Like AZT (zidovudine, Retrovir), ddI (didanosine, Videx / VidexEC) and ddC (zalcitabine, Hivid), FLT is a modified form of one of the building blocks of DNA (known as nucleosides). When HIV replicates in the presence of these nucleoside analogue drugs, the virus' reverse transcriptase enzyme incorporates the drug in the place of a normal nucleoside in the growing DNA strand. This prevents the proper assembly of viral genetic material and halts viral replication.

FLT is an abbreviation for the chemical name fluorothymidine. The drug is manufactured by Lederle.

Current use

FLT is an unlicensed, experimental drug. In a phase 1 trial it decreased levels of detectable HIV in the blood of people with ARC or AIDS. However, it also had significant side-effects, causing serious shortages of white blood cells, platelets and haemoglobin. Further studies were stopped when two participants died of liver failure. A test-tube study found that FLT caused extensive damage to the DNA of human cells, possibly explaining its severe toxicity.

Key research

Matthes found that FLT was more readily phosphorylated than AZT to a triphosphate form and confirmed FLT's ability to protect MT-4 cells from the cytopathic effects of HIV.

Polsky reported that of 14 people with ARC or AIDS enrolled in a phase I dose-ranging study of multiple oral doses of FLT, 11 were followed long enough to assess changes in one or more quantitative laboratory measures of antiretroviral activity. 7/11 (64%) had a significant (greater than 8-fold) decrease in HIV-1 titre isolated from PBMC and/or plasma. 6/7 participants with baseline p24 antigen levels of above 60 pg/mL had a greater than 50% reduction in antigenaemia. However, dose-escalation was halted when haematologic toxicity (significant decreases in haemoglobin, white blood cells and/or platelet count) was observed in 11/12 participants at the first dose level (0.25 mg/kg daily).

Phase I multi-centre concentration-control studies were halted when two patients died from acute liver failure while being treated. Sundseth reported that FLT caused extensive DNA fragmentation and induced apoptosis in CEM cells, providing a possible mechanism for its toxicity.

References

Barditch-Crovo PA et al. Phase I pharmacokinetic evaluation of 3'-deoxy-3'-fluorothymidine (FLT), a new potent anti-HIV nucleoside. Seventh International Conference on AIDS, Florence, abstract WB 2114, 1991.

Barditch-Crovo PA et al. Early markers of hematologic toxicity with FLT therapy. Eighth International Conference on AIDS, Amsterdam, abstract WeB 1012, 1992.

Matthes E et al. Phosphorylation, anti-HIV activity and cytotoxicity of 3'-fluorothymidine. Biochem & Biophys Res Comm 153:825-831, 1988.

Polsky B et al. Anti-HIV-1 activity of FLT: preliminary results from a clinical trial. Eighth International Conference on AIDS, Amsterdam, abstract PoB 3025, 1992.

Sundseth R et al. The anti-human immunodeficiency virus agent 3'-fluorothymidine induces DNA damage and apoptosis in human lymphoblastoid cells. Antimicrobial Agents and Chemotherapy 40(2):331-335, 1996.