Lack of mitochondrial toxicity in CEM cells treated with carbovir.
Carbovir (CBV) is a guanine nucleoside analog with potent in vitro anti-HIV activity. A prodrug of CBV is currently being evaluated in clinical trials as a potential agent for the treatment of AIDS. The ability of CBV to inhibit mitochondrial DNA synthesis in intact CEM cells was evaluated in the present study, because most of the currently available anti-HIV nucleoside analogs have significant toxicities that result from their inhibition of mitochondrial DNA synthesis. No delayed cytotoxicity was observed in CEM cells treated with 50 microM CBV for 4 weeks. In addition, CBV at concentrations as high as 1 mM did not cause a decline in mitochondrial DNA levels and only minimally increased the concentration of lactic acid in the medium. In contrast to these results with CBV, treatment of CEM cells with 0.5 microM 2',3'-dideoxycytidine resulted in delayed cytotoxicity, a decrease in mitochondrial DNA content and increases in lactic acid levels in the medium. These results indicated that treatment of CEM cells with CBV did not result in the inhibition of mitochondrial DNA synthesis and suggested that treatment of AIDS patients with CBV, or a prodrug of CBV, would not result in some of the toxicities seen with the other anti-HIV nucleoside analogs.
Parker
W B
WB
Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, AL 35205, USA. Parker@SRI.ORG
Shaddix
S C
SC
Vince
R
R
Bennett
L L
LL
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000821:virology; D019380:Anti-HIV Agents / Q000633:toxicity*; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000096:biosynthesis; D015224:Dideoxynucleosides / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D011355:Prodrugs / Q000633:toxicity; D016047:Zalcitabine / Q000633:toxicity
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D015224:Dideoxynucleosides; D011355:Prodrugs; C057503:carbovir; D019344:Lactic Acid; D016047:Zalcitabine