘤细胞有毒性，可将它们杀死。本综述描述了我们基于合成黑色素生成相关小分子衍生物并与磁铁矿纳米颗粒偶联而开展化学-热-免疫疗法的过程。我们还介绍了其他与黑色素生成相关的化疗和热医学方法，并讨论了目前引入的针对不可切除/转移性黑色素瘤的免疫检查点抑制剂靶向疗法。
