Deoxycytidine in human plasma: potential for protecting leukemic cells during chemotherapy.
Degradation of DNA produces deoxycytidine. Metabolism of deoxycytidine to dCTP inhibits phosphorylation of cytosine arabinoside (araC), fludarabine (FaraA) and 2-chlorodeoxyadenosine (CdA) by deoxycytidine kinase. This study measured plasma deoxycytidine in healthy adults and two leukemia patients and then determined how clinically relevant deoxycytidine levels would affect drug toxicity in human leukemia and lymphoma cells. Deoxycytidine was well below 0.05 microM in ten healthy persons. In the leukemia patients it was <0.05 and 0.44 microM before chemotherapy, rising to 10.3 and 5.5 microM during treatment. A broad range of clinically relevant deoxycytidine levels were high enough to profoundly decrease araC, FaraA and CdA toxicity in MOLT3, CA46 and HL60 leukemia/lymphoma cells and to change dCTP, DNA synthesis and drug incorporation into DNA in a manner consistent with prior mechanistic studies. Varying deoxycytidine levels could be an important factor influencing leukemia therapy.
Cohen
J D
JD
Division of Medical Oncology, University of Colorado Health Sciences Center and Denver Veterans Administration Medical Center, 80262, USA.
Strock
D J
DJ
Teik
J E
JE
Katz
T B
TB
Marcel
P D
PD
D000328:Adult; D017338:Cladribine / Q000378:metabolism / Q000633:toxicity; D003561:Cytarabine / Q000378:metabolism / Q000633:toxicity; D003841:Deoxycytidine / Q000097:blood*; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy*; D014740:Vidarabine / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity
D003845:Deoxycytosine Nucleotides; D003561:Cytarabine; D003841:Deoxycytidine; C024107:2'-deoxycytidine 5'-triphosphate; D017338:Cladribine; D014740:Vidarabine; C024352:fludarabine