Comparison of some biochemical parameters of arabinosylcytosine and cyclocytidine in L1210 murine leukemia cells.
The basic biochemical characteristics of cyclocytidine hydrochloride (cC.HCl) and arabinosylcytosine (araC) were compared. It was demonstrated that despite different lipophilicity and different pK (4.15 for araC and 6.60 for cC.HCl), the mechanism of inhibition of DNA synthesis by both compounds is the same (ID50 for araC was 0.048 mumol/l and for cC. HCl 0.23 mumol/l). The compounds had a different mechanism of inhibition of RNA synthesis (ID50 for araC was 2.69 mmol/l and for cC.HCl 1.08 mmol/l) and showed a marginal effect on protein synthesis. Hydrolysis of the 0(2),2'-anhydro bond in cC.HCl and formation of araC in vivo was characterized by a Km = 280 mumol/l using HPLC. Deamination of araC in vivo was studied in healthy mice (Km = 247 mumol/l), 8.6% of arabinosyluracil 15 minutes after araC administration) and in mice with sensitive and araC resistant leukemia L1210 (15.5% and 8.5% of arabinosyluracil 15 minutes after araC administration, respectively). On the basis of different physico-chemical properties of cC.HCl and different mechanisms of inhibition of RNA synthesis it can be assumed that cC.HCl, when therapeutically used, may have its own mechanism of biological effect(s) and that its application may be therapeutically advantageous in some aspects as compared to araC.
Cancer Research Institute, Slovak Academy of Sciences, Bratislava.
L
L
Novotný
V
V
Reichelová
E
E
Balázová
V
V
Ujházy
D003504:Ancitabine / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D004351:Drug Resistance; D004355:Drug Stability; D005260:Female; D007939:Leukemia L1210 / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D014176:Protein Biosynthesis; D012313:RNA / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D003561:Cytarabine; D012313:RNA; D004247:DNA; D003504:Ancitabine