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Toxicity, metabolism, DNA incorporation with lack of repair, and lactate production for 1-(2'-fluoro-2'-deoxy-beta-D-arabinofuranosyl)-5-iodouracil in U-937 and MOLT-4 cells. 1994

R W Klecker, and A G Katki, and J M Collins
Division of Clinical Pharmacology, Food and Drug Administration, Rockville, Maryland 20850.

Two cell lines, U-937 and MOLT-4, were used to investigate the toxicity, DNA incorporation, and effect on mitochondria of 1-(2'-fluoro-2'-deoxy-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) and its putative metabolite 1-(2'-fluoro-2'-deoxy-beta-D-arabinofuranosyl)-uracil (FAU). After 72-hr incubation, the IC50 values for FIAU were 6.4 microM for U-937 cells and 26 microM for MOLT-4 cells. IC50 values for FAU were 10-fold higher in both cell lines. Incubation for 24 hr with 10 microM [2-14C]FIAU led to 2.1% and 0.93% replacement of thymidine in DNA of U-937 and MOLT-4 cells, respectively. The predominant radioactive species measurable in DNA was FIAU. A similar incubation with [2-14C]FAU resulted in 4-fold lower DNA incorporation of a single radioactive species that coeluted with 1-(2'-fluoro-2'-deoxy-beta-D-arabinofuranosyl)-5-methyluracil (FMAU). There was no evidence of a selective repair process after DNA incorporation of FIAU or FAU (FMAU). Increased intracellular concentrations of FIAU triphosphate and incorporation into DNA were associated with an increase in cellular toxicity. Continuous exposure to a clinically achievable concentration of FIAU, 0.44 microM, produced a constant DNA incorporation of 0.80% and 0.11% for U-937 and MOLT-4 cells, respectively. FIAU was not readily metabolized to FAU or iodouracil by human liver in vitro. Compared with 2',3'-dideoxycytidine as a positive control, after 12 days of continuous exposure of U-937 and MOLT-4 cells to FIAU there was no evidence of increased lactate production. These data negate several possible mechanisms (DNA chain termination, DNA polymerase inhibition, one form of selective mitochondrial poisoning, and FAU-mediated toxicity) and provide clues for possible mechanisms (FIAU triphosphate concentration and DNA incorporation). Further work is needed to develop a complete explanation for the delayed hepatic toxicity observed in the investigational clinical trials of FIAU.

UI MeSH Term Description Entries
D007773 Lactates Salts or esters of LACTIC ACID containing the general formula CH3CHOHCOOR.
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D004247 DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA, Double-Stranded,Deoxyribonucleic Acid,ds-DNA,DNA, Double Stranded,Double-Stranded DNA,ds DNA
D004260 DNA Repair The removal of DNA LESIONS and/or restoration of intact DNA strands without BASE PAIR MISMATCHES, intrastrand or interstrand crosslinks, or discontinuities in the DNA sugar-phosphate backbones. DNA Damage Response
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001086 Arabinofuranosyluracil A pyrimidine nucleoside formed in the body by the deamination of CYTARABINE. Ara-U,Arabinosyluracil,Arauridine,Sponguridine,Uracil Arabinofuranoside,Uracil Arabinoside,1-beta-D-Arabinofuranosyl Uracil,NSC 68928,1 beta D Arabinofuranosyl Uracil,Ara U,Arabinofuranoside, Uracil,Arabinoside, Uracil,Uracil, 1-beta-D-Arabinofuranosyl
D014407 Tumor Cells, Cultured Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely. Cultured Tumor Cells,Neoplastic Cells, Cultured,Cultured Neoplastic Cells,Cell, Cultured Neoplastic,Cell, Cultured Tumor,Cells, Cultured Neoplastic,Cells, Cultured Tumor,Cultured Neoplastic Cell,Cultured Tumor Cell,Neoplastic Cell, Cultured,Tumor Cell, Cultured
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular

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