Enhanced retention of cytosine arabinoside and its metabolites and synergistic cytotoxicity by sequential treatment with dipyridamole in L5178Y leukemia.
Sequential treatment of murine leukemia L5178Y with cytosine arabinoside (ara-C) followed by dipyridamole (DP) resulted in synergistic cytotoxicity. Viability of cells exposed to 1 microM ara-C for 4 h was 88% of control values, but if DP was included in the cloning medium, cell viability was reduced to only 30%. When cells exposed to 1 microM ara-C were resuspended in ara-C-free medium containing 10 microM DP, intracellular ara-C and its metabolites were retained for a significantly longer period than when cells were resuspended in drug-free medium. At 4 h after resuspension in ara-C-free medium, total intracellular [3H] was 1.9 pmol/10(6) cells in control cells but amounted to 6.2 pmol/10(6) cells in DP-treated cells. Unchanged ara-C was 5.5-fold higher in the DP-treated cells. Presumably because of its effect on the concentration of intracellular ara-C, DP increased the half-life for ara-CTP from 97 to 250 min. Ara-CDP-choline declined with a half-life of 76 min on the transfer of cells to control medium, but levels of this metabolite remained constant or increased slightly in cells transferred to medium containing DP. After 4 h in ara-C-free medium with DP, [3H]-ara-C incorporated into the acid-insoluble fraction was 140% of the level attained when cells were transferred to control medium. The increased levels of ara-C metabolites presumably represent the basis for the enhancement of ara-C cytotoxicity by sequential DP treatment.
Yang
J L
JL
Cancer Center of Wake Forest University, Winston-Salem, NC 27103.
White
J C
JC
Capizzi
R L
RL
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D003561:Cytarabine / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D013997:Time Factors; D014316:Tritium
D003561:Cytarabine; D014316:Tritium; D004176:Dipyridamole; D004247:DNA