The effect in vitro of 2'-deoxycytidine on the metabolism and cytotoxicity of 2',3'-dideoxycytidine.
We examined in vitro the effect of high, but clinically achievable and non-toxic, concentrations of 2'-deoxycytidine (dCyd) (greater than or equal to 100 mumols/l on the metabolism and cytotoxicity of 2',3'-dideoxycytidine (DDC) in normal human bone marrow mononuclear cells (BMMCs) and a cultured T-lymphocyte (HUT-102) cell line. Colony formation in semi-solid medium by bone marrow progenitor cells (CFU-GM and CFU-GEMM) was significantly protected by dCyd against the cytotoxic effects of high doses of DDC. In contrast, in HIV-infected HUT-102 cells, anti-HIV effect of DDC (10 mumols/l) was preserved in the presence of 100 mumols/l dCyd but partially reversed by higher levels of dCyd. dCyd reduced the generation of DDC triphosphate (DDC-TP) relative to dCyd triphosphate (dCTP) pools to a significantly greater extent in BMMCs versus HUT-102 cells. This might explain dCyd-mediated abrogation of DDC cytotoxicity against marrow progenitor cells with relative preservation of its anti-HIV-1 activity in HUT-102 cells.
Bhalla
K N
KN
Division of Hematology/Oncology, Medical University of South Carolina, Charleston 29425.
Li
G R
GR
Grant
S
S
Cole
J T
JT
MacLaughlin
W W
WW
Volsky
D J
DJ
D002460:Cell Line; D003841:Deoxycytidine / Q000378:metabolism / Q000494:pharmacology*; D015683:Gene Products, gag / Q000032:analysis; D016655:HIV Core Protein p24; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D014758:Viral Core Proteins / Q000032:analysis; D015215:Zidovudine / Q000494:pharmacology
D015683:Gene Products, gag; D016655:HIV Core Protein p24; D014758:Viral Core Proteins; D003841:Deoxycytidine; D015215:Zidovudine