Synergy of inhibition of DNA synthesis in human bone marrow by azidothymidine plus deficiency of folate and/or vitamin B12?
Synergy of inhibition of DNA synthesis in human bone marrow by azidothymidine plus deficiency of folate and/or vitamin B12?
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叠氮胸苷加叶酸和/或维生素 B12 缺乏对人骨髓 DNA 合成抑制的协同作用？
DOI：
10.1002/ajh.2830330305
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发表时间：
1990
影响因子：
12.8
通讯作者：
Herbert,V
中科院分区：
文献类型：
--
作者：
Herzlich,BC;Ranginwala,M;Nawabi,I;Herbert,V
研究了叠氮胸苷（齐多夫定，AZT）对叶酸和/或维生素B12缺乏和正常人骨髓细胞中嘧啶（胸苷、脱氧尿苷和三磷酸胸苷）掺入DNA的影响，以研究此类维生素缺乏是否影响对AZT诱导的血液学毒性的易感性。研究了12例患者的骨髓细胞：5例叶酸和/或维生素B12缺乏;对照组7例，其中5例为慢性病贫血，2例为缺铁。（3小时，37°C），近似药理学血清谷水平，在叶酸和/或维生素B12缺乏的细胞中，嘧啶掺入DNA的抑制率为12 - 19%，在正常细胞中为16 - 23%。在2.0 μM AZT（3小时，37°C）（近似药理学血清峰值水平）下，叶酸和/或维生素B12缺乏细胞中的抑制率为15%至40%，对照组为32%至47%。在两组中，2.0 μM AZT（3小时，37°C）对脱氧尿苷掺入DNA的抑制作用显著大于胸苷。甲基四氢叶酸或维生素B12不能逆转脱氧尿苷掺入的抑制作用。在维生素B12缺乏患者的骨髓细胞中，AZT对脱氧尿苷掺入DNA的抑制作用往往不太明显，而添加维生素B12则更加明显。这表明，一些被认为是“AZT损伤”的骨髓细胞可能实际上是同时缺乏维生素B12。AZT抑制DNA合成在3小时的骨髓培养中是相对一致的，在各种血液病中。由于大约三分之二的艾滋病患者似乎在叶酸和/或维生素B12方面处于负平衡，AZT诱导的嘧啶掺入DNA的抑制作用发生在可能是巨幼细胞的细胞中，即。例如，在DNA合成受损的状态下，表明这些细胞可能更容易受到AZT毒性的影响。这些数据也支持AZT抑制主要是由于终止DNA链延长的观点，补充叶酸或维生素B12是否可以部分克服明显的“AZT抑制”DNA合成（血液学毒性），以及这种治疗的益处是否超过风险，还需要进一步研究。
The effect of azidothymidine (Zidovudine, AZT) on pyrimidine (thymidine, deoxyuridine, and thymidine triphosphate) incorporation into DNA in folate‐ and/or vitamin B12‐deficient and normal human bone marrow cells was studied to Investigate whether such vitamin deficiency affects susceptibility to AZT‐induced hematologic toxicity. Bone marrow cells from 12 patients were studied: 5 had folate and/or vitamin B12 deficiency; 7 controls included 5 with anemia related to chronic disease and 2 with iron deficiency.At 0.2 μM AZT (3 hr, 37°C), the approximate pharmacologic serum trough level, pyrimidine incorporation into DNA was suppressed by 12 to 19% in folate‐ and/or vitamin B12‐deficient cells and by 16 to 23% in normal cells. At 2.0 μM AZT (3 hr, 37°C), the approximate pharmacologic serum peak level, this was suppressed by 15 to 40% in folate‐ and/or vitamin B12‐deficient cells and by 32 to 47% in controls. Deoxyuridine incorporation into DNA was inhibited signlficantly greater than thymidine at 2.0 μM AZT (3 hr, 37°C) in both groups. Inhibition of deoxyuridine incorporation was not reversed with methyltetrahydrofolate or vitamin B12. There tended to be less striking suppression by AZT of deoxyuridine incorporation into DNA in bone marrow cells from vitamin B12‐deficient patients, which was made more striking by adding vitamin B12. This suggests that some of what passes for “AZT damage” to bone marrow cells may in fact be coincident deficiency of vitamin B12.AZT Inhibition of DNA synthesis in 3 hr bone marrow cultures is relatively consistent in a varlety of hematologic disorders. As approximately two‐thirds of AIDS patients appear to be in negative balance with respect to folate and/or vitamin B12, the fact that AZT‐induced inhibition of pyrimidine incorporation into DNA is occurring in cells which may be megaloblastic, i. e., In a state of Impaired DNA synthesis, suggests that these cells may be more susceptible to AZT toxicity. The data also support the notion that AZT inhibition results predominantly from termination of DNA chain elongation.Whether folate or vitamin B12 supplementation may partially overcome apparent “AZT inhibition” of DNA synthesis (hematologic toxicity) and whether the benefit of such therapy exceeds the risk will require further study.