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 immunodeficie ncy 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. Th e following compounds have been examined for their toxicity to human l ymphoid CEM cells, and their ability to suppress mtDNA content: 2',3'- dideoxycytidine (ddC), 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyinos ine (ddI) and 2',3'-dideoxyguanosine (ddG); and their 2'-beta-fluoro a nalogs; beta-F-ddC, beta-F-ddA, beta-F-ddI and beta-F-ddG. Two other f luoro 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 m t-IC50 (concentration that inhibited mtDNA synthesis by 50%) was deter mined for each compound. The rank-order of this ratio was ddC > 5-F-dd C much greater than ddA > ddI > ddG > beta-F-ddC > beta-F-ddA > beta-F -ddG with the highest ratios indicating the greatest potential for del ayed toxicity. In comparison with ddC, beta-F-ddC and beta-F-ddA were 5,000 and 22,000 times less potent, respectively, in suppressing cellu lar 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 su ppression at concentrations of 500 and 1000 mu M, respectively. Lactic acid, the product of compensatory glycolysis that results from the in hibition of mitochondrial oxidative phosphorylation, was measured afte r cells were treated with these compounds. There appears to be a conce ntration-related correlation between the increase of lactic acid and t he extent of mtDNA inhibition for the compounds examined.