| 3873237 |
Richards RG, Brown OE, Sedwick WD: Misincorporation of deoxyuridine in human cells: consequences of antifolate exposure. Basic Life Sci. 1985;31:149-62.
Treatment of B and T lymphoblastoid cell lines (SB and MOLT-4, respectively) and a promyelocytic leukemia cell line (HL-60) with the lipid soluble antifolate, 2,4-diamino-5-methyl-6-(2',5'-dimeth-oxybenzyl) -pyrido (2,4-d) pyrimidine (BW301U), led to drug dose-dependent inhibition of [3H] deoxyuridine (dU) incorporation into DNA as thymidine, and to misincorporation of [3H] dU as dUMP. After a 15 min preincubation with up to 50 microM BW301U and a further 15 min incubation after addition of [3H] dU, the number of alkaline labile apyrimidinic sites increased with increasing drug dose, as demonstrated by alkaline sucrose gradient analysis. Significantly, new replication of DNA was inhibited only approximately 50% by 50 microM BW301U when [3H] dU incorporation was greater than or equal to 97% inhibited. Additional preliminary findings suggest that newly replicated DNA containing misincorporated dUMP is rapidly degraded in vivo by extensive excision-repair processes. |
31(0,1,1,1) |