Metabolism of 4'-thio-beta-D-arabinofuranosylcytosine in CEM cells.
Because of the excellent in vivo activity of 4'-thio-beta-D-arabinofuranosylcytosine (T-araC) against a variety of human solid tumors, we have studied its metabolism in CEM cells to determine how the biochemical pharmacology of this compound differs from that of beta-D-arabinofuranosylcytosine (araC). Although there were many quantitative differences in the metabolism of T-araC and araC, the basic mechanism of action of T-araC was similar to that of araC: it was phosphorylated to T-araC-5'-triphosphate (T-araCTP) and inhibited DNA synthesis. The major differences between these two compounds were: (i) T-araC was phosphorylated to active metabolites at 1% the rate of araC; (ii) T-araCTP was 10- to 20-fold more potent as an inhibitor of DNA synthesis than was the 5'-triphosphate of araC (araCTP); (iii) the half-life of T-araCTP was twice that of araCTP; (iv) the catalytic efficiency of T-araC with cytidine deaminase was 10% that of araC; and (v) the 5'-monophosphate of araC was a better substrate for deoxycytidine 5'-monophosphate deaminase than was the 5'-monophosphate of T-araC. Of these differences in the metabolism of these two compounds, we propose that the prolonged retention of T-araCTP is a major factor contributing to the activity of T-araC against solid tumors. The data in this study represent another example of how relatively small structural changes in nucleoside analogs can profoundly affect the biochemical activity.
Parker
W B
WB
Southern Research Institute, Birmingham, AL 35205, USA. PARKER@SRI.ORG
Shaddix
S C
SC
Rose
L M
LM
Waud
W R
WR
Shewach
D S
DS
Tiwari
K N
KN
Secrist
J A
JA
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D001087:Arabinonucleosides / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D001692:Biological Transport; D002455:Cell Division / Q000187:drug effects; D003561:Cytarabine / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D003564:Cytidine Deaminase / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D003641:Deamination; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000378:metabolism; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D013872:Thionucleosides / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D003845:Deoxycytosine Nucleotides; D013872:Thionucleosides; D003561:Cytarabine; D003841:Deoxycytidine; C070453:2'-deoxy-4'-thiocytidine; C024107:2'-deoxycytidine 5'-triphosphate; D004247:DNA; D003842:Deoxycytidine Kinase; D003564:Cytidine Deaminase; C411255:4'-thio-arabinofuranosylcytosine