Skog S, Lewin F, Heiden T, Tribukait B
Department of Medical Radiobiology, Karolinska Institute, Stockholm, Sweden.
Anticancer Drugs. 1994 Feb;5(1):83-9. doi: 10.1097/00001813-199402000-00013.
We examined whether an increase in the salvage and/or the de novo synthesis of thymidine (TdR) can explain the elevated DNA synthesis rate found up to 15-20 h after combined treatment with cisplatin and 5-fluorouracil (5-FU), compared with single-drug regimen. The salvage and the de novo pathways of TdR in Bp8 mouse ascites tumor cells were reduced equally after the combined treatment and the single-drug treatments. The inhibition of the de novo pathway of TdR was confirmed by a reduced thymidylate synthase activity, as measured in cell extract. A marked imbalance of the deoxyribonucleotide triphosphates were found, in particular between the deoxypyrimidines. These imbalances were similar between the 5-FU single-drug treatment and combined treatment. We conclude that neither the extracellular TdR salvage nor the de novo synthesis of TdR explain the relatively elevated DNA synthesis rate after combined treatment. We suggest that the supra-additive effect of the combined treatment is due to an interaction between the elevated DNA synthesis, the imbalanced deoxyribonucleotides and the cisplatin-induced DNA cross-links, and possibly also due to a higher concentration of 5-FU incorporated into DNA.
我们研究了胸苷（TdR）补救合成和/或从头合成的增加是否能够解释与单一药物治疗方案相比，顺铂和5-氟尿嘧啶（5-FU）联合治疗后长达15 - 20小时发现的DNA合成速率升高的现象。联合治疗和单一药物治疗后，Bp8小鼠腹水肿瘤细胞中TdR的补救途径和从头途径均同等程度地降低。通过测定细胞提取物中的胸苷酸合成酶活性，证实了TdR从头合成途径受到抑制。发现脱氧核糖核苷酸三磷酸存在明显失衡，特别是脱氧嘧啶之间。5-FU单一药物治疗和联合治疗之间的这些失衡情况相似。我们得出结论，细胞外TdR补救合成和TdR从头合成均不能解释联合治疗后相对升高的DNA合成速率。我们认为联合治疗的超加成效应是由于升高的DNA合成、失衡的脱氧核糖核苷酸和顺铂诱导的DNA交联之间的相互作用，也可能是由于掺入DNA中的5-FU浓度较高。
