The toxicity of azidothymidine (AZT) on human and animal cells in culture at concentrations used for antiviral therapy.
AZT, a chain terminator of DNA synthesis originally developed for chemotherapy, is now prescribed as an anti-human immunodeficiency virus (HIV) drug at 500 to 1500 mg/person/day, which corresponds to 20 to 60 microM AZT. The human dosage is based on a study by the manufacturer of the drug and their collaborators, which reported in 1986 that the inhibitory dose for HIV replication was 0.05 to 0.5 microM AZT and that for human T-cells was 2000 to 20,000 times higher, i.e. 1000 microM AZT. This suggested that HIV could be safely inhibited in humans at 20 to 60 microM AZT. However, after the licensing of AZT as an anti-HIV drug, several independent studies reported 20- to 1000-fold lower inhibitory doses of AZT for human and animal cells than did the manufacturer's study, ranging from 1 to 50 microM. In accord with this, life threatening toxic effects were reported in humans treated with AZT at 20 to 60 microM. Therefore, we have re-examined the growth inhibitory doses of AZT for the human CEM T-cell line and several other human and animal cells. It was found that at 10 microM and 25 microM AZT, all cells are inhibited at least 50% after 6 to 12 days, and between 20 and 100% after 38 to 48 days. Unexpectedly, variants of all cell types emerged over time that were partially resistant to AZT. It is concluded that AZT, at the dosage prescribed as an anti-HIV drug, is highly toxic to human cells.
Chiu
D T
DT
Dept. of Molecular and Cell Biology, University of California, Berkeley 94720, USA.
Duesberg
P H
PH
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D013601:T-Lymphocytes / Q000187:drug effects; D015215:Zidovudine / Q000009:adverse effects / Q000633:toxicity*
D015215:Zidovudine