New carborane-based compounds for boron neutron capture therapy: binding and toxicity of ANC-1, DAC-1 and B-Et-11-OMe in cultured human glioma and mouse melanoma cells.
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.
Lindström
P
P
Department of Radiation Sciences, Uppsala University, Sweden.
Olsson
P
P
Malmqvist
J
J
Pettersson
J
J
Lemmen
P
P
Werner
B
B
Sjöberg
S
S
Olin
A
A
Carlsson
J
J
D000818:Animals; D001880:Boranes / Q000493:pharmacokinetics / Q000633:toxicity*; D001896:Boron Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D016754:Boron Neutron Capture Therapy; D002470:Cell Survival / Q000187:drug effects; D005910:Glioma / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D013058:Mass Spectrometry; D008546:Melanoma, Experimental / Q000378:metabolism / Q000532:radiotherapy*; D051379:Mice; D010713:Phosphatidylcholines / Q000493:pharmacokinetics / Q000633:toxicity*; D011437:Propylamines / Q000493:pharmacokinetics / Q000633:toxicity*; D013052:Spectrometry, X-Ray Emission; D014407:Tumor Cells, Cultured
C087324:1-(9-o-carboranyl)nonyl-2-methyl-glycero-3-phosphocholine; D001880:Boranes; D001896:Boron Compounds; D010713:Phosphatidylcholines; D011437:Propylamines; C087323:ANC 1; C087322:DAC 1