Demidem A, Morvan D, Papon J, De Latour M, Madelmont J C
Institut National de la Santé et de la Recherche Médicale U 484, Clermont-Ferrand, France.
Cancer Res. 2001 Mar 1;61(5):2294-300.
N'-(2-Chloroethyl)-N-(2-(methylsulfonyl)-ethyl)-N'-nitrosourea (cystemustine) is a chloroethylnitrosourea that has been used in the treatment of human melanoma. Its main antitumor effect is DNA damage to malignant melanocytes. Although unreported at present, other effects may also account for its cytotoxicity, some of them could be more or less delayed with respect to its administration. In this report, we have developed a model of secondary tumor with B16 melanoma in syngeneic C57B16 recipients to investigate the impact of cystemustine treatment of primary B16 melanoma tumors on the fate of secondary implanted untreated tumors. The data presented in this report indicate that cystemustine-treated cells or the administration of cystemustine provoke an important growth delay of primary melanoma tumors, together with an increase in cell pigmentation and cell morphology changes. Data also show that prime treatment induces a dramatic decrease in tumor weight of secondary untreated tumors accompanied by an increase in melanin content and an alteration of cell morphology. Finally, 1H-NMR spectroscopy was performed on treated B16 cells, showing an alteration in the phospholipid derivatives of melanocytes, suggesting subsequent modifications of membrane phospholipid composition. In conclusion, the data highlight two important findings: (a) cystemustine produces modifications other than DNA damage, i.e., cell morphology changes, pigmentation, and phospholipid metabolism alterations, indicating an interference with cell cycle, cell redifferentiation, and proliferation programs; and (b) cystemustine-treated tumors appear to confer a protective effect against the development of secondary untreated tumors that may be mediated by cytokines or an immune response.
N'-(2-氯乙基)-N-(2-(甲基磺酰基)-乙基)-N'-亚硝基脲（顺式氮芥）是一种氯乙基亚硝基脲，已用于治疗人类黑色素瘤。其主要抗肿瘤作用是对恶性黑色素细胞造成DNA损伤。尽管目前尚未见报道，但其他作用也可能解释其细胞毒性，其中一些作用相对于给药时间可能或多或少有所延迟。在本报告中，我们建立了同基因C57B16受体中B16黑色素瘤的继发性肿瘤模型，以研究顺式氮芥治疗原发性B16黑色素瘤肿瘤对继发性未治疗植入肿瘤命运的影响。本报告中的数据表明，顺式氮芥处理的细胞或顺式氮芥的给药会导致原发性黑色素瘤肿瘤显著生长延迟，同时细胞色素沉着增加和细胞形态改变。数据还显示，初次治疗会导致继发性未治疗肿瘤的肿瘤重量显著降低，同时黑色素含量增加和细胞形态改变。最后，对处理过的B16细胞进行了1H-NMR光谱分析，结果显示黑色素细胞的磷脂衍生物发生了改变，提示膜磷脂组成随后发生了变化。总之，这些数据突出了两个重要发现：(a) 顺式氮芥除了造成DNA损伤外，还会产生其他改变，即细胞形态改变、色素沉着和磷脂代谢改变，表明对细胞周期、细胞再分化和增殖程序有干扰；(b) 顺式氮芥处理过的肿瘤似乎对继发性未治疗肿瘤的发展具有保护作用，这可能是由细胞因子或免疫反应介导的。
