In vitro toxicity and metabolism of 2',3'-dideoxycytidine, an inhibitor of human immunodeficiency virus infectivity.
U937 human monoblastoid cell growth was inhibited in a concentration-dependent manner by 2',3'-dideoxycytidine (ddCyd) (an antiretroviral drug) up to 500 microM. Cell growth inhibition was associated with a pronounced increase in cell volume, however this was not due to cell ATP or NAD+ depletion that could effect osmotic balance or DNA repair. This ddCyd toxicity paralleled the accumulation of ddCyd into acid soluble material where 2',3'-dideoxycytidine-5'-triphosphate (ddCTP) was the predominant labelled nucleotide up to an extracellular ddCyd concentration of 150 microM. At higher ddCyd concentrations, the amount of 2',3'-dideoxycytidine-5'-diphosphate (ddCDP) became predominant over ddCTP. This increase of phosphorylated dideoxycytidine in U937 cells was also associated with an increased incorporation of the drug into cell DNA suggesting a possible toxicity mechanism. That ddCyd does indeed become cytotoxic to human cell by incorporation into DNA was shown by incubating human resting and stimulated lymphocytes with ddCyd. While the drug does not affect cell viability in resting cells it strongly affects cell proliferation upon phytohemagglutinin (PHA) addition.
Brandi
G
G
Instituto di Scienze Tossicologiche, Igienistiche ed Ambientali, Urbino, Italy.
Rossi
L
L
Schiavano
G F
GF
Salvaggio
L
L
Albano
A
A
Magnani
M
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000998:Antiviral Agents / Q000378:metabolism / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D009243:NAD / Q000378:metabolism; D010766:Phosphorylation; D014407:Tumor Cells, Cultured; D016047:Zalcitabine / Q000378:metabolism / Q000633:toxicity*
D000998:Antiviral Agents; D003845:Deoxycytosine Nucleotides; D009243:NAD; D016047:Zalcitabine; D000255:Adenosine Triphosphate