Joyner SS, Novak P, Dornsife RE, Dev IK; Interscience Conference on Antimicrobial Agents and Chemotherapy.

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 1994 Oct 4-7; 93.

Wellcome Research Laboratories, Research Triangle Park, NC.

The anti-HIV agent FLT (3'-fluoro-2',3'-dideoxythymidine) exhibits enhanced hematopoietic toxicity compared to AZT (3'-azido-3'-deoxythymidine) and 935U83 (5-chloro-2',3'- dideoxy-3'-fluorouridine). To determine the molecular basis of this difference, we compared various biochemical parameters of these agents in CEM and human bone marrow mononuclear cells. Intracellular concentrations of FLT- triphosphate correlated with increased cytotoxicity of FLT in CEM and bone marrow cells. In cells exposed to 5 micromolar drug for 24 hr, the intracellular levels of FLT- triphosphate were approximately 10- and 50-fold higher than AZT- and 935U83-triphosphate, respectively. DNA from CEM cells exposed to FLT, AZT or 935U83 for 24 hr was analyzed by pulsed field gel electrophoresis. For FLT (1-100 micromolar), there was a dose-dependent increase in DNA fragmentation, seen in both the 0.2-2.2 Mb and 3.5-5.7 Mb ranges tested. Neither AZT nor 935U83 at 100 micromolar caused significant DNA damage. In contrast, when CEM cells were exposed to radiolabeled FLT, AZT or 935U83, the accumulation of radiolabeled drug into DNA did not correlate with the increased cytotoxicity of FLT. Misincorporated drugs in DNA may be rapidly excised and repaired. The data suggest that the very high levels of FLT-triphosphate that accumulate in FLT-treated cells may inhibit the repair of the damaged DNA. The single stranded DNA generated by excision of the fraudulent base is cleaved by endonuclease(s) which may result in the increased DNA damage and toxicity due to FLT. These data are consistent with the previous in vitro and in vivo toxicology data which demonstrate that 935U83 and AZT are much less cytotoxic than FLT.

Publication Types:

• Meeting Abstracts

Keywords:

• Anti-HIV Agents
• DNA
• DNA Damage
• Dideoxynucleosides
• Drug Toxicity
• Hematopoiesis
• Humans
• In Vitro
• Zidovudine
• genetics
• raluridine
• toxicity

Other ID:

• 95920790

UI: 102213733

From Meeting Abstracts