Paradoxical effect of cytosine arabinoside on mouse leukemia cell line L1210 cells.
We investigated the effects of 1-beta-D-arabinofuranosylcytosine (ara-C) on the growth of murine leukemic L1210 cells, which were cultured with high (2.0 x 10(3) ng/ml), middle (100 ng/ml) and low doses (5.0 ng/ml) of ara-C. In the analysis by flow cytometry, high dose ara-C arrested the cell cycle in the G0/G1-phase. Middle and low doses ara-C induced a block in the S-phase, that was not completely blocked by the low dose. Analysis of DNA fragmentation revealed that ara-C dose-dependently induced apoptosis, which was only slightly induced by the low dose. We measured activities of cellular thymidylate synthase (TS) and thymidine kinase (TK) after 24-h culture. Low and middle doses, but not high dose ara-C markedly enhanced TS activity to 2.9- in low and 5.3-fold in middle doses ara-C, and TK activity to 1.3- in low and 2.2-fold in middle doses, respectively, compared with those of the control. The cells accumulated in the S-phase by 48-h culture with low dose ara-C and markedly proliferated compared to that of the control in ara-C-free medium. These results indicate that non-high dose ara-C enhances DNA-synthesizing enzyme activities in L1210 cells, and withdrawal of the non-high dose ara-C results in paradoxical cell proliferation. Thus, daily intramuscular injections with an insufficient dose of ara-C may induce cells into S-phase, resulting in the proliferation of leukemic cells.
Nakayama
Tohru
T
Nursing Science, School of Allied Health Sciences, Faculty of Medicine, Tokyo Medical and Dental University, Japan.
Sakamoto
Shinobu
S
Sassa
Shuji
S
Suzuki
Satoe
S
Kudo
Hideki
H
Nagasawa
Hiroshi
H
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003561:Cytarabine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D016196:S Phase / Q000187:drug effects; D013937:Thymidine Kinase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D013940:Thymidylate Synthase; D013937:Thymidine Kinase