Lindström P, Olsson P, Malmqvist J, Pettersson J, Lemmen P, Werner B, Sjöberg S, Olin A, Carlsson J
Department of Radiation Sciences, Uppsala University, Sweden.
Anticancer Drugs. 1994 Feb;5(1):43-52.
The toxicity and binding of the three new carborane based compounds: 2 (1,2-dicarba-closo-dodecaborane (12)-1(-yl-methoxy)-2-(3-amino-propyl))-1,3-propanediol, called DAC-1; 7-(3-amino-propyl)-7,8-dicarba-nido-undecarborate (-1) called ANC-1; and rac-1-(9-o-carboranyl)-nonyl-2-methyl-glycero-3- phosphocholine, called B-Et-11-OMe, were analyzed with cultured human glioma cells, U-343MGa, and mouse melanoma cells, B16, as biological models. The previously developed compound di-sodium undecahydro-mercapto-closo-dodecarborate (BSH), which is tested for therapy of malignant gliomas, was analyzed for comparison. In the toxicity tests the cells were exposed to the substances at cell culture medium concentrations in the range 0-50 ppm boron for 1 or 20 h and thereafter analyzed regarding growth. Growth-disturbing effects were seen for the two compounds DAC-1 and B-Et-11-OMe at the concentrations corresponding to 15 and 50 ppm boron, respectively. The compounds ANC-1 and BSH showed no growth-disturbing effects at the tested concentrations. In the binding tests, the cells were incubated for 20 h at about the highest compound concentrations that did not cause growth disturbances. The boron content in the cells was then determined by inductively coupled plasma-atomic emission spectrometry (ICP-AES) and in some cases ICP-mass spectrometry (ICP-MS). The most extensive binding was seen for DAC-1 and B-Et-11-OMe, which accumulated boron to about 100 and 60 times, respectively, compared with the concentration in the culture medium. The compound ANC-1 also accumulated boron in the cells but the boron could be easily washed out indicating no or only a weak binding. BSH did not accumulate. Further analysis should be made regarding biological properties such as intracellular compartmentalization, metabolic interference and tumor specificity of the compounds DAC-1 and B-Et-11-OMe.
以培养的人胶质瘤细胞U - 343MGa和小鼠黑色素瘤细胞B16作为生物学模型，分析了三种新型碳硼烷基化合物的毒性和结合情况：2 (1,2 - 二碳 - 闭式 - 十二硼烷(12) - 1(- 基 - 甲氧基) - 2 - (3 - 氨基丙基)) - 1,3 - 丙二醇，称为DAC - 1；7 - (3 - 氨基丙基) - 7,8 - 二碳 - 巢式 - 十一硼酸盐(-1)，称为ANC - 1；以及rac - 1 - (9 - o - 碳硼烷基) - 壬基 - 2 - 甲基 - 甘油 - 3 - 磷酸胆碱，称为B - Et - 11 - OMe。为作比较，还分析了先前开发的用于恶性胶质瘤治疗试验的化合物十一氢 - 巯基 - 闭式 - 十二碳硼酸钠(BSH)。在毒性试验中，将细胞暴露于硼浓度在0 - 50 ppm范围内的细胞培养基中的这些物质中1或20小时，然后分析其生长情况。分别在相当于15和50 ppm硼的浓度下，观察到化合物DAC - 1和B - Et - 11 - OMe有生长干扰作用。化合物ANC - 1和BSH在测试浓度下未显示出生长干扰作用。在结合试验中，将细胞在约不引起生长干扰的最高化合物浓度下孵育20小时。然后通过电感耦合等离子体原子发射光谱法(ICP - AES)，在某些情况下还通过ICP - 质谱法(ICP - MS)测定细胞中的硼含量。观察到DAC - 1和B - Et - 11 - OMe的结合最为广泛，与培养基中的浓度相比，它们分别使硼积累约100倍和60倍。化合物ANC - 1也在细胞中积累硼，但硼很容易被洗出，表明没有或只有弱结合。BSH没有积累。应进一步分析化合物DAC - 1和B - Et - 11 - OMe的生物学特性，如细胞内区室化、代谢干扰和肿瘤特异性。
