Effect of anti-HIV 2'-beta-fluoro-2',3'-dideoxynucleoside analogs on the cellular content of mitochondrial DNA and on lactate production.
Many dideoxynucleosides that are effective against human immunodeficiency virus (HIV) also are potent inhibitors of mitochondrial DNA (mtDNA) synthesis, and the resulting mtDNA decrease could be responsible for the delayed clinical toxicity sometimes observed with these drugs. The following compounds have been examined for their toxicity to human lymphoid CEM cells, and their ability to suppress mtDNA content: 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyinosine (ddI) and 2',3'-dideoxyguanosine (ddG); and their 2'-beta-fluoro analogs; beta-F-ddC, beta-F-ddA, beta-F-ddI and beta-F-ddG. Two other fluoro analogs, 5-F-ddC and 2'-beta,5-di-F-ddC were also examined. The ratio of C-IC50 (concentration that inhibited cell growth by 50%) to mt-IC50 (concentration that inhibited mtDNA synthesis by 50%) was determined for each compound. The rank-order of this ratio was ddC > 5-F-ddC >> ddA > ddI > ddG > beta-F-ddC > beta-F-ddA > beta-F-ddG with the highest ratios indicating the greatest potential for delayed toxicity. In comparison with ddC, beta-F-ddC and beta-F-ddA were 5,000 and 22,000 times less potent, respectively, in suppressing cellular mtDNA content, while their anti-HIV potencies were decreased only modestly relative to their unfluorinated parent compounds. beta-F-ddI and 2'-beta,5-di-F-ddC produced neither cellular toxicity nor mtDNA suppression at concentrations of 500 and 1000 microM, respectively. Lactic acid, the product of compensatory glycolysis that results from the inhibition of mitochondrial oxidative phosphorylation, was measured after cells were treated with these compounds. There appears to be a concentration-related correlation between the increase of lactic acid and the extent of mtDNA inhibition for the compounds examined.
Tsai
C H
CH
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510.
Doong
S L
SL
Johns
D G
DG
Driscoll
J S
JS
Cheng
Y C
YC
D000998:Antiviral Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D004247:DNA / Q000032:analysis*; D015224:Dideoxynucleosides / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005461:Fluorine; D006801:Humans; D007773:Lactates / Q000032:analysis*; D008928:Mitochondria / Q000187:drug effects*; D019384:Nucleic Acid Synthesis Inhibitors; D010085:Oxidative Phosphorylation / Q000187:drug effects
D000998:Antiviral Agents; D015224:Dideoxynucleosides; D007773:Lactates; D019384:Nucleic Acid Synthesis Inhibitors; D005461:Fluorine; D004247:DNA