Selectivity of effects of redox-active cobalt(III) complexes on tumor tissue.
OBJECTIVE
To estimate the selectivity of action of cobalt complexes on tumor tissue.


METHODS
Cobalt(III) complexes containing both the tetradentate Schiff-base ligand derived from acetylacetone and ethylenediamine, and compounds of the vitamin PP series or their synthetic analogs, viz. nicotinamide, isonicotinamide or nicotinic acid, as extra (axial) ligands, were tested in vivo on transplanted mice tumors, namely Lewis lung carcinoma (3LL), melanoma B16, and mammary adenocarcinoma Ca755. concentrations of malondialdehyde in tissue extracts were measured by standard biochemical methods. The rate of DNA unwinding was used to detect DNA damage in tumor cells. Level of tumor hypoxia as well as bioenergetic status were estimated using 31P NMR spectroscopy in perchloric acid extracts of tissue.


RESULTS
A significant and selective increase of malondialdehyde in tumor tissue reflecting activation of lipid peroxidation was found after administration of the complexes. The bioenergetic status in tumor was also selectively affected by the complexes: minimization of signals of high-energy phosphates was observed two hours after injection of the complexes. An increase of the number of DNA single-strand breaks was registered in tumor tissue, supporting the suggestion that the complexes may directly affect DNA. A correlation between the above tumor effects and the structure of axial ligands was demonstrated.


CONCLUSIONS
Cobalt(III) complexes affect tumor tissue with a very high level of selectivity; in particular they activate lipid peroxidation, induce DNA single-strand breaks, suppress the bioenergetic status, and enhance hypoxia. It is supposed that the selective action of these complexes on tumor tissue is due to peculiarities of tumor microphysiology, in particular significant tumor hypoxia.
Osinsky
Sergey
S
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology of National Academy of Sciences, Kiev, Ukraine. osion@onconet.kiev.ua
Levitin
Ilia
I
Bubnovskaya
Larissa
L
Sigan
Andrey
A
Ganusevich
Irina
I
Kovelskaya
Antonina
A
Valkovskaya
Natalya
N
Campanella
Luigi
L
Wardman
Peter
P
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000378:metabolism / Q000473:pathology*; D003035:Cobalt / Q000627:therapeutic use*; D004249:DNA Damage / Q000187:drug effects; D005029:Ethylenediamines / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D000860:Hypoxia; D008024:Ligands; D015227:Lipid Peroxidation; D008315:Malondialdehyde / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009525:Niacin / Q000378:metabolism / Q000494:pharmacology; D009536:Niacinamide / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D010422:Pentanones / Q000378:metabolism / Q000494:pharmacology
D005029:Ethylenediamines; D008024:Ligands; D010422:Pentanones; D009536:Niacinamide; D009525:Niacin; D003035:Cobalt; C008790:acetylacetone; C027681:isonicotinamide; D008315:Malondialdehyde; C031234:ethylenediamine