Chloroacetaldehyde: mode of antitumor action of the ifosfamide metabolite.
BACKGROUND
The ifosfamide metabolite chloroacetaldehyde had been made responsible for side effects only. We found in previous studies a strong cytotoxicity on human MX-1 tumor cells and xenografts in nude mice. Chloroacetaldehyde is supposed to act via alkylation or by inhibition of mitochondrial oxidative phosphorylation with decrease of ATP. The aim of this study was to further elucidate chloroacetaldehyde's mode of action.


METHODS
MX-1 breast carcinoma cells were measured for ATP-content after exposure to chloroacetaldehyde. Further, the effect of chloroacetaldehyde on DNA-synthesis and its potency of causing strand-breaks or cross-links were investigated by bromodeoxyuridine-incorporation, comet-assay and a DNA interstrand cross-linking-assay.


RESULTS
Chloroacetaldehyde in high concentrations induces a reduction of ATP-levels when anaerobic glycolysis is blocked by oxamate and reduces the bromodeoxyuridine-incorporation to 46.3% after 4 h when used in IC(50) concentrations (7.49 mumol/l). In addition we observed DNA single strand-breaks in MX-1 cells treated with chloroacetaldehyde visible in the Comet assay, but no DNA-cross-linking by comet assay and cross-linking assay.


CONCLUSIONS
In summary, our results show that chloroacetaldehyde influences the oxidative phosphorylation in mitochondria, however, this is observed only in high concentrations and is not of clinical relevance because the tumor cells regenerate ATP by anaerobic glycolysis. Nevertheless, chloroacetaldehyde causes DNA-strand-breaks and strong inhibition of DNA-synthesis.
Brüggemann
Svenja K
SK
Department of Internal Medicine, Section of Hematology/Oncology, University of Luebeck, Germany.
Radike
Kerstin
K
Braasch
Kirsten
K
Hinrichs
Jürgen
J
Kisro
Jens
J
Hagenah
Wibke
W
Peters
Stefan O
SO
Wagner
Thomas
T
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000032:analysis / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000032:analysis / Q000378:metabolism; D045744:Cell Line, Tumor; D020552:Comet Assay / Q000379:methods; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000737:chemistry / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007069:Ifosfamide / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology
D018906:Antineoplastic Agents, Alkylating; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D019384:Nucleic Acid Synthesis Inhibitors; D000255:Adenosine Triphosphate; C004656:chloroacetaldehyde; D001973:Bromodeoxyuridine; D000079:Acetaldehyde; D007069:Ifosfamide