Effects of 2-chloro-2'-deoxyadenosine on the cell cycle in the human leukemia EHEB cell line.
To explain why 2-chloro-2'-deoxyadenosine (CdA) is unable to block DNA synthesis and cell cycle progression, and paradoxically enhances progression from G1 into S phase in the CdA-resistant leukemia EHEB cell line, we studied its metabolism and effects on proteins regulating the transition from G1 to S phase. A low deoxycytidine kinase activity and CdATP accumulation, and a lack of p21 induction despite p53 phosphorylation and accumulation may account for the inability of CdA to block the cell cycle. An alternative pathway involving pRb phosphorylation seems implicated in the CdA-induced increase in G1 to S phase progression.
Cardoen
S
S
Laboratory of Physiological Chemistry, Christian de Duve Institute of Cellular Pathology, Université Catholique de Louvain, Brussels, Belgium.
Van den Neste
E
E
Smal
C
C
Rosier
J F
JF
Ferrant
A
A
Van den Berghe
G
G
Bontemps
F
F
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D017338:Cladribine / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism; D003842:Deoxycytidine Kinase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000378:metabolism; D005434:Flow Cytometry; D016193:G1 Phase; D006801:Humans; D020128:Inhibitory Concentration 50; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D016196:S Phase; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D017338:Cladribine; D004247:DNA; D003842:Deoxycytidine Kinase; D001973:Bromodeoxyuridine