Helmbach Heike, Sinha Pranav, Schadendorf Dirk
Klinische Kooperationseinheit für Dermatoonkologie (DKFZ) an der Universitäts-Hautklinik Mannheim, Universität Heidelberg, 68135 Mannheim, Germany.
Recent Results Cancer Res. 2003;161:93-110. doi: 10.1007/978-3-642-19022-3_9.
Advanced malignant melanoma has a poor prognosis since chemotherapy is mostly ineffective because, in part, of the intrinsic and/or extrinsic resistance of melanoma cells to systemic treatment with antineoplastic agents. The reasons for the chemoresistant phenotype are currently unknown. The relevance of well-analyzed drug resistance mechanisms in melanoma such as intracellular and extracellular transport, drug resistance by induction of certain enzyme systems, and altered drug-target interaction is reviewed. It has been shown that most anticancer drugs kill susceptible cells through induction of apoptosis. Therefore, the significance of apoptotic deficiency caused by alteration in the apoptotic pathway is discussed in relation to specific molecules and apoptotic mechanisms like death-receptors, the Bcl-2 family, and the Hsp family of proteins. The complexity of the molecular variants involved in signal transduction along apoptotic pathways suggests that the cell may possess a variety of possibilities for regulating apoptosis and generating apoptosis deficiency. Thus apoptosis and apoptosis deficiency should be analyzed to understand the mechanisms of melanoma resistance.
晚期恶性黑色素瘤预后较差，因为化疗大多无效，部分原因是黑色素瘤细胞对使用抗肿瘤药物进行全身治疗存在内在和/或外在抗性。目前尚不清楚产生化疗抗性表型的原因。本文综述了黑色素瘤中经过充分分析的耐药机制的相关性，如细胞内和细胞外转运、通过诱导某些酶系统产生耐药性以及药物-靶点相互作用改变。研究表明，大多数抗癌药物通过诱导凋亡来杀死敏感细胞。因此，本文结合死亡受体、Bcl-2家族和热休克蛋白家族等特定分子和凋亡机制，讨论了凋亡途径改变导致的凋亡缺陷的意义。凋亡途径中信号转导所涉及的分子变体的复杂性表明，细胞可能拥有多种调节凋亡和产生凋亡缺陷的可能性。因此，应该分析凋亡和凋亡缺陷，以了解黑色素瘤耐药的机制。
