Effects of phenytoin sodium on doubling time, deoxyuridine suppression, 3H-methotrexate uptake and 57Co-cyanocobalamin uptake in HL60 cells.
Phenytoin sodium (5-50 micrograms/ml) caused a dose-dependent prolongation of the doubling time of the human promyelocytic leukaemia cell line, HL60. This effect was unassociated with any alteration in cell viability. HL60 cells which were pre-incubated with 15 micrograms/ml phenytoin sodium for 1 or 48 h and then incubated with the same concentration of the drug plus either 3H-methotrexate (3H-MTX) or 57Co-cyanocobalamin for 90 min, showed an altered accumulation of both radioactive compounds when compared with control cells. Control cells were not pre-incubated with the drug and were subsequently studied in the absence of the drug. Pre-incubation with the drug for 1 h resulted in a 34% increase, and pre-incubation for 48 h in a 19% reduction in the accumulation of 3H-MTX. Pre-incubation for 1 or 48 h caused a 29% reduction in the accumulation of 57Co-cyanocobalamin. Cells cultured in the presence of 15 micrograms/ml phenytoin sodium for 48 h also gave a slightly increased deoxyuridine-suppressed value; this abnormality was partially corrected by the addition of 50 micrograms/ml folinic acid to the test system but was unaffected by the addition of 1 microgram/ml cyanocobalamin. The data indicate that the effects of phenytoin sodium on the proliferation of HL60 cells may have been slightly mediated via a reduced uptake of folate and possibly also of vitamin B12. They also suggest that one of the mechanisms underlying some of the undesirable effects of long-term therapy with phenytoin may be a drug-related impairment of both folate and vitamin B12 uptake by certain cells, including haemopoietic and neural cells.
Latham
J
J
Department of Haematology, St Mary's Hospital Medical School, University of London.
Gill
D S
DS
Wickramasinghe
S N
SN
D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003037:Cobalt Radioisotopes; D003857:Deoxyuridine; D005492:Folic Acid / Q000378:metabolism*; D006801:Humans; D008727:Methotrexate / Q000378:metabolism*; D010672:Phenytoin / Q000494:pharmacology*; D014316:Tritium; D014407:Tumor Cells, Cultured; D014805:Vitamin B 12 / Q000378:metabolism*
D003037:Cobalt Radioisotopes; D014316:Tritium; D010672:Phenytoin; D005492:Folic Acid; D014805:Vitamin B 12; D003857:Deoxyuridine; D008727:Methotrexate