Department of Clinical Neuroscience, Huddinge Division of Neurology, Karolinska Institute, Huddinge University Hospital, SE-141 86 Stockholm, Sweden.
Invest New Drugs. 2010 Jun;28(3):299-305. doi: 10.1007/s10637-009-9254-4. Epub 2009 Apr 24.
The effects of the cyclin-dependent kinase inhibitors roscovitine and olomoucine on DNA synthesis rate during normal rat brain development were studied by using short time (90 min) incubation. Both purine analogues at 100 microM concentration decreased the DNA synthesis of rat cerebral cortex in an age-dependent manner. The maximum inhibitory effect (approximately 90% for roscovitine, approximately 60% for olomoucine) occurred in rats of 2-13 days postnatal age. In adult rats (> 60 days postnatal age), the effect of both purine analogues was low. Roscovitine even at 200 microM concentration did not inhibit the fraction of DNA synthesis insensitive to hydroxyurea (unscheduled DNA synthesis (UDS)). In addition, in the RG2 rat glioma model, roscovitine produced a strong inhibition of DNA synthesis in glioma cells when compared to adult normal tissue. Since in adult rat brain more than 60% of DNA synthesis is related to DNA repair, usually measured as UDS, our results indicate that roscovitine strongly blocks ongoing DNA synthesis connected with replicative processes.
本研究采用短期（90 分钟）孵育法，研究了细胞周期蛋白依赖性激酶抑制剂罗洛司汀和olomoucine 对正常大鼠脑发育过程中 DNA 合成速率的影响。嘌呤类似物在 100μM 浓度下，均以年龄依赖性方式降低大鼠大脑皮质的 DNA 合成。罗洛司汀（约 90%）和 olomoucine（约 60%）的最大抑制作用出现在出生后 2-13 天的大鼠中。在成年大鼠（>60 天）中，两种嘌呤类似物的作用较低。即使使用 200μM 浓度的罗洛司汀，也不会抑制对羟基脲不敏感的 DNA 合成分数（非计划 DNA 合成（UDS））。此外，在 RG2 大鼠神经胶质瘤模型中，与成年正常组织相比，罗洛司汀对神经胶质瘤细胞的 DNA 合成有强烈抑制作用。由于在成年大鼠大脑中，超过 60%的 DNA 合成与复制过程相关，通常以 UDS 测量，我们的结果表明，罗洛司汀强烈阻断与复制过程相关的正在进行的 DNA 合成。
