Serrone L, Hersey P
I Division of Medical Oncology, Regina Elena Institute, Rome, Italy.
Melanoma Res. 1999 Feb;9(1):51-8. doi: 10.1097/00008390-199902000-00007.
Malignant melanoma is considered to be a chemotherapy-refractory tumour and the commonly used anticancer drugs do not seem to modify the prognosis of metastatic disease. The cellular resistance mechanisms involved in melanoma chemoresistance have not yet been elucidated. Melanoma-derived cell lines are often markedly chemoresistant. Using the in vitro soft agar culture system to predict tumour cell sensitivity in well-established human melanoma cell lines, a high degree of resistance against all the cytostatic agents studied has been reported, suggesting the presence of intrinsic cellular resistance mechanisms. The relevance of the well-defined resistance mechanisms mediated by P-glycoprotein, multidrug resistance-associated protein (MRP), the glutathione/glutathione S-transferase system and topoisomerase II enzyme are reviewed. Mutated N-Ras oncogene has recently been implicated in melanoma resistance to cisplatin, both in vitro and in vivo, and the role of two other oncogenes, Bcl-2 and p53, which are already involved in the chemoresistance of haematological and solid malignancies, is beginning to be better elucidated. The finding that many chemotherapeutic agents can kill susceptible cells through the apoptosis pathway provides new molecular insight into chemoresistance mechanisms and suggests that apoptosis and/or resistance to apoptosis of melanoma cells should be investigated to better clarify the mechanism of melanoma chemoresistance.
恶性黑色素瘤被认为是一种对化疗耐药的肿瘤，常用的抗癌药物似乎并不能改变转移性疾病的预后。黑色素瘤化疗耐药所涉及的细胞耐药机制尚未阐明。黑色素瘤来源的细胞系通常具有明显的化疗耐药性。利用体外软琼脂培养系统预测成熟的人黑色素瘤细胞系中的肿瘤细胞敏感性，已有报道显示对所研究的所有细胞抑制剂具有高度耐药性，这表明存在内在的细胞耐药机制。本文综述了由P-糖蛋白、多药耐药相关蛋白（MRP）、谷胱甘肽/谷胱甘肽S-转移酶系统和拓扑异构酶II介导的明确耐药机制的相关性。最近，已证实突变的N-Ras癌基因在体外和体内均与黑色素瘤对顺铂的耐药性有关，另外两个已参与血液系统和实体恶性肿瘤化疗耐药的癌基因Bcl-2和p53的作用也开始得到更清晰的阐释。许多化疗药物可通过凋亡途径杀死敏感细胞这一发现为耐药机制提供了新的分子见解，并表明应研究黑色素瘤细胞的凋亡和/或对凋亡的抗性，以更好地阐明黑色素瘤化疗耐药的机制。
