Sedwick W D, Kutler M, Brown O E
Proc Natl Acad Sci U S A. 1981 Feb;78(2):917-21. doi: 10.1073/pnas.78.2.917.
In vitro exposure of a human lymphoblastoid cell line (WIL-2) to the antifolate metoprine (DDMP), when followed by the addition of exogenous deoxyuridine, led to intracellular accumulation of deoxyuridine triphosphate (dUTP) and incorporation of deoxyuridine monophosphate (dUMP) into DNA. When newly synthesized DNA was extracted from DDMP-treated cells that had been labeled with deoxyuridine for up to 3 min, most of the DNA synthesized was no larger than 4 S on alkaline sucrose gradients. In contrast, the predominant form of newly synthesized alkali-stable DNA in cells not treated with drug was larger than 4 S. Abnormal progression of DNA synthesis, degradation of newly synthesized DNA, or both occurred as a delayed consequence of DDMP treatment in the absence of exogenous deoxyuridine when thymidine was used to label DNA of DDMP-treated stability of antifolate-induced misincorporation of dUMP into DNA was not elucidated, it was clear that antifolates can directly perturb the quality as well as the quantity of DNA synthesized by drug-treated cells.
人淋巴母细胞系（WIL-2）在体外暴露于抗叶酸剂美托普林（DDMP），随后添加外源性脱氧尿苷，导致细胞内三磷酸脱氧尿苷（dUTP）积累以及脱氧尿苷单磷酸（dUMP）掺入DNA。当从用脱氧尿苷标记长达3分钟的DDMP处理的细胞中提取新合成的DNA时，在碱性蔗糖梯度上，大多数合成的DNA不大于4S。相比之下，未用药物处理的细胞中新合成的碱稳定DNA的主要形式大于4S。当使用胸苷标记DDMP处理的DNA时，在没有外源性脱氧尿苷的情况下，DNA合成异常进展、新合成DNA降解或两者兼而有之是DDMP处理的延迟后果。虽然抗叶酸剂诱导dUMP错误掺入DNA的稳定性尚未阐明，但很明显，抗叶酸剂可直接干扰药物处理细胞合成的DNA的质量和数量。
