Ask A, Persson L, Seiler N, Heby O
Department of Oncology, University of Lund, Sweden.
Cancer Lett. 1993 Apr 15;69(1):33-8. doi: 10.1016/0304-3835(93)90029-9.
To determine whether non-metabolizable derivatives of spermidine and spermine exert anticancer effects, L1210 leukemic mice were treated with 5,8-dimethylspermidine and 5,8-dimethylspermine. Both derivatives cured 5% of the leukemic mice. The increase in median survival time, however, was slight. In combination with alpha-difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, only 5,8-dimethylspermine had a favorable effect. Treatment with DFMO is known to increase the uptake of extracellular polyamines and presumably their derivatives, by depleting the intracellular putrescine and spermidine content. However, treatment of L1210 leukemia cells in vitro with DFMO did not affect the uptake of the methyl-substituted polyamines added to the growth medium. 5,8-Dimethylspermidine and 5,8-dimethylspermine repressed the ornithine decarboxylase activity when added to cultures of L1210 leukemia cells. S-Adenosylmethionine decarboxylase activity was only repressed by 5,8-dimethylspermine. This finding may explain the potentiation by this derivative and not by 5,8-dimethylspermidine, of the antileukemic effect of DFMO.
为了确定亚精胺和精胺的不可代谢衍生物是否具有抗癌作用，用5,8-二甲基亚精胺和5,8-二甲基精胺对L1210白血病小鼠进行治疗。两种衍生物均治愈了5%的白血病小鼠。然而，中位生存时间的增加很轻微。与鸟氨酸脱羧酶抑制剂α-二氟甲基鸟氨酸（DFMO）联合使用时，只有5,8-二甲基精胺具有良好的效果。已知用DFMO治疗可通过消耗细胞内腐胺和亚精胺含量来增加细胞外多胺及其衍生物的摄取。然而，在体外使用DFMO处理L1210白血病细胞并不影响添加到生长培养基中的甲基取代多胺的摄取。当添加到L1210白血病细胞培养物中时，5,8-二甲基亚精胺和5,8-二甲基精胺可抑制鸟氨酸脱羧酶活性。S-腺苷甲硫氨酸脱羧酶活性仅被5,8-二甲基精胺抑制。这一发现可能解释了该衍生物而非5,8-二甲基亚精胺对DFMO抗白血病作用的增强作用。
